Kevin Maurice Coleman, MD

• Assistant Professor of Medicine

https://medicine.duke.edu/faculty/kevin-maurice-coleman-md

Knowledge of pharmacokinetics and pharmacodynamics is vital to ensure that patients are treated effectively and safely erectile dysfunction medicines levitra jelly 20mg generic. Resistance to chemotherapeutic agents is one of the major unsurpassed hurdles which continues to pose significant challenges for the role of chemotherapy in curing cancers erectile dysfunction over 75 levitra jelly 20mg discount. References Green J erectile dysfunction ultrasound order 20mg levitra jelly with visa, Kirwan J treatment for erectile dysfunction before viagra order levitra jelly 20mg line, Tierney J et al 2005 Concomitant chemotherapy and radiotherapy for cancer of the uterine cervix erectile dysfunction prevalence age discount generic levitra jelly canada. Further lines of treatment can be given when patients relapse but cure is not possible erectile dysfunction drugs at gnc buy levitra jelly 20 mg lowest price. Ovarian cancer is considered to be a chemosensitive disease, with nearly 75% of patients initially responding to platinum-based treatment. The choice of agent upon relapse depends on the timing of relapse; if this is over 6 months from previous platinum administration, this can be repeated either as a single agent or as part of a combination regimen, as patients are still considered to be platinum sensitive. If relapse occurs within 6 months of previous platinum administration, non-platinum drugs such as pegylated liposomal doxorubicin are used. There is an increased understanding of the complicated biological pathways involved in the development of gynaecological cancers, their subsequent metastagenesis and the mechanisms involved in chemoresistance. Many clinical studies are underway investigating the use of novel agents in patients with gynaecological malignancies, either alone, concurrently with chemotherapy or sequentially, in an attempt to improve response rates/durations and thereby survival. Vascular Endothelial Growth Factor and Angiogenesis Inhibition Angiogenesis or neovascularization is a normal physiological process involving the remodelling of vasculature and formation of new blood vessels. Angiogenesis plays a vital role in tumour formation and metastasis because both primary lesions and metastatic tumours must develop a new vascular supply in order to survive (Folkman 1971, 1990). Early initiation of angiogenesis is essential for cancer survival, and occurs when stimulatory factors overcome inhibitory factors, promoting the formation of new blood vessels (Bergers and Benjamin 2003). Research investigating the molecular basis of angiogenesis has identified multiple pathways that contribute to tumour angiogenesis. This relationship seems to be independent of important clinical and pathological prognostic factors. Bevacizumab (Avastin) is the first targeted agent to show significant single-agent activity in ovarian carcinoma. These results are as good or better than typical rates from traditional second-line chemotherapeutic agents in this group of patients. Cytotoxic and antiangiogenic agents can be used in combination for enhanced activity. The patient population for this trial includes all patients with at least high-risk, earlystage disease. Wright et al (2006b) gave combination bevacizumab and 5-fluorouracil or capecitabine to women with recurrent cervical cancer. Most of these toxicities (such as proteinurea, hypertension and bleeding) are generally mild and are either self-limiting or easily manageable. Other adverse effects, although uncommon, may be serious; these include arterial thromboembolism, wound-healing complications, and gastrointestinal perforation or fistulae. The increase in arterial thromboembolic events, including cerebral infarction, transient ischaemic attacks, myocardial infarction and angina, may be related to this phenomenon. This could be of particular importance when considering antiangiogenic therapy as front-line adjuvant treatment of ovarian cancer after cytoreductive surgery. Concerns about wound healing in postoperative patients have resulted in the decision to start bevacizumab/placebo therapy at cycle 2 within the Gynaecologic Oncology Group 218 trial. The complication of bowel perforation is now well documented with bevacizumab and, although uncommon, is of concern. It has been suggested that the number of prior cytotoxic regimens and the presence of bowel obstruction might predispose to this complication, although our ability to identify high-risk patients requires further investigation. Common toxicities included hypertension (n = 13), fatigue (n = 5) and diarrhoea (n = 3). Further studies involving larger patient groups are warranted in order to further assess the efficacy of sunitinib in gynaecological cancers. Toxicities (grade three to four) included rash (n = 12), metabolic (n = 10), gastrointestinal (n = 3), cardiovascular (n = 2) and pulmonary (n = 2). Patients with advanced or recurrent disease who had experienced one or fewer prior regimens were treated with sorafenib 400 mg bd. This subgroup of receptors mediate cell growth, differentiation and survival, and are dysregulated in many types of cancer. Ligand binding to the extracellular domain of the receptors enables receptor homo- or heterodimerization, which initiates phosphorylation of the intracellular tyrosine kinase domain and activation of cell signalling to reduce apoptosis and increase tumour cell proliferation. Objective responses are relatively low but prolonged disease stabilization has been seen in a subset of women. It should be noted that these patients were heavily pretreated and the median number of prior therapies was five. Data from initial clinical experience with lapatinib have only shown mild adverse events (rash, diarrhoea, nausea, vomiting) and no grade four events. The doselimiting toxicity was mucositis, and common treatmentrelated adverse events included mouth sores and rash. The dose-limiting toxicities were mucositis, fatigue, myelotoxicity with prolonged moderate neutropenia, and skin rash. The most common toxicities were mucositis, fatigue, anaemia, diarrhoea and nausea/vomiting. An initial dose-escalation phase I trial administered temsirolimus weekly (Raymond et al 2004). Although thrombocytopenia was dose limiting and a reversible maculopapular rash and stomatitis were observed, the formal definition of a maximum tolerated dose was not met. In addition, objective partial and minor responses were observed at lower dose levels. The results of this study indicated that temsirolimus had modest Src activity, with only 7. Preclinical studies have shown enzastaurin to have anticancer effects as a single agent and in combination with carboplatin and paclitaxel in breast and ovarian carcinomas (Teicher et al 2002, Keyes et al 2004). In a study of the effect of enzastaurin on ovarian cancer cell lines with selective resistance against various cytostatic drugs, taxaneresistant cells showed the most prominent response to low concentrations of enzastaurin (Meinhold-Heerlein et al 2006). In phase I trials, prolonged stabilization of disease was seen in several patients treated with enzastaurin, with acceptable toxicities (Carducci et al 2006). Synergistic activity with standard-of-care chemotherapies was seen, with no significant alterations in the pharmacokinetic variables of the cytotoxic drugs with which it was combined (Beerepoot et al 2006, Rademaker-Lakhai et al 2007). Reported data have shown an association between intratumoral T cells and improved clinical outcome, lending support for immune-mediated disease control (Zhang et al 2003). Ovregovomab has been compared with placebo in a randomized trial of women with ovarian cancer who had achieved complete remission after first-line chemotherapy. Patients were treated until recurrence or for up to 5 years, and the primary endpoint was time to recurrence. Three hundred and seventy-one patients were randomized, but unfortunately there were no significant differences in the clinical outcomes between the two groups. Conclusions drawn were that although it was not effective as a single agent, its use in combination with other cytotoxic agents should be investigated further. Ovregovomab has been evaluated in combination with carboplatin/ paclitaxel as front-line chemoimmunotherapy in patients with advanced ovarian cancer (Braly et al 2007). Chemotherapy-induced bone marrow suppression has been assumed to inhibit the generation of augmented immune responses; however, contrary to expectations, concurrent carboplatin/paclitaxel resulted in enhanced immune stimulation with ovregovomab. The biological Src Src, a non-receptor tyrosine kinase, is an attractive therapeutic target in ovarian cancer because it is expressed and activated in the majority of ovarian cancers and regulates a myriad of intracellular signal cascades responsible for critical tumour cell functions, including cell proliferation and differentiation, through extracellular stimulation by growth factors, growth hormones and integrins (Ishizawar and Parsons 2004). Src has been found to be overexpressed in the majority of late-stage ovarian tumours, as well as a panel of ovarian cancer cell lines (Wiener et al 2003). They concluded that Src inhibition might be an attractive therapeutic approach for patients with ovarian carcinoma. The response rate was 14% and 7% in platinum-sensitive patients and platinum-resistant patients, respectively, with a median time to progression of 2 months. Common toxicities reported were neuropathy (30% grade two or three) and hypersensitivity (8%). Epothilones