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Opioids are a critical component of pain relief strategies for the management of patients with cancer and sickle cell disease. The escalation of opioid addiction and overdose in the United States has led to increased scrutiny of opioid prescribing practices. Multiple reports have revealed that regulatory and coverage policies, intended to curb inappropriate opioid use, have created significant barriers for many patients. The Centers for Disease Control and Prevention, National Comprehensive Cancer Network, and ASCO each publish clinical practice guidelines for the management of chronic pain. A recent JAMA Oncology article highlighted perceived variability in recommendations among these guidelines. In response, leadership from guideline organizations, government representatives, and authors of the original article met to discuss challenges and solutions. The meeting featured remarks by the Commissioner of Food and Drugs, presentations on each clinical practice guideline, an overview of the pain management needs of patients with sickle cell disease, an overview of perceived differences among guidelines, and a discussion of differences and commonalities among the guidelines. The meeting revealed that although each guideline varies in the intended patient population, target audience, and methodology, there is no disagreement among recommendations when applied to the appropriate patient and clinical situation. It was determined that clarification and education are needed regarding the intent, patient population, and scope of each clinical practice guideline, rather than harmonization of guideline recommendations. Clinical practice guidelines can serve as a resource for policymakers and payers to inform policy and coverage determinations.

Opioids are a critical component of pain relief strategies for the management of patients with cancer and sickle cell disease. The escalation of opioid addiction and overdose in the United States has led to increased scrutiny of opioid prescribing practices. Multiple reports have revealed that regulatory and coverage policies, intended to curb inappropriate opioid use, have created significant barriers for many patients. The Centers for Disease Control and Prevention, National Comprehensive Cancer Network, and American Society of Clinical Oncology each publish clinical practice guidelines for the management of chronic pain. A recent JAMA Oncology article highlighted perceived variability in recommendations among these guidelines. In response, leadership from guideline organizations, government representatives, and authors of the original article met to discuss challenges and solutions. The meeting featured remarks by the Commissioner of Food and Drugs, presentations on each clinical practice guideline, an overview of the pain management needs of patients with sickle cell disease, an overview of perceived differences among guidelines, and a discussion of differences and commonalities among the guidelines. The meeting revealed that although each guideline varies in the intended patient population, target audience, and methodology, there is no disagreement among recommendations when applied to the appropriate patient and clinical situation. It was determined that clarification and education are needed regarding the intent, patient population, and scope of each clinical practice guideline, rather than harmonization of guideline recommendations. Clinical practice guidelines can serve as a resource for policymakers and payers to inform policy and coverage determinations.

Purpose ASCO provisional clinical opinions (PCOs) offer direction to the ASCO membership after publication or presentation of potential practice-changing data. This PCO addresses second-line hormonal therapy for chemotherapy-naïve men with castration-resistant prostate cancer (CRPC) who range from being asymptomatic with only biochemical evidence of CRPC to having documented metastases but minimal symptoms. Clinical Context The treatment goal for CRPC is palliation. Despite resistance to initial androgen deprivation therapy, most men respond to second-line hormonal therapies. However, guidelines have neither addressed second-line hormonal therapy for nonmetastatic CRPC nor provided specific guidance with regard to the chemotherapy-naïve population. Recent Data Six phase III randomized controlled trials and expert consensus opinion inform this PCO. Provisional Clinical Opinion For men with CRPC, a castrate state should be maintained indefinitely. Second-line hormonal therapy (eg, antiandrogens, CYP17 inhibitors) may be considered in patients with nonmetastatic CRPC at high risk for metastatic disease (rapid prostate-specific antigen doubling time or velocity) but otherwise is not suggested. In patients with radiographic evidence of metastases and minimal symptoms, enzalutamide or abiraterone plus prednisone should be offered after discussion with patients about potential harms, benefits, costs, and patient preferences. Radium-223 and sipuleucel-T also are options. No evidence provides guidance about the optimal order of hormonal therapies for CRPC beyond second-line treatment. Prostate-specific antigen testing every 4 to 6 months is reasonable for men without metastases. Routine radiographic restaging generally is not suggested but can be considered for patients at risk for metastases or who exhibit symptoms or other evidence of progression. Additional information is available at www.asco.org/genitourinary-cancer-guidelines and www.asco.org/guidelineswiki .

PURPOSE To provide 2019 ASCO standards on the safe handling of hazardous drugs. METHODS An Expert Panel was formed, and a systematic review of the literature on closed system transfer devices was performed to May 2017 using PubMed. The Cochrane Database of Systematic Reviews, PubMed, and Google Scholar were used to search for studies of medical surveillance and external ventilation/health effects of exposure to vapors to November 2017. Available standards were considered for endorsement. Public comments were solicited and considered in preparation of the final manuscript. RESULTS The search for primary research found no studies that addressed health outcomes as they relate to the identified interventions of interest. The ASCO Expert Panel endorses the best practices for safe handling of hazardous drugs as issued by the Occupational Safety and Health Administration, US Pharmacopeia Chapter 800, and Oncology Nursing Society with clarifications in four key areas: medical surveillance, closed system transfer devices, external ventilation of containment secondary engineering controls or containment segregated compounding areas, and alternative duties. CONCLUSION The ASCO standards address the need for clear standards concerning safe handling of hazardous oncology drugs. More research is needed in several key areas to quantify the level of risk associated with handling hazardous drugs in current workplace settings where the hierarchy of controls is consistently applied. Additional information is available at www.asco.org/safe-handling-standards .

Purpose.—Clinical use of analytical tests to assess genomic variants in circulating tumor DNA (ctDNA) is increasing. This joint review from the American Society of Clinical Oncology and the College of American Pathologists summarizes current information about clinical ctDNA assays and provides a framework for future research.Methods.—An Expert Panel conducted a literature review on the use of ctDNA assays for solid tumors, including preanalytical variables, analytical validity, interpretation and reporting, and clinical validity and utility.Results.—The literature search identified 1338 references. Of those, 390, plus 31 references supplied by the Expert Panel, were selected for full-text review. There were 77 articles selected for inclusion.Conclusions.—The evidence indicates that testing for ctDNA is optimally performed on plasma collected in cell stabilization or EDTA tubes, with EDTA tubes processed within 6 hours of collection. Some ctDNA assays have demonstrated clinical validity and utility with certain types of advanced cancer; however, there is insufficient evidence of clinical validity and utility for the majority of ctDNA assays in advanced cancer. Evidence shows discordance between the results of ctDNA assays and genotyping tumor specimens, and supports tumor tissue genotyping to confirm undetected results from ctDNA tests. There is no evidence of clinical utility and little evidence of clinical validity of ctDNA assays in early-stage cancer, treatment monitoring, or residual disease detection. There is no evidence of clinical validity or clinical utility to suggest that ctDNA assays are useful for cancer screening, outside of a clinical trial. Given the rapid pace of research, reevaluation of the literature will shortly be required, along with the development of tools and guidance for clinical practice.

