Thomas Charles Becker, PhD

• Assistant Professor in Medicine
• Member of Sarah W. Stedman Nutrition and Metabolism Center

https://medicine.duke.edu/faculty/thomas-charles-becker-phd

This immobility leads to further calcium mobilization and enhances the hypercalcemia antibiotic for staph infection generic augmentin 625 mg mastercard. As hypercalcemia continues to worsen antibiotics for sinus infection didn't work generic augmentin 1000mg fast delivery, severe symptomatology virus game online buy augmentin 625 mg cheap, including changes in mental status infection 5 weeks after hysterectomy generic augmentin 1000mg line, confusion bacteria zapper for face buy 1000mg augmentin, and finally coma may supervene antibiotic use in poultry order online augmentin. Clearly, bone pain can be related to the presence of metastases within bone that cause areas of increased intramedullary pressure, ischemia, or microfractures, but the symptom is also present in the absence of demonstrable metastatic disease. Laboratory Investigations Measurement of the serum calcium is the first step in evaluation of suspected hypercalcemia. Total serum calcium, which includes both carrier-bound (40% bound to albumin) and unbound calcium, is most commonly used. If the albumin is abnormal, the serum calcium should be corrected for the serum albumin using the following formula: Ca (corrected mg/dL) = serum Ca (mg/dL) = [0. For example, in hyperventilation causing respiratory alkalosis the ionized calcium decreases acutely, whereas acidosis resulting in reductions of pH can cause the ionized calcium to rise acutely, both resulting in relatively rapid shifts in ionized calcium. Therefore it is advised to confirm elevated serum calcium with a repeat test to ensure these are not spurious results. However, it is important to note that more than one mechanism of malignancyassociated hypercalcemia can be seen in a particular patient. Other investigations should include a complete blood cell count, measurement of blood urea nitrogen, and measurement of creatinine with estimated glomerular filtration rate to assess renal status. Measures of osteoblastic function, such as alkaline phosphatase and osteocalcin, have little to offer in the diagnosis or management of hypercalcemia. Rare causes of hypercalcemia can include vitamin A toxicity; levels may be checked if the patient is suspected to have taken a large dose of supplements. If multiple myeloma is suspected based on evaluation, serum and urine protein electrophoresis or immunofixation along with a skeletal survey is indicated. If the cause is clear based on the findings of the aforementioned workup, then a 24-hour urine analysis for calcium and creatinine is not routinely performed. Treatment the severity of hypercalcemia and associated symptoms should dictate the aggressiveness of therapy for hypercalcemia of malignancy. Severe hypercalcemia is usually associated with renal insufficiency, volume contraction, and neurologic symptoms requiring immediate treatment, often on an inpatient basis. Moderate hypercalcemia can be associated with fewer symptoms and end-organ manifestations, and mild hypercalcemia can be asymptomatic and may not require immediate therapy. Workup for underlying etiology is important in those who do not need immediate therapy; however, if hypercalcemia is severe, treatment needs to be initiated simultaneously with the workup. For those with moderate to severe hypercalcemia, additional concurrent therapy is also indicated. Additional treatment modalities focus on the cause and mechanism of action causing the hypercalcemia. In general, all patients with malignancy-associated hypercalcemia have volume depletion, increased osteoclastic bone resorption, and increased renal tubular calcium reabsorption, so additional therapies should target these mechanisms. Early mobilization is important but can be difficult in patients with advanced malignant disease. Restoration of the normal circulating blood volume and the glomerular filtration rate will increase the fractional excretion of calcium as well as improve renal function. A common regimen is to start with an initial bolus of 1 to 2 L followed by maintenance fluids of 150 to 300 mL/h for the next 2 to 3 days or until volume repletion has been achieved. Furosemide has historically been used to promote calciuresis; however, it should not be routinely used in the treatment of hypercalcemia of malignancy. It should be reserved only for those with congestive heart failure and for those who need diuresis. Reduction of Bone Resorption Bisphosphonates After initial volume repletion, treatment targeting reduction of bone resorption should be considered. The standard of care for treatment of acute hypercalcemia of malignancy is antiresorptive therapy with bisphosphonates. Zoledronic acid is the most potent bisphosphonate-100 times more potent than pamidronate. Both zoledronic acid and pamidronate block osteoclast activity and stimulate osteoclast death. Both compounds inhibit calcium release from bone by inhibiting osteoclast activity driven by tumor-mediated cytokines and enzymes. Pamidronate has been shown to permit bone formation while limiting bone resorption. In patients with severe hypercalcemia, treatment with a single dose of 90 mg given intravenously over 2 to 24 hours is recommended. The recommended dose is 4 mg administered as a single dose intravenously over no less than 15 minutes. Like pamidronate, the vast majority of zoledronic acid is not metabolized but excreted renally and intact. Dose adjustment is not indicated for patients with hypercalcemia of malignancy with mild to moderate renal impairment. If