Like the taxanes, epothilones are microtubule stabilizers and have activity against cancer cell lines which are resistant to paclitaxel and other cytotoxic drugs (Rowinsky 1997). This is partially due to the fact that they are not substrates for multidrug transporter proteins. Dilawari et al (2008) reported an expanded phase I study of ixabepilone 40 mg/m2 in patients previously treated with taxanes (n = 44) who had ovarian, endometrial, fallopian tube, cervical, breast or another cancer. A range of one to 14 cycles was given, primarily to examine activity and neurotoxicity. Onequarter of the patients had grade two to three neuropathy, which was preceded by vibration perception threshold changes. Other toxicities included hypersensitivity (n = 1) and neutropenia (grade three or more in 18 patients). Alpha Folate Receptor Alpha folate receptor is a membrane-bound protein with high affinity for binding and transporting physiological levels of folate into cells. Overexpression is associated with increased tumour aggressiveness (Toffoli et al 1997). It thereby affects transcription factors involved in cell proliferation, blocks cell division in the G(2) phase and inhibits overexpression of the multidrug resistance-1 gene that leads to development of resistance to many anticancer drugs. The toxicity profile was manageable with 10% of patients having alanine aminotransferase elevation and 8% of patients having neutropenia (Krasner et al 2007). Novel Taxanes Paclitaxel conjugates have an extended half-life compared with paclitaxel, leading to increased exposure of a tumour to the agent. The main adverse events were gastrointestinal (77% grade two or less), neurotoxicity (25% grade two or less) and haematological toxicity (21% grade three or less). The study is still open and complete results are awaited with interest to further define the possible synergy with this combination. Reported toxicity included haematological toxicity (neutropenia in 71% of patients and thrombocytopenia in 43%) and weight decrease (9. Further studies were felt to be warranted to further investigate the use of brostacillin in this patient group. Three patients were treated with 7 mg/kg qwk and six patients were treated with 15 mg/kg qwk in combination with liposomal doxorubicin until disease progression. Preliminary data suggest that this is a well-tolerated combination, with the main toxicities reported as asthenia (n = 6), nausea (n = 3), abdominal pain (n = 2), flu-like sumptoms (n = 2) and vomiting (n = 1). Thirty patients were treated, and no pharmacokinetic interactions were seen between the three drugs. The combination was well tolerated with dose-limiting toxicities including neutropenia, thrombocytopenia, nausea and vomiting. Dose-limiting toxicities included grade four neutropenia, rises in serum transaminases and grade three diarrhoea. Of the patients in group 1, nine patients achieved disease stabilization and six progressed. Grade three adverse events included thrombosis (n = 3), dyspnoea (n = 2), fatigue (n = 2), elevated alkaline phosphatase (n = 2) and nausea (n = 2). The second study also tested belinostat but in combination with carboplatin and paclitaxel in platinum-resistant and platinum-sensitive patients. Common grade three to four adverse events were neutropenia (n = 4), transaminitis (n = 4) and fatigue (n = 3). Conclusion the treatment of gynaecological malignancies in the future will no doubt make use of our increased understanding of the biology of these diseases. Whether the novel agents discussed above are used alone, in combination with each other or with other chemotherapeutics remains to be defined. The exact benefit of many of these agents in terms of response rates and disease-free survival is also largely unknown. In addition, it is uncertain whether they will simply be unaffordable in most health economies. However, this is certainly an exciting time in the field of gynaecological oncology, and it is hoped that the use of targeted agents will have a significant impact on disease progression and outcome in the near future. The alpha folate receptor is overexpressed in the majority of ovarian cancers but is largely absent from normal tissue, and is a promising target. It remains to be defined whether the novel targeted agents will be best utilized as single agents or in combination with each other or cytotoxics. Target agents have the potential to be used as maintenance therapy following remission induction. Beerepoot L, Rademaker-Lakhai J, Witteveen E et al 2006 Phase I and pharmacokinetic evaluation of enzastaurin combined with gemcitabine and cisplatin in advanced cancer. Beevers C, Li F, Liu L, Huang S 2006 Curcumin inhibits the mammalian target of rapamycin-mediated signaling pathways in cancer cells. Dupont J, Bienvenu B, Aghajanian C et al 2004 Phase I and pharmokinetic study of the novel oral cell-cycle inhibitor Ro 31-7453 in patients with advanced solid tumors. Gore M, Kaye S, Oza A et al 2005 Phase I trial of patupilone plus carboplatin in patients with advanced cancer. Hu L, Hofmann J, Holash J et al 2005 Vascular endothelial growth factor trap combined with paclitaxel strikingly inhibits tumor and ascites, prolonging survival in a human ovarian cancer model.

Further attacks can occur and it is recommended that tampons should not be used until Staphylococcus aureus has been eradicated from the vagina erectile dysfunction pills review purchase levitra jelly 20mg online. Other Vaginal Pathology Atrophy this is seen following the menopause xylitol erectile dysfunction order generic levitra jelly online, but can also occur prior to puberty and during prolonged lactation erectile dysfunction drugs names purchase levitra jelly pills in toronto. The patient may present with vaginal bleeding impotence journal purchase levitra jelly canada, vaginal discharge erectile dysfunction exercises wiki discount levitra jelly 20 mg with mastercard, or vaginal dryness and dyspareunia impotence treatments natural buy levitra jelly 20 mg low cost. Superficial infection, with Gram-positive cocci or Gram-negative bacilli, may be associated. Bacterial vaginosis Bacterial vaginosis is now believed to be due to a vibrio or comma-shaped organism named Mobiluncus. These organisms are believed to be sexually transmitted, although the condition may be due to imbalance in the vaginal ecosystem. Examination will reveal a thin, grey-white discharge and a vaginal pH greater than 5. The absence of lactobacilli will be confirmed if a characteristic fishy amine smell is released when a drop of vaginal discharge is added to saline on a glass slide, along with one drop of 10% potassium hydroxide. There are claims that bacterial vaginosis is associated with increased risk of preterm labour (Hay et al 1994), pelvic inflammatory disease and postoperative pelvic infection (Paavonen et al 1987, Eschenbach et al 1988). The treatment of bacterial vaginosis is metronidazole, either as 400 mg two or three times a day for 7 days or as a single 2 g dose. Alternatively, clindamycin 2% can be used as a vaginal cream but, unlike metronidazole, this is active against lactobacilli and will delay the restoration of normal vaginal flora. Trauma A torn hymen following a first attempt at intercourse may result in profuse, frightening haemorrhage. Suture of the bleeding vessel under general anaesthesia should be accompanied by one or more radial incisions in the hymen to prevent recurrence. Trauma in young girls or women may be the result of falling astride an object like a bicycle or fence. It may result from sexual abuse, sometimes self-inflicted, but may represent sexual assault or rape. It may also occur following normal sexual intercourse, particularly in a postmenopausal woman who has not had intercourse for some time. In these cases, the laceration is usually at the vault of the vagina in the posterior fornix. Examination under anaesthesia is often required to determine the extent of the damage. A closed haematoma is best managed conservatively, but bleeding lacerations will require suture. Devitalized tissues will need to be excised, and tears in bowel or bladder must be repaired in layers. Toxic shock syndrome this topic has been included here because it is associated with the use of vaginal tampons during menstruation or less frequently in the puerperium (Shands et al 1980). The manifestations are usually systemic with occasionally life-threatening consequences. Removal of Seminal fluid allergy Patients may present with a history of dyspareunia with itching, burning or swelling, or occasionally more widespread symptoms such as urticaria, bronchospasm or even angioneurotic oedema, after intercourse. The allergic reaction appears to be due to sensitization to seminal fluid 609 40 Benign disease of the vulva and the vagina (Poskitt et al 1995). Symptoms may arise following first coitus or after exposure to several sexual partners. Treatment has included long-term immunotherapy following skin testing (Friedman et al 1984). Treatment with desensitization may be helpful, and antihistamines and intravaginal cromoglycate are described (Poskitt et al 1995). Acute complications include pain, infection, bleeding, injury to the urethra/vagina/rectum, urinary retention, faecal incontinence and death. More chronic complications include urinary and menstrual difficulty, haematocolpos, sexual difficulty if not impossibility from fibrous scarring, and epidermoid cysts. Incompetent attempts at defibulation have caused urethral and rectal injuries, further scarring and persistent dyspareunia. As mentioned above, Gordon et al (2007) advocated reversal as an elective procedure rather than during