Dyspnea is a cardinal symptom of chronic obstructive pulmonary disease (COPD), and its severity and magnitude increases as the disease progresses, leading to significant disability and a negative effect on quality of life. Refractory dyspnea is a common and difficult symptom to treat in patients with advanced COPD. There are many questions concerning optimal management and, specifically, whether various therapies are effective in this setting. The present document was compiled to address these important clinical issues using an evidence-based systematic review process led by a representative interprofessional panel of experts.The evidence supports the benefits of oral opioids, neuromuscular electrical stimulation, chest wall vibration, walking aids and pursed-lip breathing in the management of dyspnea in the individual patient with advanced COPD. Oxygen is recommended for COPD patients with resting hypoxemia, but its use for the targeted management of dyspnea in this setting should be reserved for patients who receive symptomatic benefit. There is insufficient evidence to support the routine use of anxiolytic medications, nebulized opioids, acupuncture, acupressure, distractive auditory stimuli (music), relaxation, hand-held fans, counselling programs or psychotherapy. There is also no evidence to support the use of supplemental oxygen to reduce dyspnea in nonhypoxemic patients with advanced COPD.Recognizing the current unfamiliarity with prescribing and dosing of opioid therapy in this setting, a potential approach for their use is illustrated. The role of opioid and other effective therapies in the comprehensive management of refractory dyspnea in patients with advanced COPD is discussed.

What is the most appropriate follow-up strategy for patients with cervical cancer who are clinically disease-free after receiving primary treatment? For women with cervical cancer who have been treated with curative intent, follow-up includes identification of complications related to treatment and intervention in the event of recurrent disease. Most women who recur with cervical cancer are not curable, however, early identification of recurrence can alter disease management or treatment-planning options, and for those with a central pelvic recurrence and no evidence of distant disease, there is a potential for cure with additional therapy. Follow-up protocols in this population are variable, using a number of tests at a variety of intervals with questionable outcomes. Outcomes of interest included recurrence, survival, and quality of life. The Gynecology Cancer Disease Site Group (dsg) conducted a systematic review of the literature and a narrative review of emerging clinical issues to inform the most appropriate follow-up strategy for patients with cervical cancer. The evidence was insufficient to specify a clinically useful recommended follow-up schedule, and therefore, the expert consensus opinion of the Gynecology Cancer dsg was used to develop recommendations on patient surveillance. The resulting recommendations were reviewed and approved by the Gynecology Cancer dsg and by the Program in Evidence-Based Care Report Approval Panel. An external review by Ontario practitioners completed the final phase of the review process. Feedback from all parties was incorporated to create the final practice guideline. The systematic review of the literature identified seventeen retrospective studies. The Gynecology Cancer dsg used a consensus process to develop recommendations based on the available evidence from the systematic review, the narrative review, and the collective clinical experience and judgment of the dsg members. The recommendations in this practice guideline are based on the expert consensus opinion of the Gynecology Cancer dsg, informed by evidence from retrospective studies. These are some general features of an appropriate follow-up strategy: At a minimum, follow-up visits with a complete physical examination, including a pelvic&ndash, rectal exam and a patient history, should be conducted by a physician experienced in the surveillance of cancer patients. There is little evidence to suggest that vaginal vault cytology adds significantly to the clinical exam in detecting early disease recurrence. Routine use of various other radiologic or biologic follow-up investigations in asymptomatic patients is not advocated, because the role of those investigations has yet to be evaluated in a definitive manner. A reasonable follow-up schedule involves follow-up visits every 3&ndash, 4 months in the first 2 years and every 6&ndash, 12 months in years 3&ndash, 5. Patients should return to annual population-based general physical and pelvic examinations after 5 years of recurrence-free follow-up.

To determine the front-line chemotherapeutic options for women with recurrent, metastatic, or persistent cervical cancer. The Medline, Embase, and Cochrane Library databases were searched for randomized controlled trials (RCTs) comparing chemotherapy regimens for patients with recurrent, metastatic, or persistent cervical cancer. Studies were included if response rate, survival, toxicity, or quality of life data were reported. Fifteen RCTs were identified. The proportion of patients with prior chemoradiotherapy ranged from 0% to 57%. Four of the 15 RCTs detected significant improvements in overall response with combination cisplatin-based chemotherapy when compared with single-agent cisplatin. One of the 15 RCTs reported a significant median survival advantage with topotecan and cisplatin when compared with single-agent cisplatin (9.4 vs 6.5 months,P= 0.017); 57% of patients in this trial had previous chemoradiotherapy. Significant increases in grade 3 and 4 adverse events, especially severe hematologic toxicities, were detected among patients treated with that combination of chemotherapy. Thus, we conclude that cisplatin and topotecan should be discussed as a reasonable treatment option for appropriate patients who may wish to maximize the response and survival benefits associated with combination chemotherapy. Patients should understand that prior chemoradiotherapy with cisplatin may moderate the benefits observed, and that the relative benefits in response and survival outcomes come at the expense of increased toxicity. The improvement in median survival of 2.9 months represents a novel survival benefit in this difficult-to-treat patient population. Further randomized trials are needed to inform the role of single-agent or combination chemotherapy regimens, particularly in patients with prior chemoradiotherapy.

Objective. To determine the optimum follow-up of women who are clinically disease-free following potentially curative treatment for endometrial cancer. Methods. A systematic search of MEDLINE, EMBASE and the Cochrane Library databases (1980 to October 2005) was conducted. Data were pooled across trials to determine overall estimates of recurrence patterns. Results. Sixteen non-comparative retrospective studies were identified. The overall risk of recurrence was 13% for all patients and 3% or less for patients at low risk. Approximately 70% of all recurrences were symptomatic, and 68% to 100% of recurrences occurred within approximately the first 3 years of follow-up. No reliable differences in survival were detected between patients with symptomatic or asymptomatic recurrences nor were differences in patient outcomes reported by type of follow-up strategy employed. Detection of asymptomatic recurrences ranged from 5% to 33% of patients with physical examination, 0% to 4% with vaginal vault cytology, 0% to 14% with chest X-ray, 4% to 13% with abdominal ultrasound, 5% to 21% with abdominal/pelvic CT scan, and 15% in selected patients with CA 125. Conclusions. There is limited evidence to inform whether intensive follow-up schedules with multiple routine diagnostic interventions result in survival benefits any more or less than non-intensive follow-up schedules without multiple routine diagnostic interventions. Routine testing seems to be of limited benefit for patients at low risk of disease. Most recurrences tend to occur in high risk patients within 3 years, and most recurrences involve symptoms. The most appropriate follow-up strategy is likely one based upon the risk of recurrence and the natural history of the disease. Counseling on the potential symptoms of recurrence is extremely important because the majority of patients with recurrences were symptomatic. A proposed routine follow-up schedule is offered.

