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Utkarsh H Acharya, Joanne M Jeter Department of Medicine, Division of Hematology-Oncology, University of Arizona Cancer Center, Tucson, AZ, USA Abstract: Ipilimumab is a monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4 that has been approved by the US Food and Drug Administration for the treatment of metastatic melanoma. Phase III trials have demonstrated an overall survival benefit with its use when compared with standard treatments and other investigational therapies. However, the drug poses a notable challenge, given its propensity for toxicity, and requires close surveillance when administered in clinical practice. This review discusses the mechanism of action for ipilimumab, its preclinical data, and the clinical trials that led to its approval by the Food and Drug Administration in 2011. Keywords: melanoma, immunotherapy, ipilimumab

Purpose: Non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with lower risk of certain cancers, but data on the effect on skin cancer risk have been limited and contradictory. We prospectively examined whether use of NSAIDS or acetaminophen was associated with a lower risk of skin cancer in women.Methods: The 92,125 Caucasian women in the Nurses' Health Study provided information on aspirin use in 1980. Other NSAIDs and acetaminophen were added in 1990. Medication use, frequency, and quantity were reassessed on biennial questionnaires. Through 2008, we confirmed 658 melanoma cases, 1,337 squamous cell carcinoma (SCC) cases, and had 15,079 self-reports of basal cell carcinoma (BCC). We used COX proportional hazards models to compute relative risks (RR) adjusted for known skin cancer risk factors.Results: Neither aspirin nor non-aspirin NSAID use was associated with a lower risk of melanoma, SCC, or BCC, even for women with high quantity, frequency, or duration of use. Instead, we observed an increased risk of melanoma among current aspirin users (RR = 1.32, 95 % CI 1.03-1.70), though an increase of similar magnitude among past users and lack of a dose-response effect did not support a pharmacologic mechanism. We observed a mild reduction in SCC risk in current acetaminophen users (RR = 0.88, 95 % CI 0.75-1.02), with a linear decrease in risk with greater frequency of use (p = 0.04).Conclusions: Aspirin and other NSAIDs were not associated with a lower risk of melanoma, SCC, or BCC in women. Our large, prospective study does not support a chemoprotective effect of NSAIDs against skin cancers. [ABSTRACT FROM AUTHOR]

Background : The efficacy of germline testing in colorectal cancer has been proven; however, germline testing in individuals with sebaceous neoplasms is less well defined. This review aims to summarize the literature on sebaceous neoplasms to date, describing the somatic tumor profiles, tumor screening methods, and personal and family history that are suspicious of a germline mutation. Sebaceous neoplasms can be attributed to a variety of etiologies, including UV exposure, immunodeficiency, germline mutations, or multifactorial influences associated with aging. Sebaceous tumors with abnormal microsatellite instability and mismatch repair deficiency are indicative of a germline mutation in 20-50% of cases, which is similar to rates found in colorectal tumors. Personal and familial history can also be suggestive of a germline etiology in these patients and should be assessed routinely, as approximately 30% of individuals with sebaceous neoplasms carry a germline mutation. We outline a strategy for the identification of individuals at risk for germline mutations, recommendations for the management of mutation carriers, and treatment options for individuals with sebaceous neoplasms. Conclusions : Sebaceous tumors are most often sporadic; however, evaluations of a germline etiology are prudent to effectively identify those at risk of additional malignancies as well as at-risk family members. Referral to genetic counseling and germline genetic testing for individuals at risk can significantly impact cancer treatment and screening in patients and their families.