labour. If it is performed during labour, the fused labia minora should be incised in the midline anteriorly as far as the urethral meatus, and further anterior dissection of clitoral structures should be deferred because of risk of urethral damage and difficult haemostasis. It is illegal to close the infibulations following delivery, even if the husband insists. Examples have been seen where careless use of electrodiathermy has left damage to underlying clitoral glans when dissecting a paraclitoral epidermoid cyst. Certainly, the scenario of a patient presenting in advanced labour with undisclosed infibulated labia and the threat of imminent tearing should be avoided. The diagnostic criteria include ocular and oral symptoms, ocular signs, salivary gland histology, other evidence of salivary gland involvement and the presence of autoantibodies. The frondlike surface is usually characteristic, but it is wise to await the result of a biopsy before instituting treatment. Similarly, management of anterior wall cysts must include the exclusion of a bladder or urethral diverticulum. Adenosis (multiple mucus-containing vaginal cysts) is a rare condition which, even more rarely, gives rise to symptoms. A variety of abnormalities are reported in the daughters of women who took diethylstilboestrol during their pregnancy. Gordon et al (2007) emphasized that reversal procedures are better performed in non-pregnant or antenatal patients, rather than when the patient presents in labour and is dealt with by junior or inexperienced staff. Belfiore P, Di Fede O, Cabibi D et al 2006 Prevalence of vulval lichen planus in a cohort of women with oral lichen planus: an interdisciplinary study. Carli P, Moretti S, Spallanzani A et al 1997 Fibrogenic cytokines in vulvar lichen sclerosus. Dalziel K, Millard P, Wojnarowska F 1989 Lichen sclerosus et atrophicus treated with a potent topical steroid (clobetasol dipropionate 0. Fischer G, Spurett B, Fischer A 1995 the chronically symptomatic vulva: aetiology and management. Haverhoek E, Reid C, Gordon L, Marshman G, Wood J, Selva-Nayagam P 2008 Prospective study of patch testing in patients with vulval pruritus. Howard A, Dean D, Cooper S, Kirtshig G, Wojnarowska F 2004 Circulating basement membrane zone antibodies are found in lichen sclerosus of the vulva. Jonsson M, Karlsson R, Evander M 1997 Acetowhitening of the cervix and vulva as a predictor of subclinical human papillomavirus infection: sensitivity and specificity in a population based study. Leibovitz A, Kaplun V, Saposhnicov N, Habot B 2000 Vulvovaginal examinations in elderly nursing home women residents. Leibowitch M, Neill S, Pelisse M, MoyalBaracco M 1990 the epithelial changes associated with squamous cell carcinoma of the vulva: a review of the clinical, histological and viral findings in 78 women. In: 611 40 Benign disease of the vulva and the vagina circulating autoantibodies to extracellular matrix protein 1 in lichen sclerosus. Powell J, Wojnarowska F 2002 Childhood vulvar lichen sclerosus: the course after puberty. Renaud-Vilmer C, Cavelier-Balloy B, Porcher R, Dubertret L 2004 Vulvar lichen sclerosus - effect of long-term application of a potent steroid on the course of the disease. Scurry J, Vanin K, Osters A 1997 Comparison of histological features of vulvar lichen sclerosis with and without adjacent squamous cell carcinoma. Association with tampon use and Staphylococcus aureus, and clinical features in 52 cases. Thomas R, Barnhill D, Bibro M 1985 Hidradenitis suppurativa: a case presentation and review of the literature. The Office of National Statistics recorded 842 cases in 2005 (Office of National Statistics 2008). The most recent mortality figures recorded 270 deaths for all age groups, giving a death rate of 1. The changing population demographics will result in an increase in the incidence of the disease as a result of an ageing population, and an increase in the associated comorbidity, providing additional medical challenges to effective multimodality care. However, if the diagnosis is delayed or if managed inappropriately, the outcome is variable with the potential for a miserable, degrading death. Effective surgical treatment seems deceptively simple, but few gynaecologists and their nursing colleagues acquire sufficient experience of this disease to offer the highest quality of care for these women. This is a disease where there is a compelling case for centralized care, and where one might expect the reorganization of gynaecological cancer services to benefit women significantly. Case-controlled studies have failed to confirm an association with diabetes mellitus, obesity, vascular disease and syphilis. The histology has a bearing on management, largely because of the different risks of nodal metastases and the predilection for distant spread. Lymphatic Drainage An understanding of the lymphatic drainage is important as the regional nodes are a potential site of metastases. Lymph drains from the vulva to the superficial inguinal glands and then to the deep femoral glands in the groin. Drainage to both groins occurs from midline structures - the perineum and the clitoris - but some contralateral spread may take place from other parts of the vulva (Iversen and Aas 1983). Direct spread to the pelvic nodes along the internal pudendal vessels occurs very rarely, and no direct pathway from the clitoris to the pelvic nodes has been demonstrated consistently. An important aspect of the lymphatic drainage is the concept of sentinel nodes in each groin. This is the first node that draining lymph encounters as it drains bilaterally from the vulvar basin (Cabanas 1977). This anatomical concept has been exploited recently to develop selective lymphadenectomy in this disease. Source: Office of National Statistics 2008 Cancer Statistics Registration, Registration of Cancer Diagnosed in 2005, England. The tumour is less than 2 cm in lateral dimension, and there is less than 1 mm invasion when measured from the base of an adjacent dermal papilla. Accurate identification and classification of this stage requires expert pathological interpretation, and is exceptionally important as the current consensus would suggest a virtually negligible risk of lymph node metastases. As the cancer gradually increases in size and progressively invades the deeper layers of the dermis, it spreads locally. The tumour will eventually involve the local lymphatics, hence the propensity for groin lymph node involvement (Table 41. In advanced stages, there can be extensive local destruction and involvement (often with superadded infection), groin node metastases and potentially lymph node involvement in the pelvis, para-aortic and neck nodes. Metastases in adjacent skin may also be noted, and haematogenous spread can also occur in late disease. If widespread disease is seen with small vulvar tumours, a more aggressive histotype may be present, such as a melanoma or sarcoma. The vulva may also be a site for lym614 Presentation the medial aspects of the labia majora are the most common sites for disease to develop (70%). However, both Hacker et al (1981) and Monaghan (1990) have commented that, in a significant minority of patients, there appears to be considerable delay in presentation. The intimate nature of the disease, fear and/or ignorance and the advanced age of many patients might partly explain this observation. The fact that the disease is uncommon may also be contributory, as primary carers may not recognize the significance of symptoms or fail to recognize the clinical signs. Whatever the cause, a significant number of cases continue to present in advanced stages. Pruritus is the most common presenting symptom (71%), and an ulcer or mass will have been noted in nearly 80% of cases. Bleeding (26%), discharge (13%) and urinary tract dysfunction (14%) are other common reasons for presentation. Due to the potential for other genital tract malignancies, the vagina and cervix should also be assessed thoroughly and biopsied as necessary. Biopsies should be of a sufficient size to allow differentiation between superficially invasive tumours and frankly invasive tumours, and orientated to allow quality pathological interpretation. Radical excision should not be undertaken without prior biopsy confirmation of malignancy unless there are extenuating circumstances. The histopathological report should include: Assessment the assessment of these women should include confirmation of the diagnosis, an assessment of disease extent, and an holistic approach to the patient to assess relevant comorbidity and/or other factors that may impact on the management plan. Particular attention should be paid to assess any involvement of the vagina, urethra, bladder base or anus. Palpation is important to determine possible involvement of the surrounding bony structures. Discomfort and tenderness may necessitate an examination (and biopsies) under general anaesthesia. The groin should be examined, although a negative assessment cannot reliably exclude cancer. The grading of the tumour is based on the percentage of undifferentiated cells, with grade 1 having no undifferentiated cells, grade 2 having less than half undifferentiated cells and grade 3 having more than half poorly differentiated cells. Staging There are two staging systems: the Tumour, Node, Metastasis system and the International Federation of Gynaecology and 615 41 Malignant disease of the vulva and vagina Table 41. No nodal metastasis Lesions >2 cm in size or with stromal invasion >1 mm confined to the vulva or perineum. Most gynaecologists use the latter which, since its last update in 2000, is based upon clinical and surgical findings.