Objective. To evaluate the chemotherapeutic options for women with advanced or recurrent endometrial cancer. Methods. The MEDLINE, CANCERLIT and the Cochrane Library databases were searched from 1984 to March 2005 for randomized controlled trials (RCTs) comparing chemotherapy regimens in patients with advanced or recurrent endometrial cancer. Studies were included only if patients had measurable or evaluable disease, and/or response rates were reported. Results. Seventeen RCTs compared regimens involving chemotherapy and/or hormonal therapies. Three chemotherapy trials demonstrated a statistically significant difference in response rates between treatment arms, but only one of these trials showed a modest survival advantage. The addition of cisplatin to doxorubicin in two RCTs significantly improved response rates (1.7- to 2.5-fold higher) but did not impact on survival. In two other RCTs using cisplatin and doxorubicin as standard therapy, the addition of paclitaxel improved response rates (57% versus 34%) and median survival (15.3 versus 12.3 months) when combined with cisplatin and doxorubicin but not when combined with doxorubicin only. Toxicity was increased with the three-drug combination. Quality of life was assessed in one trial, which is currently only in abstract form. Medroxyprogesterone acetate (200 mg/day) was effective in one RCT, particularly in patients with well-differentiated, receptor-positive tumors. Conclusions. Combination chemotherapy with doxorubicin and cisplatin results in higher response rates than doxorubicin alone. The addition of paclitaxel to either of these regimens resulted in a small survival advantage in one trial using all three drugs. In light of the limited survival advantage associated with this regimen, the use of less toxic combinations of taxanes with carboplatin requires further study. Medroxyprogesterone acetate is useful in selected patients.

Prostate cancer is the second leading cause of cancer death among American men.1,2 Recent epidemiologic trends have shown a lower proportion of men diagnosed with advanced prostate cancer and a steady decrease in prostate cancer mortality rates, with an estimated number of deaths exceeding 30,000 deaths in 20113 and 28,000 in 2012.4 Whether prostate cancer screening with prostate-specific antigen (PSA) testing is a potential explanation for these trends is uncertain. What is known, on the basis of two large and moderate quality randomized trials, is that men tested for PSA had significantly more prostate cancer detected when compared with men who did not receive PSA testing.5,6 To date, this has resulted in a significant reduction in prostate cancer–specific mortality in one of the randomized trials,6 but no difference in overall mortality detected in either of the trials.5,6 There are well-known limitations associated with the randomized trials7–9; however, they currently represent the best evidence on the topic. Recommendations from major organizations in the United States vary widely on the topic of PSA testing for prostate cancer screening.10–15 The rationale for PSA testing is the detection of prostate cancer at a stage that is potentially curable. There is evidence of an approximate 20% reduction in prostate-specific mortality over time, but the extent to which PSA screening may play a role is unclear.6 It is difficult to predict for individual men whether treatment of prostate cancer identified through screening will lead to this benefit. For many men, it will not. Approximately three out of four elevated PSA test results turn out to be false positive for prostate cancer. In one trial, approximately 167 men out of 1,000 underwent a biopsy after an elevated PSA; of those, approximately 127 did not have prostate cancer.6 The adverse effects associated with prostate biopsies are generally manageable; however, they are on the rise, especially infection-related hospitalizations, and death is a very small but real possibility.16,17 For those who do have prostate cancer, a large proportion will ultimately be diagnosed and treated for low-risk disease that may not have presented itself clinically during their lifetimes. Thus, with benefit for some (lower prostate cancer–specific mortality) and harm for others (overdiagnosis, overtreatment, and adverse events), it is important for physicians and their patients to consider whether to have PSA levels tested and to determine the likely course of action if the PSA level is suspicious for prostate cancer. Options include doing nothing, checking PSA again at a certain time point, or undergoing a prostate biopsy. Men's clinician-informed choices should depend largely on their values and preferences and how they weigh the available information. Recommendations ASCO's PSA Testing Expert Panel based their recommendations on a systematic review of recent (March 2012) evidence on the benefits and harms of PSA-based screening. Journal of Clinical Oncology (JCO) published the Provisional Clinical Opinion (PCO) in July 2012.18 The Bottom Line Box includes the recommendations from the PCO with permission from JCO. A decision aid and PowerPoint slide set are available as Data Supplements to this article and through the ASCO Web site at www.asco.org/pco/psa. Authors The PSA Testing for Prostate Cancer Screening PCO was developed and written by Ethan Basch, Thomas K. Oliver, Andrew J. Vickers, Ian Thompson, Philip W. Kantoff, Howard L. Parnes, Andrew Loblaw, Bruce J. Roth, Jim Williams, and Robert K. Nam THE BOTTOM LINE PSA SCREENING FOR PROSTATE CANCER: ASCO PROVISIONAL CLINICAL OPINION Clinical Question For asymptomatic men in the general population, do the benefits of PSA screening for prostate cancer outweigh the potential harms? Population of Interest Asymptomatic men from the general population considering PSA-based screening for prostate cancer. Target Audience Primary health care providers and asymptomatic men from the general population are the primary audience; however, it also applies to oncologists and other health care providers who treat patients for whom this PCO may apply. Interventions and Comparisons As part of prostate cancer screening for asymptomatic men in the general population: PSA testing compared with no PSA testing. Recommendations Based on the identified evidence and the expert opinion of the panel: In men with a life expectancy ≤ 10 years,* it is recommended that general screening for prostate cancer with total PSA be discouraged, because harms appear to outweigh potential benefits. Type and strength of recommendation: evidence-based, strong Strength of evidence: Moderate, based on five randomized controlled trials (RCTs) with intermediate to high risk of bias, moderate follow-up, and limited data on subgroup populations In men with a life expectancy >10 years*, it is recommended that physicians discuss with their patients whether PSA testing for prostate cancer screening is appropriate for them. PSA testing may save lives but is associated with harms, including complications, from unnecessary biopsy, surgery, or radiation treatment. Type and strength of recommendation: evidence-based, strong Strength of evidence: for benefit, moderate; for harm, strong; based on five five RCTs (and several cohort studies) with intermediate to high risk of bias, moderate follow-up, indirect data, inconsistent results, and limited data on subgroup populations It is recommended that information written in lay language be available to clinicians and their patients to facilitate the discussion of the benefits and harms associated with PSA testing prior to the routine ordering of a PSA test. Type and strength of recommendation: Informal consensus, strong Strength of evidence: Indeterminate. Evidence was not systematically reviewed to inform this recommendation; however, randomized trials are available on the topic * Calculation of life expectancy is based on a variety of individual factors and circumstances. A number of life expectancy calculators (eg, http://www.socialsecurity.gov/OACT/population/longevity.html) are available in the public domain; however, ASCO does not endorse any one calculator over another.