Background: Although universal germline genetic testing is recommended for patients with exocrine pancreatic cancer (PC), access to genetic testing remains limited in low- and middle-income countries. This study aims to narrow the gap in our understanding of the spectrum of germline pathogenic and likely pathogenic variants (PVs) in cancer susceptibility genes in the Mexican population., Methods: The landscape of PVs in cancer susceptibility genes was identified by next-generation sequencing multigene panel assays among patients with PC who were enrolled in the Clinical Cancer Genomics Community Research Network prospective registry in Mexico City., Results: From August 2019 to April 2023, 137 patients underwent genetic testing. The median age at diagnosis was 60 years (range 36-85), 58.4 % were women, and 38.7 % were metastatic at diagnosis. The frequency of germline PVs was 16 % (n = 22): ATM 36.4 % (n = 8), CDKN2A/p16 INK4A 27.3 % (n = 6), BRCA2 9.1 % (n = 2), PALB2 9.1 % (n = 2), CHEK2 9.1 % (n = 2), TP53 4.5 % (n = 1), and NF1 4.5 % (n = 1). Additionally, 2 carriers of monoallelic germline variants in MUTYH were identified. No significant differences were observed between carriers and non-carriers in terms of family history of pancreatic cancer., Conclusions: We identified a significant frequency of actionable germline PVs in Mexicans with PC, wherein the majority were in a broad spectrum of genes associated with the homologous recombination DNA repair mechanism. Most pancreatic cancer associated PVs were detected in non-BRCA genes, so our findings support the recommendation of multigene panel testing for genetic cancer risk assessment of Mexican individuals with PC., (Copyright © 2024 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: Pancreatic adenocarcinoma (PC) is a highly lethal malignancy with a survival rate of only 12%. Surveillance is recommended for high-risk individuals (HRIs), but it is not widely adopted. To address this unmet clinical need and drive early diagnosis research, we established the Pancreatic Cancer Early Detection (PRECEDE) Consortium., Methods: PRECEDE is a multi-institutional international collaboration that has undertaken an observational prospective cohort study. Individuals (aged 18-90 years) are enrolled into 1 of 7 cohorts based on family history and pathogenic germline variant (PGV) status. From April 1, 2020, to November 21, 2022, a total of 3,402 participants were enrolled in 1 of 7 study cohorts, with 1,759 (51.7%) meeting criteria for the highest-risk cohort (Cohort 1). Cohort 1 HRIs underwent germline testing and pancreas imaging by MRI/MR-cholangiopancreatography or endoscopic ultrasound., Results: A total of 1,400 participants in Cohort 1 (79.6%) had completed baseline imaging and were subclassified into 3 groups based on familial PC (FPC; n=670), a PGV and FPC (PGV+/FPC+; n=115), and a PGV with a pedigree that does not meet FPC criteria (PGV+/FPC-; n=615). One HRI was diagnosed with stage IIB PC on study entry, and 35.1% of HRIs harbored pancreatic cysts. Increasing age (odds ratio, 1.05; P<.001) and FPC group assignment (odds ratio, 1.57; P<.001; relative to PGV+/FPC-) were independent predictors of harboring a pancreatic cyst., Conclusions: PRECEDE provides infrastructure support to increase access to clinical surveillance for HRIs worldwide, while aiming to drive early PC detection advancements through longitudinal standardized clinical data, imaging, and biospecimen captures. Increased cyst prevalence in HRIs with FPC suggests that FPC may infer distinct biological processes. To enable the development of PC surveillance approaches better tailored to risk category, we recommend adoption of subclassification of HRIs into FPC, PGV+/FPC+, and PGV+/FPC- risk groups by surveillance protocols.

Background: International chemoprevention preferences and approaches in Lynch syndrome (LS) and APC- associated polyposis, including Familial adenomatous polyposis (FAP) and attenuated FAP (AFAP) have not been previously explored., Aim: To describe current chemoprevention strategies for patients with LS or FAP/AFAP (referred to collectively as FAP) practiced by members of four international hereditary cancer societies through administration of a survey., Results: Ninety-six participants across four hereditary gastrointestinal cancer societies responded to the survey. Most respondents (91%, 87/96) completed information regarding their demographics and practice characteristics relating to hereditary gastrointestinal cancer and chemoprevention clinical practices. Sixty-nine percent (60/87) of respondents offer chemoprevention for FAP and/or LS as a part of their practice. Of the 75% (72/96) of survey respondents who were eligible to answer practice-based clinical vignettes based off of their responses to ten barrier questions regarding chemoprevention, 88% (63/72) of those participants completed at least one case vignette question to further characterize chemoprevention practices in FAP and/or LS. In FAP, 51% (32/63) would offer chemoprevention for rectal polyposis, with sulindac - 300 mg (18%, 10/56) and aspirin (16%, 9/56) being the most frequently selected options. In LS, 93% (55/59) of professionals discuss chemoprevention and 59% (35/59) frequently recommend chemoprevention. Close to half of the respondents (47%, 26/55) would recommend beginning aspirin at time of commencement of the patient's first screening colonoscopy (usually at age 25yrs). Ninety-four percent (47/50) of respondents would consider a patient's diagnosis of LS as an influential factor for aspirin use. There was no consensus on the dose of aspirin (≤100 mg, >100 mg - 325 mg or 600 mg) to offer patients with LS and there was no agreement on how other factors, such as BMI, hypertension, family history of colorectal cancer, and family history of heart disease, would affect the recommendation for aspirin use. Possible harm among older patients (>70 years) was identified as the most common reason to discourage aspirin use., Conclusion: Although chemoprevention is widely discussed and offered to patients with FAP and LS by an international group of hereditary gastrointestinal cancer experts, there is significant heterogeneity in how it is applied in clinical practice., Competing Interests: SA has patents and/or pending patents related to colorectal cancer diagnostics and treatment. SA performs collaborative research with no funding with Caris Life Sciences, Foundation Medicine, Inc., Ambry Genetics, and Invitae Corporation. SA’s spouse is employed by Akoya Biosciences and has stocks in Akoya Biosciences, HTG Molecular Diagnostics, Abcam Plc., and Senzo Health. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mraz, Hodan, Rodgers-Fouche, Arora, Balaguer, Guillem, Jeter, Kanth, Li, Liska, Melson, Perez, Ricker, Shirts, Vilar, Katona and Dominguez-Valentin.)