this does not occur, readministration is recommended after electrolyte levels and kidney function have been monitored carefully for at least 7 days. The median time to relapse of hypercalcemia is 30 days after a single dose of 4 mg of zoledronic acid and 40 days with a dose of 8 mg. Less common but well-recognized complications of bisphosphonates are osteonecrosis of the jaw, atypical fractures, and hypocalcemia. Hypocalcemia occurred in 1% of patients receiving zoledronic acid and 2% of patients receiving pamidronate. It is not possible to determine the rate of osteonecrosis of the jaw or to definitively attribute that effect to bisphosphonates, but it is suggested that avoiding dental procedures after administration of bisphosphonates can reduce this risk. In a comparison of zoledronic acid 4-mg and pamidronate 90-mg infusions, 11% of patients had renal deterioration after treatment with zoledronic acid compared with 9% with pamidronate. The risk of renal toxicity is decreased with administration of zoledronic acid over 15 minutes instead of 5 minutes. Focal segmental glomerular sclerosis has been documented after administration of pamidronate. Steroids have also been reported to reduce tumor production of locally active cytokines in addition to having direct tumorolytic effects. They found that cinacalcet resulted in a dose-dependent reduction of calcium and normalization of phosphorus levels in mice with hypercalcemia due to Leydig and colon tumors. It is second-line therapy in patients with bisphosphonate-resistant hypercalcemia of malignancy45 and has also specifically been used in those with multiple myeloma and renal dysfunction. Only 31% of those receiving denosumab developed hypercalcemia, compared with 40% of the zoledronic acid group. One study administered 120 mg weekly for 4 weeks and then every 4 weeks after that. No renal adjustment is reported to be necessary, given that pharmacokinetics and pharmacodynamics are not affected by renal status. However, the effect has been reported to be more pronounced in those with renal failure, so dose reduction has been advised by some authors22,46. However, it has been reported to inhibit osteoclast mediated bone resorption, stimulate bone formation, and alter mineral composition of bone. Calcitonin inhibits osteoclasts and also increases calcium excretion in the urine. Side effects include nausea and hypersensitivity to the salmon or porcine preparations. Levels of other electrolytes, specifically phosphorus, need to be monitored closely. Hemodialysis Hemodialysis or continuous renal replacement therapy with low or no calcium in the dialysate bath has been used in severe refractory hypercalcemia. Current indications include those with oliguric or anuric renal failure and volume overload refractory to fluids and diuretics and those with severe symptoms despite the use of the aforementioned therapies. Haematological emergencies managing hypercalcaemia in adults and children with haematological disorders. Association of primary hyperparathyroidism and humoral hypercalcemia of malignancy in a patient with clear cell renal carcinoma. Estrogens and antiestrogens stimulate release of bone resorbing activity by cultured human breast cancer cells. Small cell carcinoma of the ovary with hypercalcemia causes severe pancreatitis and altered mental status. Concurrent primary hyperparathyroidism and humoral hypercalcemia of malignancy in a patient with clear cell endometrial cancer. Hypercalcemia and ectopic secretion of parathyroid hormone by an ovarian carcinoma with rearrangement of the gene for parathyroid hormone. Pseudohypercalcemia in an elderly patient with multiple myeloma: report of a case and review of literature. Posterior reversible encephalopathy syndrome due to hypercalcemia associated with parathyroid hormone-related peptide: a case report and review of the literature. Posterior reversible encephalopathy syndrome due to malignant hypercalcemia: physiopathological considerations. Ventricular fibrillation in hypercalcaemic crisis due to primary hyperparathyroidism. Letter to the editor: Distinguishing typical primary hyperparathyroidism from familial hypocalciuric hypercalcemia by using an index of urinary calcium. Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone. Denosumab for the management of hypercalcemia of malignancy in patients with multiple myeloma and renal dysfunction. The role of denosumab in the prevention of hypercalcaemia of malignancy in cancer patients with metastatic bone disease. The emerging role of denosumab in the long-term management of parathyroid carcinomarelated refractory hypercalcemia. Cinacalcet hydrochloride reduces the serum calcium concentration in inoperable parathyroid carcinoma. Effect of gallium nitrate on tamoxifen induced hypercalcemia in rats bearing mammary tumor. Combination of calcitonin and pamidronate for emergency treatment of malignant hypercalcemia. Indeed, as extremely effective new therapies have become available for a variety of cancers, tumor lysis syndrome has become more common. For example, 70% of drugs approved in the past 5 years for management of hematologic malignancies now include warnings about tumor lysis syndrome in their package inserts, and in some cases the dose-limiting toxicity in phase I studies was tumor lysis syndrome, which demonstrates the high cell lysis potential that results from use of extremely effective anticancer therapies. Acute kidney injury, seizures, cardiac arrhythmias, nausea, and vomiting may occur because of these metabolic abnormalities. To reduce morbidity and mortality, early diagnosis and identification of patients at risk for