The ideal assay should be able to recognize all forms equally well and be sufficiently sensitive to limit the risk of false-negative results (Mitchell and Seckl 2007) erectile dysfunction pills at gnc generic levitra jelly 20 mg with amex. Moreover erectile dysfunction and proton pump inhibitors order cheap levitra jelly line, the assay should not produce falsepositive results as this is well recognized to be associated with unnecessary medical interventions and potentially lifethreatening complications (Cole et al 2001) erectile dysfunction adderall generic levitra jelly 20mg visa. The assays can produce both false-positive and falsenegative results (Cole et al 2001 erectile dysfunction newsletter buy levitra jelly 20mg on-line, Mitchell and Seckl 2007) impotence after 40 buy levitra jelly once a day. The false-positive results occur because there is another molecule (often a heterophile antibody) which sticks the capture and detection antibodies together impotence at 70 generic levitra jelly 20mg with visa. False-negative results can potentially result in failure to diagnose disease or early termination of treatment, and therefore higher relapse rates. Consequently, these assays are several orders of magnitude more sensitive than the best imaging modalities available today. The uterus is often not enlarged for gestational age, and vaginal bleeding tends to occur later so that patients most often present in the late first or early second trimester with a missed or incomplete abortion. In fact, the diagnosis is often only suspected when the histology of curettings is available. This can result in late presentation of disease, sometimes with life-threatening complications. However, for women attending termination centres, it may be possible to establish a screening procedure to help prevent subsequent problems from missed diagnosis. With specialist obstetric care, 40% of such cases have continued into the third trimester and delivered live babies (Sebire et al 2002b). Clinical Features Complete and partial moles these most commonly present in the first trimester as a threatened abortion with vaginal bleeding. If the diagnosis is delayed, patients may notice the passing of grape-like structures (vesicles), and occasionally the entire mole may be evacuated spontaneously. Although pulmonary, vaginal and cervical metastases can occur, they may disappear spontaneously following removal of the mole. Thus the presence of metastases does not necessarily imply that an invasive mole or choriocarcinoma has developed. Patients may rarely present with acute respiratory distress, not only because of pulmonary metastases or anaemia but occasionally as a result of tumour embolization (Savage et al 1998). Patients may complain of persistent vaginal bleeding and lower abdominal pains and/or swelling. This may occur as a result of haemorrhage from leaking tumour-induced vasculature as the trophoblast invades through the myometrium, or because of vulval, vaginal or intra-abdominal metastases. The tumour may also involve other pelvic structures, including the bladder or rectum, producing haematuria or rectal bleeding, respectively. Enlarging pulmonary metastases or tumour emboli growing in the pulmonary arteries can contribute to lifethreatening respiratory complications (Seckl et al 1991). Choriocarcinoma following a normal pregnancy or nonmolar abortion usually presents within 1 year of delivery but 655 43 Gestational trophoblastic tumours can occur 17 years later (Tidy et al 1995). However, one-third of all choriocarcinomas present without pelvic symptoms but have symptoms from distant metastases. In these cases, lives can be saved by remembering to include choriocarcinoma in the differential diagnosis of metastatic malignancy (particularly in lungs, brain or liver) presenting in a woman of childbearing age. Any site may be involved, including skin (producing a purple lesion), cauda equina and the heart. Pulmonary disease may be parenchymal, pleural or may result from tumour embolism and subsequent growth in the pulmonary arteries (Savage et al 1998). Thus, respiratory symptoms and signs can include dyspnoea, haemoptysis and pulmonary artery hypertension. Cerebral metastases may produce focal neurological signs, convulsions, evidence of raised intracranial pressure, and intracerebral or subarachnoid haemorrhage. In half of the reported cases, tumours arise in the lower uterine segment or cervix, and the distinction from a keratinizing squamous cell carcinoma can sometimes be difficult. Extrauterine locations such as broad ligament as the primary site have also been observed (Kuo et al 2004). The most common metastatic appearance on chest X-ray is of multiple, discrete, rounded lesions, but large solitary lesions, a miliary pattern or pleural effusions can occur (Bagshawe and Noble 1965). Furthermore, tumour emboli to the pulmonary arteries can produce an identical picture to venous thromboembolism, with wedge-shaped infarcts and areas of decreased vascular markings. The uterine volume and uterine artery blood flow correlate with the amount of disease and the degree of abnormal tumour vasculature, respectively. This is attributed to large vascular channels forming in the myometrium, resulting in arteriovenous shunting (Long et al 1992). Interestingly, the vascular abnormalities within the pelvis and uterus can persist long after the disease has been eradicated with chemotherapy. Indeed, patients with repeated vaginal haemorrhage from these vas- Infantile choriocarcinoma Choriocarcinoma in the fetus or newborn is exceptionally rare, with approximately 30 reported cases (Blohm and Gobel 2004, Sebire et al 2005). While a primary choriocarcinoma within the infant is possible, the mother also had the tumour in 17 cases. Only a few cases have been treated successfully with platinum chemotherapy (Johnson et al 2003), with the rest dying within weeks of the initial diagnosis, which may have been delayed. Rarely, patients can develop nephrotic syndrome, haematuria and disseminated intravascular coagulopathy. Metastases may occur in the vagina, extrauterine pelvic tissues, retroperitoneum, lymph nodes, lungs and brain (Newlands et al 1998a). Epithelioid trophoblastic tumours There are currently only a few recorded cases of this recently described tumour in the literature. This can have an impact on determining appropriate therapy and prognosis (Fisher and Newlands 1998, Fisher et al 2007). The latter condition is rarely compatible with a normal pregnancy, and preimplantation diagnosis is not yet possible. Uterine artery pulsatility index showing low values indicative of arteriovenous shunting associated with an abnormal tumour vasculature. Metastatic spread outside the pelvis, such as to the liver or kidneys, can also be identified and shown to have an abnormal Doppler signal. Management Molar evacuation Evacuation of the uterine cavity using suction gives the lowest incidence of sequelae. When the molar trophoblast invades the myometrium, it is relatively easy to perforate the uterus if a metal curette is used. Medical induction involving repeated contraction of the uterus induced by oxytocin or prostaglandin, or other surgical approaches including hysterectomy or hysterotomy increase the risk of requiring chemotherapy two- to three-fold compared with suction evacuation. This is thought to be because tumour is more likely to be disseminated by uterine contraction and manipulation. For similar reasons, the use of