Five years ago, the Melanoma Research Foundation (MRF) conducted an assessment of the challenges and opportunities facing the melanoma research community and patients with melanoma. Since then, remarkable progress has been made on both the basic and clinical research fronts. However, the incidence, recurrence, and death rates for melanoma remain unacceptably high and significant challenges remain. Hence, the MRF Scientific Advisory Council and Breakthrough Consortium, a group that includes clinicians and scientists, reconvened to facilitate intensive discussions on thematic areas essential to melanoma researchers and patients alike, prevention, detection, diagnosis, metastatic dormancy and progression, response and resistance to targeted and immune-based therapy, and the clinical consequences of COVID-19 for patients with melanoma and providers. These extensive discussions helped to crystalize our understanding of the challenges and opportunities facing the broader melanoma community today. In this report, we discuss the progress made since the last MRF assessment, comment on what remains to be overcome, and offer recommendations for the best path forward., (©2021 American Association for Cancer Research.)

Importance: Use of prognostic gene expression profile (GEP) testing in cutaneous melanoma (CM) is rising despite a lack of endorsement as standard of care., Objective: To develop guidelines within the national Melanoma Prevention Working Group (MPWG) on integration of GEP testing into the management of patients with CM, including (1) review of published data using GEP tests, (2) definition of acceptable performance criteria, (3) current recommendations for use of GEP testing in clinical practice, and (4) considerations for future studies., Evidence Review: The MPWG members and other international melanoma specialists participated in 2 online surveys and then convened a summit meeting. Published data and meeting abstracts from 2015 to 2019 were reviewed., Findings: The MPWG members are optimistic about the future use of prognostic GEP testing to improve risk stratification and enhance clinical decision-making but acknowledge that current utility is limited by test performance in patients with stage I disease. Published studies of GEP testing have not evaluated results in the context of all relevant clinicopathologic factors or as predictors of regional nodal metastasis to replace sentinel lymph node biopsy (SLNB). The performance of GEP tests has generally been reported for small groups of patients representing particular tumor stages or in aggregate form, such that stage-specific performance cannot be ascertained, and without survival outcomes compared with data from the American Joint Committee on Cancer 8th edition melanoma staging system international database. There are significant challenges to performing clinical trials incorporating GEP testing with SLNB and adjuvant therapy. The MPWG members favor conducting retrospective studies that evaluate multiple GEP testing platforms on fully annotated archived samples before embarking on costly prospective studies and recommend avoiding routine use of GEP testing to direct patient management until prospective studies support their clinical utility., Conclusions and Relevance: More evidence is needed to support using GEP testing to inform recommendations regarding SLNB, intensity of follow-up or imaging surveillance, and postoperative adjuvant therapy. The MPWG recommends further research to assess the validity and clinical applicability of existing and emerging GEP tests. Decisions on performing GEP testing and patient management based on these results should only be made in the context of discussion of testing limitations with the patient or within a multidisciplinary group.

The association of BRCA mutation status with hypersensitivity reactions (HSRs) to carboplatin has gained interest in recent years, particularly in patients with ovarian, fallopian tube, and primary peritoneal cancer. The primary objective of this study is to determine whether the presence of BRCA mutations increased the likelihood of HSRs to carboplatin. The incidence of HSRs to paclitaxel and symptom grade based on the Common Terminology Criteria for Adverse Events, version 4.0, were explored as secondary endpoints. A retrospective chart review of patients with ovarian, fallopian tube, or primary peritoneal cancer at the University of Arizona Cancer Center who underwent treatment with carboplatin-containing regimens and received genetic testing was performed. Institutional review board approval was obtained for this study. Fisher's exact test was used to analyze the primary outcome. Out of 167 initial patients, 62 with germline test results constituted the evaluable sample. 15 of 62 (24.2%) BRCA -tested patients were treated with carboplatin monotherapy, while 44 of 62 (71.0%) patients were treated with paclitaxel-containing regimens. Hypersensitivity reactions occurred in 4 of 13 (30.8%) BRCA -mutated patients and 22 of 49 (44.9%) BRCA wild-type patients ( p = .5291). Hypersensitivity reactions to paclitaxel occurred in 1 of 13 (7.7%) BRCA -mutated patients and 26 of 49 (53.1%) BRCA wild-type patients ( p = .0039). Overall, there were 11 grade 1 reactions, 14 grade 2 reactions, and 16 grade 3 reactions to carboplatin. All reactions to carboplatin in BRCA -mutated patients were grade 1. All paclitaxel reactions manifested as grade 2. The sample size was the main study limitation. The presence of BRCA mutations was not statistically significantly associated with a higher incidence of HSRs to carboplatin, but was statistically significant with regards to paclitaxel., Competing Interests: The authors have no conflicts of interest to disclose., (© 2019 Harborside™.)