tumor lysis syndrome are of the utmost importance. Xanthine is then oxidized by xanthine oxidase, leading to the production of uric acid, which is excreted by the kidneys. When the accumulation of phosphate, potassium, xanthine, or uric acid is more rapid than excretion, tumor lysis syndrome develops. Cytokines cause hypotension, inflammation, and acute kidney injury, which increase the risk for tumor lysis syndrome. The bidirectional dashed line between acute kidney injury and tumor lysis syndrome indicates that acute kidney injury increases the risk of tumor lysis syndrome by reducing the ability of the kidneys to excrete uric acid, xanthine, phosphate, and potassium. By the same token, development of tumor lysis syndrome can cause acute kidney injury by renal precipitation of uric acid, xanthine, and calcium phosphate crystals and by crystal-independent mechanisms. Allopurinol inhibits xanthine oxidase and prevents the conversion of hypoxanthine and xanthine into uric acid but does not remove existing uric acid. In contrast, rasburicase removes uric acid by enzymatically degrading it into allantoin, a highly soluble product that has no known adverse effects on health. Phosphate combines with calcium, generating calcium phosphate salts that deposit in the renal tubules and other soft tissues, including the conducting system of the heart. The binding of calcium by phosphate leads to hypocalcemia, which in turn can cause vomiting, muscle cramps, tetany, paresthesias, seizures, and cardiac dysrhythmias. Hyperkalemia from cellular lysis can lead to cardiac dysrhythmias, ventricular tachycardia, fibrillations, or cardiac arrest. Numerous risk factors for tumor lysis syndrome can be classified into cancer factors (cancer bulk and cell lysis potential), unmodifiable patient factors. Furthermore, the proportion of cancer cells exposed to initial chemotherapy is very high in these cancers, compared with a large solid tumor mass with areas of hypoxia and poor perfusion that may not be accessible at the onset of therapy. In the current risk stratification system, all cancer-related risk factors are reduced to two: cancer bulk and cell lysis potential. Risk Stratification-Cancer Factors Cell lysis potential includes the biology of the cancer and the efficacy of the treatment and therefore is expected to increase as more effective treatments and therapeutic combinations are developed. Any new agents or combinations for which published experience is limited should be assumed to have high lysis potential. Estimating cancer bulk causes confusion for clinicians, and inaccurate bulk assessment can lead to undertreatment or overtreatment for tumor lysis syndrome. Each mass or node contributes "bulk points" according to its volume, and these bulk points are added to those from other sites of disease, including bone marrow, spleen, liver, and kidneys. As urine pH rises from 5 to 7, the solubility increases 25-fold, from 8 mg/dL to 200 mg/dL.

However infection vaginal 1000mg augmentin otc, the requirement for tissue biopsies presents logistical virus 50 nm microscope purchase augmentin 1000mg without prescription, patient safety topical antibiotics for acne list purchase discount augmentin line, and ethical challenges antibiotics for uti if allergic to sulfa purchase augmentin 1000mg online. This approach may be necessary if dose selection cannot rely on a biologic marker antibiotic resistance documentary generic augmentin 375 mg. One trial design proposed to overcome some of these concerns is the randomized discontinuation design antibiotics for acne breakout discount augmentin 375mg on line, which is considered a type of enrichment trial. Only the patients who show evidence of stable disease undergo randomization to receive either the study drug or placebo. Thus the randomized population is enriched with sensitive patients because only the patients who do not experience early drug failure continue to receive therapy. The fact that all patients have the opportunity to receive the investigational drug is considered a major attraction of this study design. The "add-on" approach is useful for the evaluation of agents expected to have little efficacy when used alone, and it is particularly attractive because all patients receive an active agent or regimen. For example, these designs were critical to the successful development of trastuzumab in breast cancer and bevacizumab in colorectal cancer. Furthermore, for agents with targets expressed in only a small proportion of patients, the study should be enriched with patients who have tumors that express the target or have another marker predictive of activity. To do so, the assay must be accurate, precise, reproducible, sensitive, and robust and have a dynamic range tight enough to detect differences between baseline and posttreatment values31 (Box 26. Furthermore, the assay methodology assessing drug effect on the target should be developed and authenticated first in in vivo animal models and then in first-in-human clinical trials. The development of mechanism-based biomarker assays can significantly expedite drug development because such assays aid in Box 26. Traditional methods of establishing accuracy include recovered fraction of a known mass of the analyte added to a clinical specimen (spike recovery) and measurement of interferences from materials likely to be found in a typical specimen. Dynamic range: the range of concentrations within which the assay is capable of accurately measuring analyte; ideally, concentrations present in both treated and untreated specimens without additional specimen dilutions or processing steps. Precision: A measure