Purpose To provide treatment recommendations for men with metastatic castration-resistant prostate cancer (CRPC). Methods The American Society of Clinical Oncology and Cancer Care Ontario convened an expert panel to develop evidence-based recommendations informed by a systematic review of the literature. Results When added to androgen deprivation, therapies demonstrating improved survival, improved quality of life (QOL), and favorable benefit-harm balance include abiraterone acetate/prednisone, enzalutamide, and radium-223 (223Ra; for men with predominantly bone metastases). Improved survival and QOL with moderate toxicity risk are associated with docetaxel/prednisone. For asymptomatic/minimally symptomatic men, improved survival with unclear QOL impact and low toxicity are associated with sipuleucel-T. For men who previously received docetaxel, improved survival, unclear QOL impact, and moderate to high toxicity risk are associated with cabazitaxel/prednisone. Modest QOL benefit (without survival benefit) and high toxicity risk are associated with mitoxantrone/prednisone after docetaxel. No benefit and excess toxicity are observed with bevacizumab, estramustine, and sunitinib. Recommendations Continue androgen deprivation (pharmaceutical or surgical) indefinitely. Abiraterone acetate/prednisone, enzalutamide, or 223Ra should be offered; docetaxel/prednisone should also be offered, accompanied by discussion of toxicity risk. Sipuleucel-T may be offered to asymptomatic/minimally symptomatic men. For men who have experienced progression with docetaxel, cabazitaxel may be offered, accompanied by discussion of toxicity risk. Mitoxantrone may be offered, accompanied by discussion of limited clinical benefit and toxicity risk. Ketoconazole or antiandrogens (eg, bicalutamide, flutamide, nilutamide) may be offered, accompanied by discussion of limited known clinical benefit. Bevacizumab, estramustine, and sunitinib should not be offered. There is insufficient evidence to evaluate optimal sequences or combinations of therapies. Palliative care should be offered to all patients.

This study aims to provide recommendations on the optimal strategies and interventions for the prevention, screening, assessment, and management of cancer-related sleep disturbance (insomnia and insomnia syndrome) in adult cancer populations.A systematic search of the published health literature was conducted to identify randomized controlled trials, clinical practice guidelines, systematic reviews, and other guidance documents. The Sleep Disturbance Expert Panel [comprised of nurses, psychologists, primary care physicians, oncologists, physicians specialized in sleep disturbances, researchers, and guideline methodologists] reviewed, discussed, and approved the final version of the guideline. Health care professionals across Canada were asked to provide feedback through an external review process.Three clinical practice guidelines and 12 randomized controlled trials were identified as the evidence base. Overall, despite the paucity of evidence, the evidence and expert consensus suggest that it is important to screen and assess adult cancer patients for sleep disturbances using standardized screening tools on a routine basis. While prevention of sleep disturbance is the desired objective, cognitive behavioral therapies are effective in improving sleep outcomes. As part of the external review with 16 health care providers, 81 % indicated that they agreed with the recommendations as written.Sleep difficulty is a prevalent problem in cancer populations that needs greater recognition by health professionals. Prevention, screening, assessment, and treatment strategies supported by the best available evidence are critical. Recommendations and care path algorithms for practice are offered.

In Canada, approximately 4,400 women are diagnosed with endometrial cancer each year and approximately 800 die from the disease [1]. The majority of patients present with early-stage disease and this is reflected in an overall 5-year survival rate of approximately 85 % [1]. Five-year survival rates range from approximately 96 % for patients with local disease, 66 % for those with regional disease, and 25 % for those with more advanced disease [2]. Factors predictive of recurrence and survival include lymph node status, histological type, histological grade, stage of disease, depth of myometrial invasion, lymphovascular space involvement, and cervical involvement [3].

Cervical cancer is the second most common cancer worldwide, resulting in approximately 275,000 deaths yearly [1]. In Canada, approximately 1,350 Canadian women are diagnosed annually, and approximately 400 women per year die from their disease [2]. According to the SEER database, approximately 50 % of patients are diagnosed with local disease (stage IA or IB) that is confined to the cervix, while 35 % are diagnosed with locoregional disease that has extended beyond the cervix but not to the pelvic wall or the lower third of the vagina (stage IIA or IIB). The remaining patients represent those with more advanced disease (stage III or IV) that has spread to the lower third of the vagina, the pelvic wall, or beyond (11 %). For a small proportion of patients (5 %), staging information was not available [3]. The 5-year survival rates were approximately 92 % for patients with local disease, 58 % with locoregional disease, and 17 % with distant disease [3].

Purpose An American Society of Clinical Oncology (ASCO) provisional clinical opinion (PCO) offers timely clinical direction to the ASCO membership after publication or presentation of potentially practice-changing data from major studies. This PCO addresses the role of prostate-specific antigen (PSA) testing in the screening of men for prostate cancer. Clinical Context Prostate cancer is the second leading cause of cancer deaths among men in the United States. The rationale for screening men for prostate cancer is the potential to reduce the risk of death through early detection. Recent Data Evidence from a 2011 Agency for Healthcare Research and Quality systematic review primarily informs this PCO on the benefits and harms of PSA-based screening. An update search was conducted to March 16, 2012, for additional evidence related to the topic. Results In one randomized trial, PSA testing in men who would not otherwise have been screened resulted in reduced death rates from prostate cancer, but it is uncertain whether the size of the effect was worth the harms associated with screening and subsequent unnecessary treatment. Although there are limitations to the existing data, there is evidence to suggest that men with longer life expectancy may benefit from PSA testing. Adverse events associated with prostate biopsy are low for the majority of men; however, several population-based studies have shown increasing rates of infectious complications after prostate biopsy, which is a concern. Provisional Clinical Opinion On the basis of identified evidence and the expert opinion of the panel ( Table 1 provides a description of how recommendations and evidence are rated): In men with a life expectancy ≤ 10 years,* it is recommended that general screening for prostate cancer with total PSA be discouraged, because harms seem to outweigh potential benefits. Type and strength of recommendation. Evidence based: strong. Strength of evidence. Moderate: based on five randomized clinical trials (RCTs) with intermediate to high risk of bias, moderate follow-up, and limited data on subgroup populations. In men with a life expectancy > 10 years,* it is recommended that physicians discuss with their patients whether PSA testing for prostate cancer screening is appropriate for them. PSA testing may save lives but is associated with harms, including complications, from unnecessary biopsy, surgery, or radiation treatment. Type and strength of recommendation. Evidence based: strong. Strength of evidence. For benefit, moderate; for harm, strong: based on five RCTs (and several cohort studies) with intermediate to high risk of bias, moderate follow-up, indirect data, inconsistent results, and limited data on subgroup populations. It is recommended that information written in lay language be available to clinicians and their patients to facilitate the discussion of the benefits and harms associated with PSA testing before the routine ordering of a PSA test. Type and strength of recommendation. Informal consensus: strong. Strength of evidence. Indeterminate: evidence was not systematically reviewed to inform this recommendation; however, randomized trials are available on the topic. *Calculation of life expectancy is based on a variety of individual factors and circumstances. A number of life expectancy calculators (eg, http://www.socialsecurity.gov/OACT/population/longevity.html) are available in the public domain; however, ASCO does not endorse any one calculator over another. NOTE. ASCO PCOs reflect expert consensus based on clinical evidence and literature available at the time they are written and are intended to assist physicians in clinical decision making and identify questions and settings for further research. Because of the rapid flow of scientific information in oncology, new evidence may have emerged since the time a PCO was submitted for publication. PCOs are not continually updated and may not reflect the most recent evidence. PCOs cannot account for individual variation among patients and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It is the responsibility of the treating physician or other health care provider, relying on independent experience and knowledge of the patient, to determine the best course of treatment for the patient. Accordingly, adherence to any PCO is voluntary, with the ultimate determination regarding its application to be made by the physician in light of each patient's individual circumstances. ASCO PCOs describe the use of procedures and therapies in clinical practice and cannot be assumed to apply to the use of these interventions in the context of clinical trials. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of ASCO PCOs or for any errors or omissions.