Recent progress in the treatment of advanced melanoma has led to unprecedented improvements in overall survival and, as these new melanoma treatments have been developed and deployed in the clinic, much has been learned about the natural history of the disease. Now is the time to apply that knowledge toward the design and clinical evaluation of new chemoprevention agents. Melanoma chemoprevention has the potential to reduce dramatically both the morbidity and the high costs associated with treating patients who have metastatic disease. In this work, scientific and clinical melanoma experts from the national Melanoma Prevention Working Group, composed of National Cancer Trials Network investigators, discuss research aimed at discovering and developing (or repurposing) drugs and natural products for the prevention of melanoma and propose an updated pipeline for translating the most promising agents into the clinic. The mechanism of action, preclinical data, epidemiological evidence, and results from available clinical trials are discussed for each class of compounds. Selected keratinocyte carcinoma chemoprevention studies also are considered, and a rationale for their inclusion is presented. These data are summarized in a table that lists the type and level of evidence available for each class of agents. Also included in the discussion is an assessment of additional research necessary and the likelihood that a given compound may be a suitable candidate for a phase 3 clinical trial within the next 5 years., (© 2018 American Cancer Society.)

Background: Non-Hodgkin lymphoma (NHL) is the most common cancer in people with HIV. Although 95% of HIV patients are in developing countries like Peru, the majority of these studies have been conducted in developed countries. In this study we aim to evaluate prognostic factors associated with outcomes in HIV positive patients undergoing systemic therapy for treatment of NHL., Methods: This retrospective study includes patients with NHL seen in the Instituto Nacional de Enfermedades Neoplasicas (INEN) between 2004 to 2014. Patients were divided into two groups: antiretroviral therapy (ART) -naïve ( n  = 34) and those previously treated, ART-exposed ( n  = 13), at the time of diagnosis. All patients received chemotherapy and ART. The medical records were reviewed. Data were analyzed using t-test and chi-square test. Survival curves were estimated by the Kaplan-Meier method and comparison was done by log-rank test. Multivariate analysis for overall survival (OS) was performed with the Cox proportional hazard regression model., Results: All ART-exposed patients were from the capital city ( p  = 0.039); they had significantly lower hemoglobin levels compared to ART-naïve patients ( p  = 0.026). The median OS was 47.7 months with a 5-yr OS of 36.1%. The median OS for ART naïve patients was significantly higher than that for ART-exposed patients (57.05 and 21.09 months, respectively; p  = 0.018). Advanced stage and low serum albumin were associated with lower OS in both groups. Age > 60 was associated with worse outcomes in the ART-naïve cohort., Conclusions: Advanced stage, low serum albumin and previous ART treatment were the primary prognostic factors associated with poorer outcomes in patients with NHL and HIV infection. In ART-naïve patients, age > 60 was associated with worse outcomes but in this cohort, older patients still had better overall outcomes than ART-exposed patients., Competing Interests: The protocol was approved by the Research Ethics Committee of INEN.It was determined that informed consent was not necessary because data was obtained from medical records and anonymized. The clinical and pathological characteristics of the patients at diagnosis were retrieved from the institutional paper medical records and organized in a deidentified database.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Melanoma is usually apparent on the skin and readily detected by trained medical providers using a routine total body skin examination, yet this malignancy is responsible for the majority of skin cancer-related deaths. Currently, there is no national consensus on skin cancer screening in the USA, but dermatologists and primary care providers are routinely confronted with making the decision about when to recommend total body skin examinations and at what interval. The objectives of this paper are: to propose rational, risk-based, data-driven guidelines commensurate with the US Preventive Services Task Force screening guidelines for other disorders; to compare our proposed guidelines to recommendations made by other national and international organizations; and to review the US Preventive Services Task Force's 2016 Draft Recommendation Statement on skin cancer screening., Competing Interests: Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Background: This analysis describes the outcome for patients who received targeted therapy (TT) prior to or following high-dose interleukin-2 (HD IL-2)., Patients and Methods: Patients with renal cell carcinoma (n = 352) receiving HD IL-2 were enrolled in Proleukin R Observational Study to Evaluate the Treatment Patterns and Clinical Response in Malignancy (PROCLAIM SM ) beginning in 2011. Statistical analyses were performed using datasets as of September 24, 2015., Results: Overall, there were 4% complete response (CR), 13% partial response (PR), 39% stable disease (SD), and 43% progressive disease (PD) with HD IL-2. The median overall survival (mOS) was not reached in patients with CR, PR, or SD, and was 15.5 months in patients with PD (median follow-up, 21 months). Sixty-one patients had prior TT before HD IL-2 with an overall response rate (ORR) to HD IL-2 of 19% (1 CR, 9 PR) and an mOS of 22.1 months. One hundred forty-nine patients received TT only after HD IL-2 with an mOS of 35.5 months. One hundred forty-two patients had no TT before or after HD IL-2, and mOS was not reached. The mOS was 8.5 months in PD patients who received HD IL-2 without follow-on TT and 29.7 months in PD patients who received follow-on TT after HD IL-2., Conclusions: HD IL-2 as sole front-line therapy, in the absence of added TT, shows extended clinical benefit (CR, PR, and SD). Patients with PD after HD IL-2 appear to benefit from follow-on TT. Patients who progressed on TT and received follow-on HD IL-2 experienced major clinical benefit. HD IL-2 therapy should be considered in eligible patients., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: A range of doses of supplemental vitamin D has been shown to be effective in preventing rickets in breastfed infants, but the effect of different doses of vitamin D on bone metabolism and mineral content has not been delineated., Methods: In a randomized trial, breastfed infants received from 2 to 9 months daily supplements of vitamin D in doses of 200 IU/d, 400 IU/d, 600 IU/d or 800 IU/d. Measures of bone metabolism (plasma) were determined periodically and bone mineral content (DXA) was determined at study entry and at the end of winter when infants were 5.5 to 9 months old. The main findings have been reported; here we report findings related to bone metabolism., Results: There were no consistent meaningful effects of vitamin D dose on markers of bone metabolism. Some markers showed changes with age. Bone mineral content increased with age but showed no effect of vitamin D dose., Conclusion: Vitamin D in daily doses from 200 IU/d to 800 IU/d had no measurable effect on bone mineral content or bone metabolism of breastfed infants.