of variability of results for a specimen around the determined value, performed in the range within which measured values approximate the true value; usually accomplished by repeated assays of a set of specimens by multiple technicians on multiple days. Reproducibility: the closeness of agreement between independent results obtained with the same method on identical test material but under different conditions (different operators, different apparatus, different laboratories, and/or after different intervals of time). It is measured as the total imprecision of the assay from all sources, measured at several points within the dynamic range of the assay. This imprecision must be much less than the clinical end pointselected-thatis,ifanundevelopedassayhadatotal imprecision of about 40%, this would make measurement of a 50% effect impossible. The assay should be sensitive enough to allow repeat determinations of the same specimen. This approach could also help select the lead agent from a group of compounds, help determine dose, guide patient selection and assessment of response, and provide the basis for combination trials. To perform this evaluation effectively, such trials require careful attention to the use of standardized and validated procedures for tissue acquisition, handling, processing, and assay methodology. Such careful attention is critical because these factors could influence biologic processes and increase interpatient and intrapatient variability, making the interpretation of the results problematic. In addition, different tissue-handling procedures may change the level of expression or activity of targets-for example, enzymes and protein substrates. Unless care is taken to stabilize the analyte immediately, it may degrade completely and produce a false-positive result, simulating target inhibition. The standard operating procedures from tissue acquisition to target assay methodology should be developed and qualified before clinical trials are initiated. Exploratory efficacy trials should also use newer techniques such as molecular profiling of the tumor and normal tissue, and there should be a clear understanding of the effects of inhibiting the target both in tumor and in host tissue. Accordingly, these approaches depend heavily on the availability of clinical- and laboratory-based investigators and their willingness to collaborate. Progress in the clinical application of molecular imaging depends on the development of probes that have better sensitivity and specificity, as well as increases in the signal-to-noise or spatial resolution of molecular imaging devices. Unquestionably, noninvasive imaging will play an increasingly important role in the development and application of molecularly targeted therapy. This optimization is not feasible unless the patients enrolled have tumors that express or have a high probability of expressing the target. However, an increasing amount of evidence shows that tumors are heterogeneous at the molecular level within any given histologic type and that genetic variations in the tumor may significantly affect drug sensitivity. Clearly, patient selection beyond histologic type is becoming increasingly important in drug development, especially for agents likely to benefit specific patient subsets. Unlike anatomic imaging, molecular imaging displays biochemical and physiologic abnormalities underlying disease, rather than the structural consequences of these abnormalities. Functional and molecular imaging modalities can be helpful in phase I studies for dose determination, as discussed earlier, and may be applicable as noninvasive tools to detect drug-target effect, as well as to provide early evidence of efficacy. The approved indication for vemurafenib specifically includes the limitation that treatment of patients with wild-type melanoma is not recommended because essentially no safety or efficacy data are available for these patients. However, depending on the agent and disease context, it is useful to obtain at least some information about how a drug affects target (test)-negative as well as target (test)positive patients; the data may be important for the validation of the biomarker assay and to make certain the drug is not effective in test-negative patients. Molecular abnormalities in cancer are usually complex, and multiple processes and pathways are responsible for tumor proliferation and survival, so the likelihood that engaging any one specific target will have a major antitumor impact is relatively low. Various strategies are being used to devise rational drug combinations that optimize antitumor efficacy while limiting toxicity3 (Table 26. Another approach is to design a single agent with specificity against multiple targets of interest. Regardless of whether developing single agents with multiple targets or combinations of Table 26. These target assay procedures are best developed and performed in preclinical in vitro and in vivo models and, if feasible, in first-in-human clinical studies in a limited number of patients in advance of larger, more definitive trials. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. Utilizing targeted cancer therapeutic agents in combination: novel approaches and urgent requirements. Oncogene addiction as a foundational rationale for targeted anti-cancer therapy: promises and perils. Mechanisms of disease: oncogene addiction-a rationale for molecular targeting in cancer therapy Cancer. Genetically engineered mouse models: closing the gap between preclinical data and trial outcomes. Drug development in oncology: classical cytotoxics and molecularly targeted agents. Acquired resistance mechanisms to tyrosine kinase inhibitors in lung cancer with activating epidermal growth factor receptor mutation-diversity, ductility, and destiny. Differential degradation rates of inactivated alkyltransferase in blood mononuclear cells and tumors of patients after treatment with O(6)-benzylguanine. Randomized Discontinuation design: application to cytostatic antineoplastic agents. Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer. Minimally, invasive pharmacokinetic and pharmacodynamic technologies in hypothesis-testing clinical trials of innovative therapies. Quantitative fluoroestradiol positron emission tomography imaging predicts response to endocrine treatment in breast cancer. Whereas the/ratiocanbeusedasa metricfordescribingcellular radiosensitivity,ithasalsobeen adaptedtodescribethetime,dose, andfractionationresponseof irradiatedtissues. Thesephenomena weretermedsublethal and potentially lethal damage repair or recovery. Radiation therapy is one of the three established cancer treatment modalities and is used for the therapy of most types of solid tumors and for selected hematologic malignancies. It is used almost entirely for therapy of malignant disease, although it has a small role in preventing proliferation in selected benign diseases. Radiation therapy is routinely combined with surgery, chemotherapy, or both to improve therapeutic results. It is often used with surgery to destroy microscopic regions of tumor extension and with chemotherapy to destroy more effectively the primary tumor. An understanding of the therapeutic use of ionizing radiation requires a basic comprehension of both the physics of radiation therapy delivery and the biologic effects of the interaction of radiation with matter. These biologic effects are initiated when packets of energy are deposited in a volume of tissue and remove electrons from constituent atoms through a process called ionization. Accordingly, the physics of radiation oncology is focused on the details of how, where, and how much energy can be deposited in diseased tissue in the hopes of eradicating it while minimizing the energy released in healthy tissue. This requires an understanding of the nature of the radiation and the matter through which it passes, and how that matter is changed as a result of the energy deposition events. Nature of Matter and Radiation All matter, biologic or otherwise, is composed of atoms. Atoms are made up of groups of electrons (small negatively charged particles) orbiting a nucleus consisting of protons (larger positively charged particles) and neutrons (uncharged particles having mass similar to that of a proton). A number of electrons that matches the number of protons is held in orbit around the nucleus by electrostatic attraction. A specific discrete set of possible electron orbits exists for each kind of atom, with each electron orbit corresponding to a specific energy. Moving an electron from one orbit to another requires adding or subtracting the energy difference between the two orbitals, and removing an electron from the atom entirely, a process called ionization, requires adding the full energy of the electron orbital. The properties of a nucleus are defined by the number of protons and neutrons, with the number of protons defining the type of element and the number of protons and neutrons together defining the isotope. Analogously to the arrangement of electrons in an atom, protons and neutrons are arranged in discrete energy levels specific to a particular nucleus, and transitioning between energy levels requires adding or removing a comparable amount of energy. Of the 1400 known isotopes of the 92 naturally occurring elements, approximately 80% are unstable and spontaneously undergo a transition between energy levels, emitting energy in the process. The phenomenon of spontaneous energy release from a nucleus, called radioactivity, can take many forms, including combinations of the emission of -rays, the ejection of electrons, positrons, or alpha particles, and the transmutation of one element to another. The term radiation refers to energy emitted from a source that is transmitted through a material or space. This radiation can then deposit its energy by interacting with the matter through which it passes. Regardless of source, most radiation used in radiation therapy involves electromagnetic interactions. This energy can take the form of packets of electromagnetic waves called photons, or it can be carried as the kinetic energy of freely propagating particulate radiation such as electrons, protons, or alpha particles. Photons are characterized by their wavelength, which is the distance traversed by a wave over the course of a single oscillation. Photons that have a shorter wavelength oscillate at a higher frequency (more oscillations per unit time) and are more energetic. Each eV is equivalent to the kinetic energy required to move one electron through a potential difference of 1 volt. Diagnostic (kilo-electron-volts [keV]) and therapeutic (mega-electron-volts [MeV]) photons can penetrate much more deeply, allowing therapeutic effects anywhere in the body. Photons at therapeutic energies can pass through many centimeters of tissue before experiencing any interactions. The electric fields around these particles cause them to interact with all the other charged particles in the surrounding medium. Charged particles are therefore much more efficient at depositing energy in matter, as the particles will continuously lose their energy as they attract or repel other charged particles along their path. Many of these interactions will cause ionization, which correlates with the amount