prostanoids to ripen a nulliparous cervix is not recommended, even in nulliparous women (Royal College of Obstetricians and Gynaecologists 2004). If bleeding is severe immediately after suction evacuation, a single dose of ergometrine to produce one uterine contraction may stem the haemorrhage, and does not appear to increase the chance of requiring chemotherapy. In the past, it has been common practice for gynaecologists to perform a second and sometimes a third evacuation of the uterine cavity in patients with a molar pregnancy. Indications for chemotherapy Factors associated with an increased risk of requiring chemotherapy are summarized in Table 43. These complications can be life-threatening and their risk can be reduced by starting chemotherapy. This was internationally accepted in 2002, so that all centres managing this rare group of diseases can compare their results more easily (Kohorn 2002). The authors currently use both the Charing Cross system and the new combined system as outlined in Tables 43. In both systems, each variable carries a score which, when added together for an individual patient, correlates with the risk of the tumour becoming resistant to single-agent therapy. It is this score, rather than the stage, that determines treatment; thus far, there appears to be excellent concordance for assigning patients to either lowor high-risk groups (see section on chemotherapy below). Liver metastases correlate with a worse prognosis than brain metastases (Bower et al 1997), so patients with liver involvement score six points rather than four. Chemotherapy At Charing Cross Hospital, the prognostic scoring system in Table 43. Formerly, each risk group corresponded with a separate treatment regimen and so there were three types of therapy (low, medium and high risk). Ten years ago, the medium-risk treatment was discontinued for three reasons: Table 43. Moreover, there is no evidence that prior treatment failure with methotrexate is an adverse prognostic variable (Bower et al 1997, McNeish et al 2002). Accordingly, patients who score between five and eight now receive low-risk chemotherapy, which was previously only given to those with a score = five. Patients are admitted for the first 3 weeks of either therapy, principally because the tumours are often highly vascular and may bleed vigorously in this early period of treatment. Approximately 33% of low-risk patients will need to change therapy: 31% because of drug resistance and 2% due to treatment toxicity (usually mucositis, occasionally severe pleuritic pain or drug-induced hepatitis) (McNeish et al 2002). Moreover, there is no evidence that methotrexate alone increases the risk of developing a second cancer (Rustin et al 1996). Low-risk patients Patients with low-risk disease have a 5-year survival rate of nearly 100% (Bower et al 1997). The regimen used since 1964 at Charing Cross Hospital and widely followed in other centres is shown in Table 43. This schedule is well tolerated with no alopecia, and since the folinic acid dose has been increased from 7. Methotrexate can induce serositis, resulting in pleuritic chest pain or abdominal pain. Myelosuppression is rare, but a full blood count should be obtained before each course of treatment. All patients are advised to avoid sun exposure or use complete sun block for 1 year after chemotherapy because the drugs can induce photosensitivity. A recent meta-analysis has failed to demonstrate superiority of any other chemotherapy combination (Xue et al 2006). It is also myelosuppressive, but prolonged gaps in therapy, which may permit tumour regrowth, can usually be avoided by the following measures: continuing to treat unless the white cell count is less than 1. The introduction of granulocyte colony-stimulating factor in patients who have a low neutrophil count also helps to maintain treatment intensity and has reduced the number of neutropenic febrile episodes. While these results were good, the presence of liver or brain metastases correlated with only 30% or 70% long-term survival, respectively. Indeed, long-term survival in patients with both liver and brain metastases is only 10% (Newlands et al 2002). Interestingly, for patients with brain metastasis, if one excludes patients who were too sick to receive chemotherapy and died within a few days of admission, the survival rates appear to be the same as those for patients without brain involvement (Newlands et al 2002). The authors are currently undertaking a new analysis on patients with liver metastasis; of 38 patients treated more recently, the overall survival rate appears to be higher at just under 50% (Seckl et al, unpublished observations). Other adverse prognostic variables include a longer interval from the antecedent pregnancy, and term delivery in the antecedent pregnancy (Powles et al 2007). Early deaths accounted for a significant proportion of the overall mortality, with the causes being respiratory failure, cerebral metastases, hepatic failure and pulmonary embolism (Bower et al 1997). Clearly, it will be difficult to improve the survival of this particular subgroup. This drug is more toxic than methotrexate, inducing some hair thinning (occasional complete alopecia), myelosuppression and more oral ulceration. The cure rate, even in those rare cases that need three or more lines of treatment, remains nearly 100% (Powles et al 2007). Indeed, the combination of surgical removal of the main site of drug resistance (usually uterus, lung or brain) together with chemotherapy is particularly effective. Although this regimen is very toxic, the outcome has been impressive with survival rates in excess of 80% (Newlands et al 2000). Other options that can be considered include use of some of the newer anticancer agents such as the taxanes, topotecan, gemcitabine and temozolomide. Another approach in patients with refractory disease involves high-dose chemotherapy with autologous bone marrow or peripheral stem cell transplantation. Patient selection here is important in determining outcome as it has been shown for refractory germ cell tumours that patients with drug-sensitive disease stay in remission (Beyer et al 1996, Lyttelton et al 1998). Since the time of writing, the authors have treated several more cases and now appear to have two long-term survivors. However, occasionally, the bleeding can be torrential, requiring massive transfusion. In this situation, if the bleeding is coming from the uterus, it may be necessary to consider a uterine pack or emergency embolization of the tumour vasculature. If the bleeding is intraperitoneal and does not settle with transfusion and chemotherapy, laparotomy may be required. Respiratory failure Occasionally patients present with respiratory failure due to multiple pulmonary metastases or, more rarely, as a result of massive tumour embolism to the pulmonary circulation (Savage et al 1998). Oxygen support may be required, including masked continuous positive airway pressure ventilation, but mechanical ventilation is usually contraindicated as it results in trauma to the tumour vasculature, leading to massive intrapulmonary haemorrhage and death. Since the introduction of this policy, the development of brain metastases without evidence of drug resistance elsewhere has been much less frequent (Athanassiou et al 1983). Early resection of solitary brain deposits in patients with serious neurological signs can sometimes be life-saving (Ishizuka 1983, Song and Wu 1988, Rustin et al 1989).