Context Lung cancer is the leading cause of cancer death. Most patients are diagnosed with advanced disease, resulting in a very low 5-year survival. Screening may reduce the risk of death from lung cancer. Objective To conduct a systematic review of the evidence regarding the benefits and harms of lung cancer screening using low-dose computed tomography (LDCT). A multisociety collaborative initiative (involving the American Cancer Society, American College of Chest Physicians, American Society of Clinical Oncology, and National Comprehensive Cancer Network) was undertaken to create the foundation for development of an evidence-based clinical guideline. Data Sources MEDLINE (Ovid: January 1996 to April 2012), EMBASE (Ovid: January 1996 to April 2012), and the Cochrane Library (April 2012). Study Selection Of 591 citations identified and reviewed, 8 randomized trials and 13 cohort studies of LDCT screening met criteria for inclusion. Primary outcomes were lung cancer mortality and all-cause mortality, and secondary outcomes included nodule detection, invasive procedures, follow-up tests, and smoking cessation. Data Extraction Critical appraisal using predefined criteria was conducted on individual studies and the overall body of evidence. Differences in data extracted by reviewers were adjudicated by consensus. Results Three randomized studies provided evidence on the effect of LDCT screening on lung cancer mortality, of which the National Lung Screening Trial was the most informative, demonstrating that among 53 454 participants enrolled, screening resulted in significantly fewer lung cancer deaths (356 vs 443 deaths; lung cancer−specific mortality, 247 vs 309 events per 100 000 person-years for LDCT and control groups, respectively; relative risk, 0.80; 95% CI, 0.73-0.93; absolute risk reduction, 0.33%; P = .004). The other 2 smaller studies showed no such benefit. In terms of potential harms of LDCT screening, across all trials and cohorts, approximately 20% of individuals in each round of screening had positive results requiring some degree of follow-up, while approximately 1% had lung cancer. There was marked heterogeneity in this finding and in the frequency of follow-up investigations, biopsies, and percentage of surgical procedures performed in patients with benign lesions. Major complications in those with benign conditions were rare. Conclusion Low-dose computed tomography screening may benefit individuals at an increased risk for lung cancer, but uncertainty exists about the potential harms of screening and the generalizability of results.

The Canadian Thoracic Society (CTS) published an executive summary of guidelines for the diagnosis and treatment of sleep disordered breathing in 2006/2007. These guidelines were developed during several meetings by a group of experts with evidence grading based on committee consensus. These guidelines were well received and the majority of the recommendations remain unchanged. The CTS embarked on a more rigorous process for the 2011 guideline update, and addressed eight areas that were believed to be controversial or in which new data emerged. The CTS Sleep Disordered Breathing Committee posed specific questions for each area. The recommendations regarding maximum assessment wait times, portable monitoring, treatment of asymptomatic adult obstructive sleep apnea patients, treatment with conventional continuous positive airway pressure compared with automatic continuous positive airway pressure, and treatment of central sleep apnea syndrome in heart failure patients replace the recommendations in the 2006/2007 guidelines. The recommendations on bariatric surgery, complex sleep apnea and optimum positive airway pressure technologies are new topics, which were not covered in the 2006/2007 guidelines.

Objective To determine the optimal recommended program for the follow-up of patients who are disease free after completed primary therapy for cervical cancer. Methods Systematic search of MEDLINE, EMBASE and the Cochrane Library databases (1980–November 2007). Results Seventeen retrospective trials were identified. Most studies reported similar intervals for follow-up and ranged from a low of 9 visits to a high of 28 visits over 5 years. Follow-up visits typically occurred once every 3–4 months for the first 2 years, every 6 months for the next 3 years and then annually until year 10. All 17 trials reported that a physical exam was performed at each visit. Vaginal vault cytology was analyzed in 13 trials. Other routine surveillance tests included chest x-ray, ultrasound, CT scans, MRI, intravenous pyelography and tumour markers. Median time to recurrence ranged from 7–36 months after primary treatment. Rates of recurrence ranged from 8–26% with 14–57% of patients recurring in the pelvis, and 15–61% of patients recurring at distant or multiple sites. Of the 8–26% of patients who experienced disease recurrence, the vast majority, 89–99%, had recurred by year 5. Upon recurrence, median survival was 7–17 months. Asymptomatic recurrent disease was detected using physical exam in 29–71%, chest x-ray in 20–47%, CT in 0–34% and vaginal vault cytology in 0–17% of patients, respectively. Conclusion There is modest low quality evidence to inform the most appropriate follow-up strategy for patients with cervical cancer who are clinically disease free after receiving primary treatment. Follow-up visits should include a complete physical examination whereas, frequent vaginal vault cytology does not add significantly to the detection of early disease recurrence. Patients should return to annual population-based screening after 5 years of recurrence-free follow-up.

What is the role of hormonal therapy as adjuvant therapy in patients with stage i endometrial cancer? There is little consensus on the role of adjuvant treatment for patients with stage i endometrial cancer. Although the use of hormonal therapy has been established in advanced disease, less agreement has emerged concerning the benefits of adjuvant hormonal therapy for patients with early-stage disease. The objective of the present evidence series was to review the existing literature on the role of hormonal therapy as adjuvant therapy in patients with stage i endometrial cancer. Reports were sought that included at least one of the following outcomes: overall survival, disease-free survival, recurrence (local, or distant, or both), adverse effects, and quality of life. Because of the potential for long-term adverse effects with adjuvant hormonal treatment in this patient population, especially with regard to thromboembolic or cardiovascular events, the rates of non-cancer-related death were also of interest. The medline, embase, and Cochrane Library databases were systematically searched for randomized controlled trials, practice guidelines, systematic reviews, and meta-analyses. The resulting evidence informed the development of the clinical practice guideline. The systematic review with meta-analyses and practice guideline were approved by the Report Approval Panel of the Program in Evidence-Based Care, and by the Gynecology Cancer Disease Site Group (dsg). Nine randomized trials and one published meta-analysis comparing adjuvant hormonal therapy with no adjuvant therapy in women with stage i endometrial cancer constituted the evidence base. One trial reported a statistically significant survival benefit with adjuvant progestogen as compared with no further treatment (97% vs. 69%, p < 0.001). In that trial, the treatment group had a higher number of patients with less myometrial invasion, and a lower number of patients with advanced-stage disease. These differences in baseline characteristics between the randomized groups were considered to be clinically important. In addition, the results of that trial were not consistent with those of other trials, and the trial was a source of statistical heterogeneity when data were pooled across trials. In two of the nine randomized trials, statistically significant recurrence-free benefits were detected with adjuvant hormonal therapy as compared with no further therapy. In one trial, the difference between the rates of recurrence was 16%, however, the methodologic concerns related to that that trial limited its relevance. In the other trial, the difference between the rates of recurrence was 5%. In that trial, patients were at a high risk of recurrence. None of the remaining seven randomized trials reported any significant difference in recurrence rates between treatment groups. The meta-analysis identified in the literature detected no statistically significant recurrence-free or overall survival benefit associated with adjuvant hormonal therapy as compared with no adjuvant therapy [odds ratio (or): 1.05, 95% confidence interval (ci): 0.88 to 1.24). Those results are consistent with the results of the meta-analysis in the present report, which included an additional two trials (or: 1.10, 95% ci: 0.91 to 1.34).