Prevention of nonmelanoma skin cancers remains a health priority due to high costs associated with this disease. Diclofenac and difluoromethylornithine (DFMO) have demonstrated chemopreventive efficacy for cutaneous squamous cell carcinomas. We designed a randomized study of the combination of DFMO and diclofenac in the treatment of sun-damaged skin. Individuals with visible cutaneous sun damage were eligible. Subjects were randomized to one of the three groups: topical DFMO applied twice daily, topical diclofenac applied daily, or DFMO plus diclofenac. The treatment was limited to an area on the left forearm, and the duration of use was 90 days. We hypothesized that combination therapy would have increased efficacy compared with single-agent therapy. The primary outcome was change in karyometric average nuclear abnormality (ANA) in the treated skin. Individuals assessing the biomarkers were blinded regarding the treatment for each subject. A total of 156 subjects were randomized; 144 had baseline and end-of-study biopsies, and 136 subjects completed the study. The ANA unexpectedly increased for all groups, with higher values correlating with clinical cutaneous inflammation. Nearly all of the adverse events were local cutaneous effects. One subject had cutaneous toxicity that required treatment discontinuation. Significantly more adverse events were seen in the groups taking diclofenac. Overall, the study indicated that the addition of topical DFMO to topical diclofenac did not enhance its activity. Both agents caused inflammation on a cellular and clinical level, which may have confounded the measurement of chemopreventive effects. More significant effects may be observed in subjects with greater baseline cutaneous damage., (©2015 American Association for Cancer Research.)

Purpose: To assist in determining barriers to an oncology career incorporating cancer prevention, the American Society of Clinical Oncology (ASCO) Cancer Prevention Workforce Pipeline Work Group sponsored surveys of training program directors and oncology fellows., Methods: Separate surveys with parallel questions were administered to training program directors at their fall 2013 retreat and to oncology fellows as part of their February 2014 in-training examination survey. Forty-seven (67%) of 70 training directors and 1,306 (80%) of 1,634 oncology fellows taking the in-training examination survey answered questions., Results: Training directors estimated that ≤ 10% of fellows starting an academic career or entering private practice would have a career focus in cancer prevention. Only 15% of fellows indicated they would likely be interested in cancer prevention as a career focus, although only 12% thought prevention was unimportant relative to treatment. Top fellow-listed barriers to an academic career were difficulty in obtaining funding and lower compensation. Additional barriers to an academic career with a prevention focus included unclear career model, lack of clinical mentors, lack of clinical training opportunities, and concerns about reimbursement., Conclusion: Reluctance to incorporate cancer prevention into an oncology career seems to stem from lack of mentors and exposure during training, unclear career path, and uncertainty regarding reimbursement. Suggested approaches to begin to remedy this problem include: 1) more ASCO-led and other prevention educational resources for fellows, training directors, and practicing oncologists; 2) an increase in funded training and clinical research opportunities, including reintroduction of the R25T award; 3) an increase in the prevention content of accrediting examinations for clinical oncologists; and 4) interaction with policymakers to broaden the scope and depth of reimbursement for prevention counseling and intervention services., Competing Interests: Authors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article., (© 2015 by American Society of Clinical Oncology.)