Where delivery of radical radiotherapy with curative intent is not possible because of tumour-related impotence zargan discount levitra jelly 20mg with visa. Doses typically used include 8 Gy in a single fraction erectile dysfunction drugs south africa cheap levitra jelly 20 mg overnight delivery, 20 Gy in five fractions over 1 week or 30 Gy in 10 fractions over 2 weeks erectile dysfunction drugs medicare cheap levitra jelly 20 mg with amex. The simulator - a diagnostic X-ray machine connected to a television screen which emulates a treatment machine - continues to have a useful role for palliative radiotherapy planning erectile dysfunction treatment michigan order discount levitra jelly. The patient is scanned in the supine position unless a belly board is used to displace the small bowel anteriorly to minimize small bowel irradiation erectile dysfunction treatment cincinnati cheap levitra jelly online, in which case she is placed in the prone position erectile dysfunction in diabetes pdf purchase on line levitra jelly. A vaginal probe can aid in defining the extent of vaginal involvement, although this is not universally utilized. Intravenous contrast may be administered to enhance identification of blood vessels which are anatomical landmarks for the regional lymph nodes. The superior border is extended to include the lower thoracic vertebrae if para-aortic lymph node irradiation is required. The patient is asked to have a comfortably full bladder to reduce the volume of small bowel within the pelvis. Instillation of radioactive fluids into the peritoneal or pleural cavity for treating small volume disease is rarely used and will not be discussed in detail. Pelvic external beam radiotherapy remains integral to the treatment of gynaecological malignancies as it permits irradiation of the primary tumour and regional lymph nodes. Technological advances in the methods of radiation delivery are increasingly permitting the use of techniques which minimize the dose received by normal tissues whilst allowing a higher dose to be delivered to the tumour. The gross tumour volume includes the palpable and/or radiologically visible tumour; it is absent if it has been surgically resected. The organs at risk for pelvic radiation include the rectum, bladder, small bowel and both hip joints. The kidneys and spinal cord are the dose-limiting organs at risk when radiating the para-aortic lymph nodes. The clinician specifies the dose fractionation to be used in the radiation treatment of the patient. Following the process described above, a radiotherapy treatment plan is produced by medical physicists using complex computer algorithms which simulate the effects of a radiation beam passing through the designated area and the radiation dose deposited at any one site. Three or more 541 Radiotherapy planning the aim of radiotherapy planning is to deliver a homogenous dose to the primary tumour and potential areas of micrometastatic disease whilst minimizing the dose to the organs at risk. These have replaced the lead blocks previously manually placed in the beam to provide shielding of the organs at risk, thus speeding up the treatment process and reducing the heavy manual work required of therapy radiographers. Verification checks are performed to validate the treatment plan and to detect for any unforeseen errors prior to starting radiation treatment. The patient is treated in a specially designed room to prevent radiation of personnel outside the room. Computerized transfer of planning data from the planning computer to the linear accelerator minimizes the risk of human error in transferring data. The radiographers control the linear accelerator from outside the room using a console which is used to start and stop the radiation beam, and to set the duration of treatment and the dose to be delivered. The patient is monitored using cameras in the treatment room, and communication with the patient is possible via a microphone. These safety features are designed to optimize radiation treatment and are subject to frequent quality assurance checks. The superior border has been extended superiorly to include the common iliac lymph nodes. The red (A) and green (B) delineated areas denote the planning target volume; the white rectangles represent the multi-leaf collimators used to shield organs at risk which do not need to be irradiated. Conventional radiotherapy Conventional external beam radiotherapy uses bony landmarks to define the target volume for pelvic radiotherapy. A simulator film is obtained after the patient is aligned on the simulator couch using orthogonal lasers. As diagnostic X-rays have poor soft tissue resolution, the clinician must rely on information gathered from clinical examination and radiological investigations to determine the target volume. Studies have reported underdosing of the regional lymph nodes in up to 40% of patients using conventional radiotherapy. This is achieved by using numerous non-coplanar beams of varying intensity to improve conformity to treatment targets whilst further reducing the dose to selected organs at risk. The majority are single-centre retrospective analyses involving fewer than 100 patients. A B Brachytherapy this entails the delivery of ionizing radiation using sealed sources placed as close to the tumour as possible. The principal advantage of brachytherapy lies in the delivery of a very high dose of radiation to the tumour whilst relatively sparing normal tissues due to a rapid fall-off of dose away from the source according to the principle of the inverse square law. Other advantages over external beam radiation include: the accurate localization of tumour and immobilization of the area being treated reduces set-up errors; and delivery of treatment over a significantly shorter period, thus eliminating the risk of accelerated tumour repopulation associated with protracted courses of radiotherapy. A major disadvantage includes the need to access the tumour, which frequently requires an operative procedure subject to the competency of the brachytherapist. In gynaecological cancers, brachytherapy is commonly used to boost the tumour following external beam radiotherapy, as in cervical cancer. It may be used as the primary treatment for early cancers where surgery is contraindicated. Vaginal vault brachytherapy is increasingly used as the sole adjuvant treatment following surgery for endometrial cancer with a good prognosis. Other artificially produced radionuclides are likely to become available for brachytherapy use in the future. Sufficient data are available to suggest that both are equally effective in achieving tumour control when used in the treatment of gynaecological malignancies. The patient is required to remain flat and immobile during this period to prevent displacement of the applicators. This leads to prolongation of the overall treatment time, associated with a theoretical disadvantage of allowing tumour repair and repopulation between treatment fractions. Radionuclides used in gynaecological malignancies Radium-226 was the first radionuclide used in gynaecological brachytherapy. It has a half-life of 1620 years and decays by alpha emission to its gaseous daughter product, radon222. There were several disadvantages associated with the use of radium-226, including emission of high-energy photons which required thick shielding and storage of the daughter nuclides for prolonged time periods. Radium-226 has been replaced with more convenient radionuclides such 544 Radiotherapy Delivery systems in gynaecological brachytherapy the manual insertion of radioactive sources into tumours has almost become obsolete and has been superseded by afterloading systems. Afterloading involves the initial placement of non-radioactive applicators within the patient with subsequent insertion of the radioactive material. This has the advantage of significantly reducing the risk of exposing personnel to the radioactive sources. The use of machine (remote) afterloading techniques virtually eliminates the risk of radiation exposure for all personnel, and has become the standard of care in gynaecological brachytherapy. Intracavitary brachytherapy this technique is routinely used for the radical treatment of cervical cancer where hysterectomy has not been performed, and occasionally in patients with inoperable endometrial cancer. The procedure is carried out under general anaesthesia unless contraindicated, in which case spinal anaesthesia provides a suitable alternative. The patient is examined to assess tumour size and parametrial involvement, and a urinary catheter is inserted. The width of the vaginal vault is estimated to guide the applicator sizes required. A rectal retractor may also be inserted to push the anterior rectal wall further away from the applicators; alternatively, a gauze pack may be used to achieve this purpose and also to secure the applicators in place. A simulator film is taken with the applicators in place once the patient is awake, which is then transferred on to a planning computer to allow dosimetry calculations to be performed. The patient is monitored via a camera inside the treatment room, and a microphone can be used to communicate with the patient. Once treatment is completed, the applicator and gauze packing are removed and the patient is discharged home. A number of applicator systems are available for intracavitary brachytherapy, all of which are based around the principle of delivering a high radiation dose to the cervix, parametrium and upper vagina. Once the applicators are inserted and a radiotherapy plan is produced, the applicators are attached to the machine using cathethers. The patient is treated in the room in isolation to allow protection of staff from the ionizing radiation. The most commonly used dose fractionation is 21 Gy in three fractions using 7 Gy per fraction. Vaginal vault brachytherapy Following hysterectomy, women with cervical or endometrial cancer with pathological features suggestive of a high risk of relapse are often recommended to have adjuvant radiotherapy, including vaginal vault brachytherapy where appropriate. Applicator insertion may be carried out on the ward or in the brachytherapy suite, although some brachytherapists prefer the procedure to be carried out in theatre under general anaesthesia. Following insertion of the applicators, patients undergo the same planning process as for intracavitary brachytherapy. This technique is considered to allow greater individualization of dose distribution. It is useful for treatment where the cervical carcinoma is extending down into the vagina. The Manchester system was developed to calculate and describe the dose distribution for intracavitary brachytherapy. This is defined as being 2 cm lateral to the centre of the uterine canal and 2 cm superior to the mucous membrane of the lateral fornix along the line of the uterine canal. An example of a vaginal cylinder applicator used for vaginal vault brachytherapy is also shown (D). It can also be used for palliating symptoms for locally recurrent or metastatic cancers of the vagina and vulva. Image-guided adaptive brachytherapy Simulator-based dosimetry for intracavitary brachytherapy relies on doses to points. For advanced cervical tumours, prescribing to Point A may lead to tumour underdosage as a proportion of the tumour may lie outside the high-dose envelope. Image-guided adaptive brachytherapy is a relatively new concept for the treatment of cervical cancer, and is only available in a few centres. Image-based adaptive brachytherapy continues to generate significant interest, with the potential of improving tumour control and significantly reducing treatment-related morbidity. Packing is applied within the vagina to keep the left vaginal wall away from the radioactive sources, thus minimizing radiation toxicity. A Radiationmorbidity Treatment-related morbidity is the dose-limiting factor when utilizing radiotherapy for the curative treatment of any cancer, and has potentially important physical and psychosocial consequences for the patient. The risk of unwanted radiation effects is determined by the interaction of tumourand patient-related factors. Unwanted radiation effects are divided into early effects, arbitrarily defined as those occurring within 90 days of starting treatment, and late effects, defined as those occurring more than 90 days after starting treatment. In pelvic radiotherapy, the small bowel, rectum and bladder are the main organs at risk. The kidneys and spinal cord are the vital organs at risk when para-aortic lymph node irradiation is required. Treatment is performed using standard intracavitary treatment and interstitial brachytherapy to boost the right parametrium, thus allowing greater conformity of treatment using image-guided brachytherapy. Conclusion Radiotherapy continues to play a central role in the treatment of gynaecological malignancies. Technological advances are allowing increasingly sophisticated ways of planning and delivering radiation treatment in this group of patients. This is accompanied by ongoing research in ways to improve tumour control whilst minimizing the unwanted effects of radiotherapy. Chemotherapy Cytotoxic chemotherapy as a primary treatment modality cures less than 5% of all malignancies. It is the definitive mode of treatment in gestational trophoblastic tumours and germ cell tumours of the ovary. Chemotherapy is often used in conjunction with other treatment modalities such as surgery and radiotherapy in the treatment of gynaecological malignancies, either in an attempt to effect cure (radical), or to palliate symptoms and prolong survival in patients with advanced or metastatic disease (palliative chemotherapy). Adjuvant chemotherapy is utilized where disease is known or suspected to be present after surgery, with the intent of prolonging disease-free and overall survival. There is increasing interest in the role for neoadjuvant chemotherapy to reduce the burden of tumour prior to definitive surgery in advanced ovarian carcinoma. The use of concurrent chemoradiation is well established in the radical treatment of cervical carcinoma. This has been replaced by rational drug design based on the expanding knowledge of the molecular mechanisms of cancer, and the use of automated in-vitro screens using panels of human tumour cell lines, some chosen for their resistance to existing agents. Of the hundreds of thousands of chemical and biological agents tested in laboratories, only a small number find their way into routine clinical use. Before any new agent can be tested on humans, it undergoes preclinical studies to assess both its efficacy and toxicity in animal models. A promising agent is then studied in phase I studies to determine the appropriate dose of the drug to be used in its subsequent development. Pharmacokinetics is the study of processes that determine the concentration of the drug and its metabolites within the body.