What is the optimal chemotherapy treatment for women with recurrent ovarian cancer who have previously received platinum-based chemotherapy? Currently, standard primary therapy for advanced disease involves a combination of maximal cytoreductive surgery and chemotherapy with carboplatin plus paclitaxel or with carboplatin alone. Despite initial high response rates, a large proportion of patients relapse, resulting in a therapeutic challenge. Because these patients are not curable, the goal of therapy becomes improvement in both quality and length of life. The search has therefore been to find active agents for women with recurrent disease following platinum-based chemotherapy. Outcomes of interest included any combination of tumour response rate, progression-free survival, overall survival, adverse events, and quality of life. The medline, embase, and Cochrane Library databases were systematically searched for primary articles and practice guidelines. The resulting evidence informed the development of clinical practice recommendations. The systematic review and recommendations were approved by the Report Approval Panel of the Program in Evidence-Based Care, and by the Gynecology Cancer Disease Site Group (dsg). The practice guideline was externally reviewed by a sample of practitioners from Ontario, Canada. Thirteen randomized trials compared various chemotherapy regimens for patients with recurrent ovarian cancer. In five of the thirteen trials in which 100% of patients were considered sensitive to platinum-containing chemotherapy, further platinum-based combination chemotherapy significantly improved response rates (two trials), progression-free survival (four trials), and overall survival (three trials) when compared with single-agent chemotherapy involving carboplatin or paclitaxel. Only two of these randomized trials compared the same chemotherapy regimens: carboplatin alone versus the combination of carboplatin and paclitaxel. Both trials were consistent in reporting improved survival outcomes with the combination of carboplatin and paclitaxel. In one trial, the combination of carboplatin and gemcitabine resulted in significantly higher response rates and improved progression-free survival when compared with carboplatin alone. Median survival with carboplatin alone ranged from 17 months to 24 months in four trials. In eight of the thirteen trials in which 35%&ndash, 100% of patients had platinum-refractory or -resistant disease, one trial reported a statistically significant 2-month improvement in overall survival with liposomal doxorubicin as compared with topotecan (15 months vs. 13 months, p = 0.038, hazard ratio: 1.23, 95% confidence interval: 1.01 to 1.50). In that trial, because of the limited clinical benefit and the unusual finding that a survival difference emerged only after a year of treatment with no corresponding improvement in the rate of response or of progression-free survival, the authors concluded that further confirmation by results from randomized trials were needed to establish the superiority of one agent over another in their trial. In one trial, topotecan was superior to treosulphan in patient progression-free survival by a span of approximately 2 months (5.4 months vs. 3.0 months, p < 0.001). Toxicity was reported in all of the randomized trials, and although data on adverse events varied by treatment regimen, the observed adverse events correlated with known toxicity profiles. As expected, combination chemotherapy was associated with higher rates of adverse events.

Objective To develop clinical practice guidelines for cervical screening and the primary management of abnormal cytology in Ontario, using an established methodological process. Data Sources Primary data sources were relevant articles listed in the Medline (1998 to July 2004), Embase (1998 to July 2004), and Cochrane Library (2004, Issue 2) databases. Study Selection Studies addressing quality or the optimization of cervical screening were considered eligible in the systematic review of the evidence. Specifically, clinical practice guidelines, technology assessments, systematic reviews, and randomized controlled trials were of primary interest. Given the variability of the data, other information sources were considered eligible if there was a demonstrated gap in the published literature. Data Extraction Data were identified and extracted by a methodologist and reviewed by four authors. Results were reviewed and discussed by members of an expert working group consisting of a diverse group of health professionals with expertise in cervical cancer. Data audits were conducted by independent reviewers. Data Synthesis Recommendations with evidence ratings were developed through a review of the evidence with expert consensus and were approved by more than 80% of 40 external practitioners who reviewed the document and responded to a standardized survey. Conclusion The development of comprehensive recommendations on cervical screening in Ontario was feasible using a rigorous methodological process. Recommendations for practice are provided.

Methods In an observer blind, phase 2 trial, 55 adults were randomized to receive one dose of Ad35.CS.01 vaccine followed by two doses of RTS,S/AS01 (ARR-group) or three doses of RTS,S/AS01 (RRR-group) at months 0, 1, 2 followed by controlled human malaria infection. Results ARR and RRR vaccine regimens were well tolerated. Efficacy of ARR and RRR groups after controlled human malaria infection was 44% (95% confidence interval 21%-60%) and 52% (25%-70%), respectively. The RRR-group had greater anti-CS specific IgG titers than did the ARR-group. There were higher numbers of CS-specific CD4 T-cells expressing > 2 cytokine/activation markers and more ex vivo IFN-γ enzyme-linked immunospots in the ARR-group than the RRR-group. Protected subjects had higher CS-specific IgG titers than non-protected subjects (geometric mean titer, 120.8 vs 51.8 EU/ml, respectively; P = .001). Conclusions An increase in vaccine efficacy of ARR-group over RRR-group was not achieved. Future strategies to improve upon RTS,S-induced protection may need to utilize alternative highly immunogenic prime-boost regimens and/or additional target antigens. Trial Registration ClinicalTrials.gov NCT01366534

Objectives. To evaluate the role of intraperitoneal (IP) chemotherapy as part of primary treatment in patients with advanced ovarian cancer and to develop standards of care within the context of current clinical practice. Methods. A multidisciplinary expert panel, convened to develop standards on the use of IP chemotherapy, searched the MEDLINE, EMBASE, and Cochrane Library databases up to December 2006 for randomized trials or published standards on the efficacy and/or delivery of IP chemotherapy. Results. Eight randomized trials comparing IP chemotherapy versus intravenous (IV) chemotherapy were identified. Three trials reported statistically significant improvements in median survival of 8.0, 11.0, and 15.9 months with cisplatin-based IP chemotherapy. In one trial, the 15.9-month improvement in median overall survival (RR=0.75, 95% CI=0.58–0.97) represented a 25% reduction in the risk of death with IP chemotherapy. Severe adverse events and catheter-related complications were often dose limiting with IP chemotherapy. Using a consensus-based approach with a nationally representative panel, multidisciplinary care standards were developed to review medical and surgical criteria, the practice setting, volume requirements, and the institutional criteria required to safely deliver IP chemotherapy. Conclusion. The survival benefits with cisplatin-based IP chemotherapy may represent a significant improvement in the outlook for select patients with advanced ovarian cancer. The delivery of IP chemotherapy is more challenging than the IV route; however, severe adverse events and catheter-related complications may be offset through research defining the optimum treatment regimen, and the standardization of care. System-wide standards for the delivery of IP chemotherapy in Canada for patients with optimally debulked stage III ovarian cancer are offered.