Objectives: Infant formulas provide more protein than breast milk. High protein intakes may place infants at risk of later obesity. The present study tested whether a formula with protein content below the regulatory level supports normal growth from age 3 months., Methods: Randomized double-blind trial enrolled healthy infants less than age 3 months. At 3 months, formula-fed infants were assigned to experimental (EXPL, 1.61 g protein/100 kcal; modified bovine whey proteins with caseinoglycomacropeptide removed) or control (CTRL 2.15 g protein/100 kcal; unmodified bovine milk protein with a whey/casein ratio of 60/40) formula; breast-fed (BF) infants were enrolled in a reference group. Complementary foods were allowed in small amounts from 4 to 6 months and unrestricted after 6 months., Results: Weight gain (g/day) from 3 to 6 months was similar in the EXPL and CTRL groups (EXPL-CTRL -0.84 g/day; 95% confidence interval -2.25 to 0.57) and faster in the EXPL and CTRL groups than in the BF group. Weight analyzed longitudinally from 4 to 12 months was lower in the EXPL group than in the CTRL group (P = 0.031) but higher than in the BF group (P < 0.0001). Longitudinal analysis of odds ratios from 4 to 12 months indicated fewer infants with weight >85th percentile in the EXPL group than in the CTRL group (P = 0.015). Length z scores were lower than, and body mass index z scores were similar to, World Health Organization Standards in all of the groups. Serum biochemical parameters in the EXPL group reflected lower protein intake and were closer to parameters in the BF infants than in the CTRL group., Conclusions: A formula with 1.61 g of protein/100 kcal supports normal growth of infants after age 3 months. This protein content is adequate if provided from a high-quality source.

Bilateral salpingo-oophorectomy (BSO) has become the standard-of-care for risk reduction in women at hereditary risk of ovarian cancer. Although this procedure significantly decreases both the incidence of and mortality from ovarian cancer, it affects quality of life, and the premature cessation of ovarian function may have long-term health hazards. Recent advances in our understanding of the molecular pathways of ovarian cancer point to the fallopian tube epithelium as the origin of most high-grade serous cancers (HGSC). This evolving appreciation of the role of the fallopian tube in HGSC has led to the consideration of salpingectomy alone as an option for risk management, especially in premenopausal women. In addition, it is postulated that bilateral salpingectomy with ovarian retention (BSOR), may have a public health benefit for women undergoing benign gynecologic surgery. In this review, we provide the rationale for salpingectomy as an ovarian cancer risk reduction strategy., (©2015 American Association for Cancer Research.)

Background: Breastfed infants require supplementation with vitamin D (vD), but little is known about the necessary dose. This double blind trial evaluated four different doses of vD., Methods: Exclusively breastfed infants (N = 213) were randomized at 1 mo to one of four doses, which they received through 9 mo while receiving no formula. The supplements provided daily 200 IU, 400 IU, 600 IU, or 800 IU of vD. The primary endpoint was plasma 25(OH)D level, and secondary outcomes were plasma parathyroid hormone and calcium, and illness incidence. The study was conducted during winter at 41° N., Results: Most infants had low (<50 nmol/l) 25(OH)D levels at 1 mo, but with supplementation levels rose. Overall, levels of 25(OH)D differed significantly in proportion to vD dose. There were no effects of vD on illness incidence or growth. Low levels were common, with 7.8% of levels being <50 nmol/l and 15 infants having 2 to 4 low levels., Conclusion: The four doses of vD produced different plasma levels of 25(OH)D. The higher doses were somewhat more efficacious in maintaining vD sufficiency in breastfed infants. The findings support the recommended dose of 400 IU/d, and stress the need to start supplementation at birth.