Urethral syndrome may represent another variation of chronic pain syndromes which are complex and poorly understood erectile dysfunction agents cheap levitra jelly 20 mg mastercard. Amitriptyline impotence pills for men levitra jelly 20mg sale, used for the treatment of other chronic pain syndromes erectile dysfunction protocol free ebook discount levitra jelly 20mg with visa, is often helpful and also has a beneficial anticholinergic effect erectile dysfunction young levitra jelly 20 mg lowest price. Pharmacological therapy should be combined with education and psychological counselling erectile dysfunction from nerve damage purchase levitra jelly without prescription. Urethral syndrome Urethral syndrome is a non-specific group of lower urinary tract symptoms erectile dysfunction treatment ppt cheap levitra jelly 20mg with amex, which include pain (suprapubic or urethral) with urinary frequency and urgency. In women with recent-onset dysuria and Summary Sensory disorders of the lower urinary tract are common and frequently unrecognized. This is distressing for both the affected individual and their family, and may be potentially serious. A sound working knowledge of the clinical presentation, differential diagnoses and diagnostic criteria for these conditions is essential for all practising gynaecologists. While some of these disorders have specific and effective therapeutic options, others remain poorly understood. Further research is required to evaluate the pathogenesis of these conditions, as it is likely that effective therapeutic protocols will only be developed when the disease process itself is understood. Abrams P, Cardozo L, Fall M et al 2002b the standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Elgavish A 2009 Epigenetic reprogramming: a possible etiological factor in bladder pain syndrome/interstitial cystitis In the context of gynaecology, we are concerned primarily with fistulae between the genital tract (vagina, cervix, uterus or perineum, in decreasing order of frequency) and either the urinary tract (bladder, urethra or ureter) or the gastrointestinal tract (rectum, colon, anal canal or small bowel). Multiple or complex fistulae are common, particularly after attempts at surgical repair. Dual involvement of the bowel and urinary tract is regularly seen, and concurrent involvement of, for example, ureter and bladder, or bladder and urethra is often seen in strategically placed or large urinary fistulae. They may also involve an intervening cavity so that the fistulous nature of an inflammatory mass may not be immediately obvious. Rarer forms may occur, such as a salpingocolic fistula in association with actinomycosis or tuberculosis. Whilst such pathologies are interesting and important as causes of diagnostic confusion and therapeutic difficulty, they are not considered further in this chapter due to their rarity. Some cases of ectopic ureter may discharge into the vagina, and their presentation may be delayed into teens or adult life, hence leading to confusion with acquired fistulae or other causes of incontinence. This occurs particularly if the abnormal ureter is only draining a small or poorly functioning part of the renal tissue. Under these circumstances, the abnormal tissue may be insufficient to show up as a soft tissue shadow on a plain X-ray, and so poorly functional that it is not easily seen on excretion urography. Obstetric the underlying factors responsible for the development of obstetric fistulae may be considered in physical, biosocial, cultural, and geographical or political terms. During normal labour, the bladder is displaced upwards and the anterior vaginal wall, bladder base and urethra are compressed between the fetal head and the posterior surface of the pubis. No harm results if this occurs for a short time, but in prolonged obstructed labour, the intervening tissues are devitalized by ischaemia. Usually, the anterior vaginal wall and underlying bladder neck are affected, although the area of necrosis is sometimes higher, in which case the anterior lip of the cervix and underlying trigone are involved. Compression of the soft tissues between the sacral promontory and the presenting part may occur at the same time, with necrosis at the posterior vaginal wall and underlying rectum. The devitalized Aetiology and Epidemiology the aetiology of urogenital fistulae is varied, and may be broadly categorized into congenital or acquired, the latter being divided into obstetric, surgical, radiation, malignant and miscellaneous causes. The same factors may be responsible for intestinogenital fistulae, although inflammatory bowel disease is an additional important aetiological factor here. Accidental injury to the vaginal wall during a difficult operative delivery may involve damage to the underlying bladder wall, particularly if the tissues are devitalized by prolonged pressure. The bladder is particularly exposed to injury following symphysiotomy if the pubic bones are too widely separated by forced abduction of the thighs. In these circumstances, the unsupported bladder neck is very likely to be damaged, especially if the head is rotated and extracted with forceps. The posterior wall of the bladder may be accidentally incised during lower segment caesarean section or repair of ruptured uterus, particularly if the bladder is not reflected sufficiently far downwards before the lower segment is opened. During the reflection itself, the bladder may be torn, especially if a previous operation has made it densely adherent to the lower segment. A B undetected at the time, urinary leakage through the abdominal wound soon develops. This is usually followed by incontinence vaginally when the urine finds its way through the uterine incision. The abdominal leakage then dries up as the bladder drains through the resulting vesicocervical fistula. Alternatively, sutures may be passed through the posterior bladder wall during repair of the uterine incision. The appearance of urinary incontinence in these cases is delayed until the intervening bladder tissue caught up in the suture sloughs. The perineum and posterior vaginal wall are, of course, at risk from even the most straightforward delivery, although primiparity, forceps delivery, birth weight over 4 kg and occipitoposterior position have been found to be significant risk factors associated with third-degree tears (Sultan et al 1994). Even when identified and repaired, this increases the risk of rectovaginal fistula. Since cuts are usually made by linear incision into healthy tissues, repair is often much easier than for those resulting from pressure necrosis. Tahzib (1983, 1985) reported on the epidemiological determinants of vesicovaginal fistulae in northern Nigeria. An area of devitalized tissue is seen on the anterior vaginal wall, about to slough with resultant fistula formation. Female circumcision has been practised in various forms in much of North Africa, being most prevalent in Ethiopia, Eritrea, Sudan, Egypt, Mali and Guinea, where currently over 75% of women are affected (World Health Organization 2008). However, in different developing world societies, these factors do seem to have variable influence. For example, in south-east Nigeria (Hilton and Ward 1998) and the northwest frontier of Pakistan (World Health Organization 1989), fistula patients seem to be somewhat older and of higher parity; they also appear to have a higher literacy rate, and to be more likely to remain in a married relationship after the development of their fistula (Hilton and Ward 1998). It is likely that the development of fistulae here reflects other biosocial variations (Table 57. It is clear that in these populations, even where skilled maternity care is available, uptake may be poor. Mistrust of hospitals is commonplace, antenatal care is poorly attended, and delivery is commonly conducted at home by elderly relatives or unskilled traditional birth attendants. Where labour is prolonged, transfer to hospital may only be used as a last resort. Surgical Genital fistula may occur following a wide range of surgical procedures within the pelvis (Table 57. Certainly, on occasions, this may be the case; careless, hurried or rough surgical technique makes injury to the lower urinary tract much more likely. Recent animal