The article by Abenhaim and colleagues in this issue presents an interesting case–control study that attempts to determine the risk of ovarian cancer associated with health care use by comparing the medical history of women with and without ovarian cancer.[1][1] In this large study, 668 women with

Prompt medical and particularly surgical therapy has caused a marked improvement in the survival of infants with necrotizing enterocolitis. In this series, the second largest reported to date, the survival is 67 per cent.

Hypoglycemia was observed in five of 16 (31 per cent) consecutively studied infants with moderate to severe erythroblastosis fetalis. Hyperinsulinemia was documented in each of four infants on whom measurements were made. All infants with erythroblastosis fetalis should have measurements of blood glucose levels in the first hours of life and after exchange transfusion. If hypoglycemia develops in an infant with erythroblastosis fetalis he should be treated with glucose given intravenously.

GENERALLY SPEAKING, major pulmonary resectional surgery is contraindicated in patients with severe restrictive pulmonary insufficiency. Nonetheless, such surgery may be necessary when a patient has a collapsed and infected lung in addition to the restriction. In this situation hypoxemia may occur because of continued perfusion of the nonventilated lung. Furthermore, a patient with this condition is continually threatened by either infection of the uninvolved lung or metastatic infection. This case is presented to demonstrate that pneumonectomy was successfully performed in a patient with severe respiratory paralysis secondary to poliomyelitis. Report of a Case A 22-year-old white male had the onset of bulbospinal poliomyelitis in July, 1957, while stationed in Korea with the armed forces. He was placed in a tank respirator on the fifth day of illness and on the next day a tracheostomy was performed. Chest pain and low-grade fever occurred during the fifth week of illness, at which

Poisoning due to prolonged ingestion of large amounts of vitamin A occurs primarily in children receiving excessive vitamin dosage. Occasional cases are seen in adults because of the very high level of vitamin A used in some disorders. Apparently on an empirical basis, 1000 to 500,000 I. U. daily have been advised in treatment or prophylaxis of the common cold, acne, a variety of dermatoses with particular selection of those exhibiting hyperkeratosis, ocular diseases manifesting themselves by night blindness or corneal degeneration, and sometimes in otologic, gynecologic, renal, and enteric disorders. Indications for such use of vitamin A are not clearly established, and serious doubt exists as to the value of this type of treatment. Since 5000 to 7000 I. U. are recommended as the minimum daily requirement for adults, it is apparent that a very wide range exists between actual need and toxic levels of vitamin A. Manifestations of

The question of safety has been raised by the recent evidence that levels of hexachlorophene in the blood of newborn infants receiving daily baths with a 3% solution are close to levels which are neurotoxic for adult rats. Hexachlorophene is widely used in newborn nurseries, but techniques vary considerably; they range from meticulous, double, early bathing followed by daily baths, to alternate day washing with a diluted solution followed by rinsing off. Blood levels associated with leg weakness progressing to paralysis in the adult rat with chronic oral administration have ranged from 0.985 to 1.48 p.p.m. Toxic manifestations have not been observed nor recognized in newborn infants with "meticulous" daily washing. The chemical is readily absorbed from the skin, resulting in blood levels of 0.009 to 0.646 p.p.m. The compound is excreted as a monoglucuronide in the bile and feces. Convulsions have been reported in an infant 4 days after repeated application of the 3% emulsion to the skin without subsequent rinsing; and, toxic manifestations have been observed in burn patients, but at relatively high serum levels (29 µg/ml), after denuded areas of the skin have been washed with hexachlorophene. It is not known whether or not this substance as currently used on infants is toxic. Although the symptoms observed in adult man and adult rats are similar, the actual blood levels at which symptoms are produced in man appear to be much higher. Symptomatology in the rat with chronic oral administration was accompanied by brain lesions, cerebral edema, and cystic spaces in the white matter of the brain; these lesions were reversible over a period of 6 weeks when hexachlorophene was discontinued.

The following recommendations will appear in the revision of the manual, Standards and Recommendations for Hospital Care of Newborn Infants, scheduled for publication early in 1971. Because the Committee felt a sense of urgency to provide these recommendations to pediatricians, family physicians, and other health professionals caring for newborn infants, they are being published prior to appearance of the manual. The statement has had extensive review by a large number of experts not on the Committee, and their comments and suggestions have been followed in the preparation of the final draft. It was also reviewed and approved by the Committee on Drugs of the Academy at their meeting in San Francisco October 24, 1970. When a newborn infant needs extra oxygen, it must be administered with great care because there is a causal relationship between a higher than normal oxygen tension in arterial blood (60 to 100 mm Hg) and retrolental fibroplasia (retinopathy of prematurity). When the normal O2 tension is exceeded, there is an increased risk of retrolental fibroplasia. The upper limit of arterial oxygen tension and its duration which are safe for these infants is not known. It is probable that even concentrations of 40% of inspired oxygen (formerly considered safe) could be dangerous for some infants. An inspired oxygen concentration of 40% may be insufficient for infants with cardiorespiratory disease to raise the oxygen tension of arterial blood to a normal level. In such instances, an inspired oxygen concentration of 60%, 80%, or higher may be necessary.

Several features of the FAS suggest intrauterine growth retardation. Traditionally, these findings have been ascribed to the direct toxic effects of ethanol (EtOH) or its metabolite, acetaldehyde (AcH). Deprivation of essential fetal nutrients at the placental level (selective fetal malnutrition) has not been considered etiologic. EtOH is known, however, to inhibit membrane transport of amino acids (A-A). We have therefore investigated the effect of EtOH and AcH upon human placental uptake of the actively transported, non-metabolized A-A, α-aminoisobutyric acid (AIB). Term human placental villi were incubated with 14C-AIB in the presence or absence of EtOH (300 mg/dl). No inhibition of uptake was seen at 30, 90 or 150 min. of incubation. However, after 90 min. of incubation with varying concentrations of AcH (readily achieved in the blood of drinking humans), there was significant (p

Recent studies in our laboratories have documented the development of allergic rhinitis (AR) and subsequent ET obstruction after provocative intranasal pollen or house dust mite antigen challenges in hypersensitive subjects. The induced ET obstruction was antigen dose dependent and inversely related to the patient's specific IgE antibody titer. Since prolonged ET obstruction underlies the pathogenesis of otitis media with effusion (OME), these data suggest a role for AR in the etiology of OME. To ascertain if ET obstruction and/or OME develop during natural pollen exposure, weekly bilateral ET function was measured by the 9-step pressure swallow tympanometric test. Eight children ages 5 to 14 years with documented ragweed AR and recurrent OME were studied before, during and after the 1984 ragweed season which was estimated by daily pollen counts. Ragweed allergy was confirmed by positive skin test with serum RAST ranging from 1 to 10 percent. Symptom score and medication diaries were kept. Whereas 9 of 16 ears (56%) showed normal ET function before pollen season and 10 of 16 (63%) after pollen season, only 2 of 15 (13%) had normal ET function at the peak of pollen season and 23 of 75 (30%) ears tested had normal ET function during the 5 week pollen season (p