of biologic damage delivered. The positively charged proton then ionizes the surrounding particles, causing most of the biologic damage. Compton effect e: e: e: e: p;np; np; n np; np; n Interactions of Radiation and Matter In order of roughly increasing energy, photons can interact with: 1. The atom as a whole Tightly bound inner shell electrons Loosely bound outer shell electrons the extranuclear space surrounding the nucleus the nucleus itself e: e: Fast electron e: Scattered photon Incident photon Photoelectric effect Incident photon e: p;np; np; n np; np; n Coherent Scatter Low-energy photons can be briefly absorbed by the bound electrons of an atom. If the photon lacks the energy to remove the electron from the atom, the photon energy will be immediately reemitted as another photon. The reemitted photon has the same energy as the incident photon, and close to the same direction of travel. Because no energy is deposited, coherent scattering does not contribute to dose deposition, but the small deflections of the photons from coherent scatter can cause blurring in diagnostic images. Coherent scattering accounts for approximately 10% of interactions at 30 keV and is negligible for most therapeutic energy beams. Some energy is lost to breaking the electron binding energy, and the rest is carried away as kinetic energy of the ejected electron. The probability of a photoelectric interaction scales with the cube of the atomic number (Z) and the inverse cube of the photon energy (E), making the photoelectric effect very sensitive to material type and much more prevalent for lower photon energies. The photoelectric effect is the dominant photon interaction in tissue below 30 keV. The result of this interaction is a photon with reduced energy and new direction, and a recoil electron with some fraction of the initial photon energy.

During this time virus taxonomy generic augmentin 625 mg online, toxic stimuli to the mother and fetus may result in fetal growth retardation antibiotic resistance spread vertically by discount 625mg augmentin otc, which can be associated with abnormal brain development and subsequent learning difficulties bacteria 7th grade science augmentin 375 mg mastercard. However virus ti snow buy cheap augmentin 625mg on line, as will be discussed antimicrobial vinyl buy generic augmentin 1000mg line, fetal growth retardation has not been demonstrated to be a significant clinical concern in women receiving chemotherapy during the second and third trimesters antibiotic 5898 cheap 375 mg augmentin with visa. Numerous studies of radiation exposure after the atomic bomb detonations in Japan confirmed that this effect is dependent on radiation dose and stage of fetal development at the time of exposure (Table 61. The baseline cancer risk in the first 15 years is about 1 in 650, and thus fetal doses of 2. Ultrasonography, Computed Tomography, and Magnetic Resonance Imaging Ultrasound examination is believed to be safe during pregnancy and can be particularly useful in assessing the breasts and liver. Antimetabolites Methotrexate is widely distributed, including into fluid spaces such as amniotic fluid, and when given during the first trimester is closely associated with fetal abnormalities, characterized by cranial dysostosis, hypertelorism, micrognathia, limb deformities, and mental retardation. In fact, methotrexate is commonly used in combination with misoprostol during the first trimester to medically induce abortions. However, methotrexate does not uniformly cause malformations, and a critical dose and timing may exist beyond which fetal malformations occur. Capecitabine is embryotoxic in animals, is classified as a category D drug, and is not recommended for use during pregnancy. Use of hydroxyurea is believed to be unsafe during pregnancy because of a case series of 31 patients in which an increased risk of intrauterine growth retardation, intrauterine fetal demise, and prematurity was noted. Most chemotherapeutic agents are category D, for which there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. Extrapolation of teratogenic and mutagenic effects of chemotherapeutic agents from animals to human organogenesis is difficult, however, because of differences in susceptibility among species. Administration of drugs within 1 week of conception may result in a spontaneous abortion or a healthy fetus. During the first trimester, when organogenesis occurs, drugs may produce congenital malformations and/or result in spontaneous abortion. Other factors that may influence the probability of teratogenesis include the frequency of drug administration, duration of exposure, synergistic effects of multiple drugs, use of radiation, and individual genetic susceptibility. Most human data about chemotherapy during pregnancy involve small series or case reports, which are prone to reporting bias. Specific or systemic information about the teratogenicity of individual cytotoxics or modern multiagent chemotherapy regimens is limited, particularly in the first trimester. Many reported malformations have occurred after exposure to multiple agents, making it difficult to assign blame to a single causative agent. It is important to note that the overall incidence of major congenital malformations with chemotherapy use after the first trimester is approximately 3% (close to the risk in the general population), although the incidence of minor malformations may be as high as 9%, and 10% to 15% of all pregnancies result in a miscarriage or spontaneous abortion. The current available literature suggests that chronic prenatal chemotherapy exposure does not result in learning or behavioral