studies suggest that the inadvertent placement of vault sutures into the bladder wall at hysterectomy may not carry as great a risk of fistula formation as previously thought (Meeks et al 1997). Although it is important to remember that the majority of surgical fistulae follow apparently straightforward hysterectomy in skilled hands, several risk factors may be identified that make direct injury more likely (Table 57. Obviously, anatomical distortion within the pelvis by ovarian tumour or fibroid will increase surgical difficulty, and abnormal adhesions between bladder and uterus or cervix following previous surgery or associated with previous sepsis, endometriosis or malignancy may make fistula formation more likely. Preoperative or early postoperative radiotherapy may decrease vascularity, and make the tissues generally less forgiving of poor technique. The ability to locate and, if necessary, dissect out the ureter must be part of routine gynaecological training, as should the first aid management of lower urinary tract injury when it arises. The use of gauze swabs to separate the bladder from the cervix at caesarean section or hysterectomy should be discouraged; sharp dissection with knife or scissors does less harm, especially where the tissues are abnormally adherent. In considering obstetric fistulae, it is important to consider the social, cultural and geographical influences just as much as the direct physical injury to the lower urinary tract. This usually results from stunting of growth by malnutrition and untreated infections in childhood and adolescence. Where women retain a subservient role in society and standards of education are limited, early marriage and the absence of family planning services result in an early start to childbearing; where first pregnancies occur soon after the menarche, before growth of the pelvis is complete, this also contributes to obstruction in labour. The influence of these factors is illustrated in the epidemiological studies alluded to earlier. Tahzib (1983) reported that over 50% of the cases of vesicovaginal fistulae seen in northern Nigeria were under 20 years of age, over 50% were in their first pregnancy, and only one in 500 had received any formal education. Sources: Hilton P, Ward A 1998 Epidemiological and surgical aspects of urogenital fistulae: a review of 25 years experience in south-east Nigeria. It has recently been shown that there is a high incidence of abnormalities of lower urinary tract function in fistula patients (Hilton 1998); whether these abnormalities antedate the surgery, or develop with or as a consequence of the fistula, cannot be answered from this data. However, it is likely that patients with a habit of infrequent voiding, or with inefficient detrusor contractility, may be at increased risk of postoperative urinary retention; if this is not recognized early and managed appropriately, the risk of fistula formation may be increased. A total fistula rate approaching 40% has been reported, and the involvement of the genital tract in females may be up to 7%. Diverticular disease can produce colovaginal fistulae and, rarely, colouterine fistulae, with surprisingly few symptoms attributable to the intestinal pathology. The obliterative endarteritis associated with ionizing radiation in therapeutic dosage proceeds over many years, and may be aetiological in fistula formation long after the primary malignancy has been treated. Not only does this ischaemia produce the fistulae, it also causes significant damage in the adjacent tissues, so ordinary surgical repair has a high likelihood of failure and modified surgical techniques are required. Miscellaneous Among other miscellaneous causes of fistulae in the genital tract, the following should be considered. Carcinoma of cervix, vagina and rectum are the most common malignancies to present in this way. It is relatively unusual for urothelial tumours to present with fistula formation, other than following surgery or radiotherapy. Prevalence United Kingdom the prevalence of genital fistulae obviously varies from country to country and continent to continent as the main causative factors vary. Accurate figures are impossible to obtain since those areas with the highest overall prevalence are also those with the poorest systems of health data col- lection. The most recent data from Health Episode Statistics for England suggest an average of 95 operations for vesicovaginal fistula and 10 operations for urethrovaginal fistula per year in England (Department of Health 2009). It is tempting to suggest that this apparent reduction in incidence of fistulae may reflect changes in the practice of 879 57 Fistulae Table 57. Preoperative radiotherapy Diabetes mellitus Sources: Hilton P, Ward A 1998 Epidemiological and surgical aspects of urogenital fistulae: a review of 25 years experience in south-east Nigeria. World Health Organization 1989 the Prevention and Treatment of Obstetric Fistulae: a Report of a Technical Working Group. Developing world In the developing world, many fistula cases are unknown to medical services, being separated from their husbands and ostracized from society. Although the true prevalence in the developing world is unknown, particularly high prevalence rates are reported in Nigeria, Ethiopia, Sudan and Chad. Whilst there are other possible explanations, it may be that as fewer hysterectomies are undertaken, those that remain are the more difficult procedures. Studies from Finland suggest a similar rate of posthysterectomy fistulae overall, with approximately one per 1000 abdominal hysterectomies and one per 450 laparoscopic hysterectomies (Harkki-Siren et al 1998). Urogenital fistulae may be classified into urethral, bladder neck, subsymphysial (a complex form involving circumferential loss of the urethra with fixity to bone), midvaginal, juxtacervical or vault fistulae; massive fistulae extending from bladder neck to vault; and vesicouterine or vesicocervical fistulae. There have been recent calls for classification systems more predictive of outcome (Arrowsmith 2007, Goh et al 2008). Presentation Fistulae between the urinary tract and the female genital tract are characteristically said to present with continuous urinary incontinence, both by day and night. In patients with large fistulae, the volume of leakage may be such that they rarely feel any sensation of bladder fullness, and normal voiding may be infrequent. Where there is extensive tissue loss, as in obstetric fistulae from obstructed labour or radiation fistulae, this typical history is usually present, the clinical findings gross, and the diagnosis rarely in doubt. With postsurgical fistulae, for example, the history may be atypical and the orifice small, elusive or occasionally completely invisible. Under these circumstances, the diagnosis can be much more difficult, and a high index of clinical suspicion must be maintained. Occasionally, a patient with an obvious fistula may deny incontinence, and this is presumed to reflect the ability of the levator ani muscles to occlude the vagina below the level of the fistula. Some patients with vesicocervical or vesicouterine fistula following caesarean section may maintain continence at the level of the uterine isthmus, and complain of cyclical haematuria at the time of menstruation, or menouria (Falk and Tancer 1956, Youssef 1957). In other cases, patients may complain of little more than a watery vaginal discharge, or intermittent leakage, which seems posturally related. Leakage may appear to occur specifically on standing or on lying supine, prone, or in left or right lateral positions, presumably reflecting the degree of bladder distension and the position of the fistula within the bladder; such a pattern is most unlikely to be found with ureteric fistulae. Although in the case of direct surgical injury, leakage may occur from the first postoperative day, in most surgical and obstetric fistulae, symptoms develop between 5 and 14 days after the causative injury; however, the time of presentation may be quite variable. This will depend, to some extent, on the severity of symptoms, but as far as obstetric fistulae in the developing world are concerned, is determined more by access to health care.

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