The birth iron endowment provides iron for growth in the first months of life. We describe the iron endowment under conditions of low dietary iron supply. Subjects were infants participating in a trial of Vitamin D supplementation from 1 to 9 months. Infants were exclusively breastfed at enrollment but could receive complementary foods from 4 months but not formula. Plasma ferritin (PF) and transferrin receptor (TfR) were determined at 1, 2, 4, 5.5, 7.5, 9 and 12 months. At 1 month PF ranged from 38 to 752 µg/L and was only weakly related to maternal PF. PF declined subsequently and flattened out at 5.5 months. PF of females was significantly higher than PF of males except at 12 months. TfR increased with age and was inversely correlated with PF. PF and TfR tracked strongly until 9 months. Iron deficiency (PF < 10 µg/L) began to appear at 4 months and increased in frequency until 9 months. Infants with ID were born with low iron endowment. We concluded that the birth iron endowment is highly variable in size and a small endowment places infants at risk of iron deficiency before 6 months. Boys have smaller iron endowments and are at greater risk of iron deficiency than girls.

The Database of Individuals at High Risk for Breast, Ovarian, or Other Hereditary Cancers at the Arizona Cancer Center in Tucson, Arizona assesses cancer risk factors and outcomes in patients with a family history of cancer or a known genetic mutation. We analyzed the subset of clinic probands who carry deleterious BRCA gene mutations to identify factors that could explain why mutations in BRCA2 outnumber those in BRCA1. Medical, family, social, ethnic and genetic mutation histories were collected from consenting patients' electronic medical records. Differences between BRCA1 and BRCA2 probands from this database were analyzed for statistical significance and compared to published analyses. A significantly higher proportion of our clinic probands carry mutations in BRCA2 than BRCA1, compared with previous reports of mutation prevalence. This also holds true for the Hispanic sub-group. Probands with BRCA2 mutations were significantly more likely than their BRCA1 counterparts to present to the high risk clinic without a diagnosis of cancer. Other differences between the groups were not significant. Six previously unreported BRCA2 mutations appear in our clinic population. The increased proportion of probands carrying deleterious BRCA2 mutations is likely multifactorial, but may reflect aspects of Southern Arizona's unique ethnic heritage.

In this issue (beginning on page 1368), Kreul and colleagues report a retrospective review of long-term efficacy and toxicity for subjects participating in a phase III study of difluoromethylornithine (DFMO) for prevention of nonmelanoma skin cancer (NMSC). They conclude that those treated with DFMO had a nonsignificant, persistent decrease in NMSC after completion of treatment and that treatment with DFMO did not result in late toxicity after the discontinuation of treatment. We review the data on DFMO as a chemopreventive agent for skin and other cancers, discuss the necessary qualities of a cancer chemopreventive agent, and reflect on the requirements for a well-conducted cancer chemoprevention study, including the rationale for long-term follow-up in cancer prevention studies., (©2012 AACR)

Immune augmentation with ipilimumab, an anti-CTLA-4 monoclonal antibody, has joined the ranks of approved immunologic agents for the treatment of metastatic melanoma. Phase III studies of ipilimumab in metastatic melanoma have demonstrated an overall survival advantage as compared to other approved and investigational therapies. However, the adverse effects associated with this medication are unique and often require management with steroids or other immunosuppressants. In addition, the time to response differs with ipilimumab as compared to traditional chemotherapy, and alternative means of assessment of response have been proposed. In this review, we will summarize the basic science of this treatment, its preclinical evaluation, and the clinical trials leading to its approval. We will also discuss the details regarding its use, assessment of response to this drug and other immune-related therapies, and further directions for investigation.

Reported here are three studies performed with the objective of finding ways to improve the iron status of breastfed infants and to prevent iron deficiency (ID). Participating infants were exclusively breastfed until 4 months of age; thereafter, they could receive complementary foods and, in some studies, supplemental formula. In the first study, infants were given medicinal iron between the ages of 1 and 5.5 months. During this period, iron status improved and ID was prevented; however, these benefits did not continue after the intervention ceased. In the second study, infants received medicinal iron or an equivalent amount of iron from an iron-fortified cereal between the ages of 4 and 9 months. Again, iron supplementation largely prevented ID from occurring, while non-anemic ID and ID anemia occurred in the control group as well as in the intervention groups before the intervention began. In the third study, infants received dry cereals fortified with electrolytic iron or with ferrous fumarate between the ages of 4 and 9 months. The cereals were equally effective in providing relative protection from ID. The results of these three studies indicate it is possible to protect breastfed infants from ID and IDA., (© 2011 International Life Sciences Institute.)