problems (also known as functional teratogenesis). Alkylating Agents Alkylating agents are commonly used in the treatment of lymphoma, acute lymphocytic leukemia, multiple myeloma, ovarian cancer, and breast cancer. Use in the first trimester has been associated with some fetal abnormalities, tempered with several reports with no abnormalities. Regarding dacarbazine use during pregnancy, congenital abnormalities were seen in two cases during the first trimester, consisting of isolated microphthalmos with secondary severe hypermetropia and a unilateral floating thumb malformation and one fetal death. In the second- or third-trimester exposure, one fetus died and one case of minor malformation (syndactyly) was observed. More data exist for paclitaxel than docetaxel, and weekly paclitaxel is the preferred regimen, in general. In a series of patients treated with single-agent vinblastine for Hodgkin lymphoma, no adverse outcomes to the pregnancy or in infants who were followed afterward were reported. In a series of 180 women who were exposed to imatinib in pregnancy, with data available for 125, 12 infants were born with abnormalities, among whom three had similar complex combinations of defects. Erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, is used in persons with metastatic lung and pancreatic cancer. Few malformations have been reported when anthracyclines are used in combination regimens in the first trimester. A few studies have shown acute myocardial dysfunction after anthracycline use in a minority of fetuses. Other Agents When administered during the first trimester, all-trans retinoic acid, which is used to treat acute promyelocytic leukemia, is associated with an 85% risk of teratogenicity; when used with chemotherapy, it is associated with an increased rate of miscarriage. Interferon- is believed to only minimally cross the placenta because of its high molecular weight. Forty cases of interferon used in pregnancy for a variety of hematologic disorders and eight cases in the first trimester showed no mutations. One case of fetal malformation was seen when interferon- was used in conjunction with hydroxyurea. Lenalidomide, also used to treat multiple myeloma, should also be avoided, given its similarity to thalidomide. In a case series of 15 patients exposed to trastuzumab in utero, three fetuses had renal failure and four died. Newer agents such as pertuzumab and trastuzumab emtansine have not been studied in pregnancy, and their use should be avoided. Bevacizumab, a humanized monoclonal antibody with an antiangiogenic effect, is used to treat multiple cancers. Because it is teratogenic in animals, consistent with a crucial role of angiogenesis during normal fetal development,55 bevacizumab should not be administered to pregnant women. The few reports that have been published seem to indicate safe use of rituximab in pregnancy in all trimesters when given for both oncologic and nononcologic indications. Other monoclonal antibodies have not been extensively used in pregnancy, and their use should be carefully evaluated in a case-by-case basis. Data on the use of these novel agents in pregnancy are scant, and their use is not recommended in pregnancy. Safe use in pregnancy has been documented,64 as has use in the prevention of recurrent miscarriage. In addition, for many malignancies, no evidence exists to indicate whether delaying chemotherapy from the first trimester until the completion of fetal organogenesis early in the second trimester adversely affects the prognosis. A therapeutic abortion is usually recommended for cancers diagnosed in the first trimester that require urgent multiagent chemotherapy. Care needs to be individualized for each patient, considering the clinical stage of disease, gestational age, urgency of the need for treatment, and the preference of the patient and her family. Treatment of the pregnant patient with cancer requires a multidisciplinary team that may include obstetricians, maternal-fetal medicine practitioners, medical and radiation oncologists, surgeons, pediatricians, geneticists, pathologists familiar with typical changes of pregnancy, psychologists, and social workers. The administration of most chemotherapeutic agents in the second and third trimesters has not been associated with specific adverse effects on the fetus; hence, in general, chemotherapy-based treatment of the underlying malignancy at this stage of pregnancy should not be delayed and should follow the same guidelines as for nonpregnant women. The main risk to the fetus appears to be a result of neutropenic sepsis, anemia, and nutritional deficiency in the mother. Accordingly, particularly when given with curative intent, chemotherapy doses should not be empirically dose-reduced. Patients should be counseled that the incidence of teratogenicity as a result of exposure to a particular chemotherapy drug or a drug combination in the first trimester has not been well established. Counseling regarding the effects of chemotherapy must include the Is immediate treatment indicated During pregnancy, breast cancer most often manifests as a painless mass or thickening. Rarely, breastfeeding women may notice a "milk rejection sign," in which the infant refuses the breast that contains an occult carcinoma. Although pregnant women are more likely to be seen with advanced-stage disease than are nonpregnant women,70 current data are inconclusive regarding the prognosis of women who are diagnosed and treated for breast cancer during pregnancy in comparison with nonpregnant women. Histologic and immunohistochemical findings for breast cancer in pregnancy are similar to those in