A recurrent problem in understanding the pathophysiology of the fetal alcohol syndrome (FAS) is separation of the effects of alcohol drinking habits from other social habits (e.g. smoking). Work in this laboratory has suggested that in vivo ethanol (EtOH) and in vitro AcH inhibit A-A transport across the placenta, thereby contributing to the etiology of the FAS. Furthermore, it is known that pharmacologic concentrations of Nic inhibit A-A uptake by human placental villi. Therefore, we investigated the effect of physiologic concentrations of EtOH, AcH and Nic upon in vitro uptake of 14C-α-amino isobutyric acid (AIB) by human placental villi. In 4 experiments with EtOH (200 mg/dl) and Nic (0.2 uM), there was no difference (p > 0.2) (matched pair analysis) in 90 minute uptake of AIB between control (C) and EtOH, Nic or EtOH plus Nic exposed tissue. In 8 additional experiments, there was no difference (p > 0.2) between C and Nic (0.2 uM). AcH (2.0 uM) showed a trend for lowered uptake (% inhibition 11.1 ± 3.7, mean ± SEM) (p < 0.1). However, AcH plus Nic resulted in a significant (p < 0.03) reduction in AIB uptake (% inhibition 22.8 ± 4.9) when compared to C or AcH alone. CONCLUSION: (1) Nic alone, at a concentration found in smokers' sera, does not impair placental uptake of A-A. (2) AcH, at the very low concentration of 2.0 uM, causes slight inhibition of uptake. (3) Nic plus AcH appear to be synergistic, significantly inhibiting placental A-A uptake. Therefore, we speculate that cigarette smoking may potentiate placental insufficiency associated with EtOH ingestion.

A form of autosomal recessive PKD naturally occurs in the mutant CPK strain of C57BL/6J mice. In order to examine the role of enviromental factors in the expression of genetically determined PKD, the organogenesis of CPK kidneys was studied in our previously described MOC system (In Vitro 18:675, 1982). In this system, advanced murine nephrogenesis occurs in a serum-free, completely controlled biochemical environment. Newborn kidneys from controls (CON) and CPK mice were microsliced into 100 μm explants and cultured in Ham's F-12: DMEM supplemented with insulin (8 × 10−7 M), T3 (2 × 10−9M), transferrin (6 × 10−8 M), PGE1(7 × 10−8 M), and Na2SeO3 (7 × 10−9 M) at 36 ± 0.5°C in mixed air:5% CO2. During 120 hours of culture:1) CON explants increased in size and demonstrated advanced tubular differentiation; and 2) CPK explants, which initially exhibited prominent proximal tubular dilatation and cyst formation, demonstrated total cyst regression in addition to overall growth and differentiation similar to CON. We conclude that in the CPK animal model of PKD: 1) early changes of proximal tubular cyst formation are totally reversible in vitro; and therefore that 2) genetically determined cyst formation can be modified by environmental factors. MOC of CPK kidneys provides a controlled experimental system in which the enviromental factors modulating cystic organogenesis may be isolated and further characterized.

We explored the possibility that a critical period exists during the first few months of life, when treatment should be started in order to obtain a normal IQ. Previous publications have not fractionated the first 6 months of therapy for comparison of IQ results by a single test procedure. Thirty-one cretins were tested by Stanford Binet after age 3 years. A significantly higher percentage had IG > 85 when treated before 3 months (Chi-Square p 85 whose parents had no more worries than those of age matched normals. Parents had anxiety about punishment of these children who were characterized as “high strung, stubborn, contrary” and whose “feelings were easily hurt.” Concern was high regarding future education and jobs. Since clinical diagnosis of cretinism is difficult during the first 2 months of life, and since it is as common (1:8,000 live births) as phenylketonuria (1:10,000), a routine screening procedure is warranted. Systematic psychological counseling should be an integral part of therapy.

A review of necropsy material reveals that idiopathic necrotizing enterocolitis was present in 13 of 427 (3.04%) premature infants. In seven of the 13 infants, the diagnosis had been clinically made or strongly suspected. All 13 patients showed variable degrees of pulmonary atelectasis with or without hyaline membranes. The association of necrotizing enterocolitis with the respiratory distress syndrome plus the high incidence of widespread hemorrhagic phenomena observed in these patients suggests that perinatal hypoxia and its effects on vessels may be an important pathogenetic factor. Notably, the hemorrhagic manifestations were most severe in the patients with necrosis of the bowel wall and perforation. There is a possible pathogenetic role of a diving reflex-like phenomenon.

This volume was apparently intended as an introduction to the general problems in poliomyelitis for medical students, nurses, and other paramedical personnel and not for those intensively involved in the care of patients with poliomyelitis. In the former instance it serves its purpose well, but with the one criticism that valuable statistical data are not included. As examples, one would like to have included the incidence of severe paralytic poliomyelitis versus that of the general paralytic disease, the incidence of renal calculi, and the fatality rates in acute paralytic disease and in long-term respirator patients. As a guide for practitioners who are responsible for the care of patients with poliomyelitis, the handbook falls short of its goal. There are errors of omission as well as of commission. Examples of the former include details of functional positioning of the patient in the body respirator, value of spirometry as a guide to

Poisoning due to prolonged ingestion of high doses of vitimain A (hypervitaminosis A) in children 3 years of age and younger was first described more than a decade ago. Several cases have also been reported in adults. Recently two children beyond 3 years of age with chronic vitamin A intoxication have been reported from England. The following report describes an additional case in an older child. Report of Case A 14-year-old white girl * was admitted to The Children's Hospital on Sept. 11, 1956, with the chief complaint of leg pain of five weeks' duration. Two years prior to admission the patient developed superficial, nonpitting acne vulgaris, for which, 10 months prior to admission, 200,000 units of vitamin A daily had been prescribed by a dermatologist. Two months prior to admission she had had her last normal menstrual period, succeeding ones being at the normal interval but scanty and of one

Hyperplasia of the Islets of Langerhans is usually found in fetuses in infants who die as a result of erythroblastosis fetalis (EF) and the pancreas contains levels of insulin comparable to those found in infants of diabetic mothers (IDM). The clinical counterpart of these observations, hypoglycemia, is believed to occur rarely if at all in infants with EF. During the last 18 months we have observed hypoglycemia (< 30 mg/100 ml in term infants; < 20 mg/100 ml pre-term) in 11 infants. Borderline levels have occurred in 2 others. Five of the infants developed hypoglycemia prior to exchange transfusion (ET). Recently 16 consecutive infants with moderate to severe EF have had frequent blood glucose measurements following ET. 6 (30 %) developed symptomatic hypoglycemia with borderline values in 2 others. 9 infants had multiple measurements of blood glucose in the 3 h period following ET and 4 of these had simultaneous measurements of serum immuno active insulin. Serum insulin was elevated in all 4 infants. Glucose disappearance constants (Kt) were calculated for the first hour following ETand compared to Kt values for normals and IDM following IV glucose tolerance tests. The infants with EF who developed hypoglycemia had significantly greater Kt values than did the normals; their values approximated IDM. Because of the necessity for prompt treatment, blood glucose should be measured frequently in infants with EF both after birth and after ET. Intravenous glucose or fructose should be effective in prevention of hypoglycemia. (APS)