nonpregnant women of similar age. Any suspicious or persistent breast mass in pregnancy warrants further investigation. Mammography is safe, because the radiation dose to the fetus is negligible with abdominal shielding, but mammography may be associated with high false-positive rates. Core biopsy is preferred over fine-needle aspiration biopsy, which can be misleading in pregnant patients. Use of the services of an experienced pathologist who is aware that the patient is pregnant is preferable. Breast and axillary surgery during any trimester appears to be reasonably safe for the mother and is associated with minimal fetal risk. Axillary lymph node dissection is important, because nodal metastases are common and nodal status may affect the choice of adjuvant therapy. The use of sentinel lymph node dissection is controversial but may safely be performed because absorbed doses of radiolabeled sulfur colloid are well below the fetal threshold. Blue dye is contraindicated and should be avoided because of the risk of a maternal anaphylactic reaction, which could lead to fetal distress. The calculated exposure to the fetus depends on both the dose administered and the gestational age-as much as 20 cGy in early pregnancy and 700 cGy in late pregnancy, which are both above the acceptable limits. If necessary, a balanced discussion of potential risks and harms for the patient and developing fetus should take place. Breast-conserving surgery is an option in the second or early third trimester with neoadjuvant chemotherapy or by itself late in the third trimester. Anthracyclines are believed to be safe, but prospective data and outcomes in children exposed in utero are limited. Trastuzumab causes oligohydramnios and anhydramnios, but severity appears to be linked to the duration of exposure. Long-term use should be avoided, but short-term use appears to be less toxic, and recommendations are to monitor amniotic fluid levels if exposure. Tamoxifen is contraindicated because of its association with spontaneous abortion, birth defects, fetal death, and, in pregnant rats, breast cancer in female offspring. Cervical Cancer Approximately 1% to 3% of women diagnosed with cervical cancer are pregnant or postpartum. As a result, cervical cancer is often detected early, and advanced disease is rare. Symptoms such as vaginal bleeding or discharge may overlap with those of pregnancy. No evidence exists that the relative immunosuppressive state of pregnancy modifies the aggressiveness of human papillomavirus infection. If no evidence of invasive carcinoma is present, treatment can be delayed until after delivery, and patients are followed with colposcopy every trimester with repeat biopsies if progression is suspected. A chest radiograph with abdominal shielding is recommended for evaluation of pulmonary metastases for all patients with more than microscopic cervical cancer. Lymphadenectomy may be indicated for selected patients at significant risk for lymph node metastases if results would alter management, such as delaying treatment. Case reports of successful laparoscopic lymphadenectomy during pregnancy have been published. At delivery, an extrafascial hysterectomy should be offered to women who have completed childbearing. If advanced disease is diagnosed and the fetus is viable, then delivery by cesarean section is recommended, followed by commencement of therapy. Neoadjuvant chemotherapy is a consideration if treatment needs to be delayed for fetal indications. Standard chemotherapy consists of cisplatin and paclitaxel every 3 weeks without bevacizumab, which is contraindicated in pregnancy. Because of existing evidence that cisplatin can concentrate in the amniotic fluid, delivery should be delayed when possible until at least 3 weeks after the last dose of chemotherapy. For epithelial tumors, a single-agent platinum derivative, favoring carboplatin over cisplatin, with or without the addition of paclitaxel is recommended with a goal of six cycles of total chemotherapy. There are some limited data on safe use of combination therapy with carboplatin and paclitaxel after the second trimester. Experience with this combination of agents in the latter trimesters of pregnancy is limited but has been associated with prematurity and ventriculomegaly in only one report. Melanoma Around one-third of women diagnosed with melanoma are of childbearing age, and a 2015 Swedish population study found it to be the most common cancer in pregnant women. Sentinel lymph node biopsy has been performed; as in breast cancer, it is recommended to avoid blue dye. The use of radiocolloid (technetium-99) alone, even when the injection site is close to the fetus, involves low radiation exposure and is likely safe. An approach to the management of pregnant women with high-risk melanoma has been published. Gestational trophoblastic disease is a highly malignant vascular neoplasm of the cytotrophoblast and syncytiotrophoblast that readily metastasizes, and it can be preceded by any gestational event; most arise after a hydatidiform mole or a spontaneous abortion or after a normal pregnancy. Simultaneous gestational trophoblastic disease in the mother and infant is rare but may be curable in both if it is recognized and treated early. Colorectal Cancer Colorectal cancer during pregnancy is rare, occurring in approximately 0. Sigmoidoscopy is safe and usually adequate, given the prevalence of distal tumors in pregnancy. Although the safety of colonoscopy during pregnancy is not well established, the limited literature suggests no increase in adverse outcome to the mother or fetus.

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