Precooked, instant (dry) infant cereals in the US are fortified with electrolytic iron, a source of low reactivity and suspected low bioavailability. Iron from ferrous fumarate is presumed to be more available. In this study, we compared a dry infant rice cereal (Cereal L) fortified with electrolytic iron (54.5 mg iron/100 g cereal) to a similar cereal (Cereal M) fortified with ferrous fumarate (52.2 mg Fe/100 g) for efficacy in maintaining iron status and preventing iron deficiency (ID) in breast-fed infants. Ascorbic acid was included in both cereals. In this prospective, randomized double-blind trial, exclusively breast-fed infants were enrolled at 1 mo and iron status was determined periodically. At 4 mo, 3 infants had ID anemia and were excluded. Ninety-five infants were randomized at 4 mo, and 69 (36 Cereal L, 33 Cereal M) completed the intervention at 9 mo. From 4 to 9 mo, they consumed daily one of the study cereals. With each cereal, 2 infants had mild ID, a prevalence of 4.2%, but no infant developed ID anemia. There were no differences in iron status between study groups. Iron intake from the study cereals was (mean ± SD) 1.21 ± 0.31 mg⋅kg(-1)⋅d(-1) from Cereal L and 1.07 ± 0.40 mg⋅kg(-1)⋅d(-1) from Cereal M. Eleven infants had low birth iron endowment (plasma ferritin < 55 μg/L at 2 mo) and 54% of these infants had ID with or without anemia by 4 mo. We conclude that electrolytic iron and ferrous fumarate were equally efficacious as fortificants of this infant cereal.

Because nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit tumor growth in vitro, we investigated the association between NSAIDs and melanoma to determine if there was epidemiologic evidence of a chemopreventive effect from these medications. Three hundred twenty-seven subjects with incident melanoma and 119 melanoma-free controls completed a structured interview assessing melanoma risk factors. The unadjusted odds ratio (OR) for use of nonaspirin NSAIDs was 0.58 (95% CI 0.31-1.11), in a comparison of subjects with melanoma to controls. After adjustment for melanoma risk factors, the OR was 0.71 (95% CI 0.23-2.02). Aspirin users had an unadjusted OR of 0.85 (95% CI 0.45-1.69) and an adjusted OR of 1.45 (95% CI 0.44-4.74). In this pilot study, we found no evidence of a significant association between analgesic use and melanoma risk when potential confounders are assessed. Based on conflicting reports in the literature, meta-analysis may be appropriate.

Objectives: Colorectal cancer (CRC) is a feared complication of chronic ulcerative colitis (UC). Annual endoscopic surveillance is recommended for the detection of early neoplasia. 5-Aminosalicylates (5-ASAs) may prevent some UC-associated CRC. Therefore, in patients prescribed 5-ASAs for maintenance of remission, annual surveillance might be overly burdensome and inefficient. We aimed to determine the ideal frequency of surveillance in patients with UC maintained on 5-ASAs., Methods: We performed systematic reviews of the literature, and created a Markov computer model simulating a cohort of 35-year-old men with chronic UC, followed until the age of 90 years. Twenty-two strategies were modeled: natural history (no 5-ASA or surveillance), surveillance without 5-ASA at intervals of 1-10 years, 5-ASA plus surveillance every 1-10 years, and 5-ASA alone. The primary outcome was the ideal interval of surveillance in the setting of 5-ASA maintenance, assuming a third-party payer was willing to pay $100,000 for each quality-adjusted life-year (QALY) gained., Results: In the natural history strategy, the CRC incidence was 30%. Without 5-ASA, annual surveillance was the ideal strategy, preventing 89% of CRC and costing $69,100 per QALY gained compared with surveillance every 2 years. 5-ASA alone prevented 49% of CRC. In the setting of 5-ASA, surveillance every 3 years was ideal, preventing 87% of CRC. 5-ASA with surveillance every 2 years cost an additional $147,500 per QALY gained, and 5-ASA with annual surveillance cost nearly $1 million additional per QALY gained compared with every 2 years. In Monte Carlo simulations, surveillance every 2 years or less often was ideal in 95% of simulations., Conclusions: If 5-ASA is efficacious chemoprevention for UC-associated CRC, endoscopic surveillance might be safely performed every 2 years or less often. Such practice could decrease burdens to patients and on endoscopic resources with a minimal decrease in quality-adjusted length of life, because 5-ASA with annual surveillance may cost nearly $1 million per additional QALY gained.

Background: Although uncommon, iron deficiency (ID) occurs in breastfed infants. The regular provision of iron may prevent ID., Objective: The objective was to test the feasibility and effectiveness of 2 modalities of providing iron (medicinal iron or iron-fortified cereal) to breastfed infants. The study tested the hypothesis that regular provision of iron improves iron status of breastfed infants without adverse effects., Design: In this prospective, randomized, open-label trial, breastfed infants received on a regular basis either medicinal iron (n = 48) or an iron-fortified fruit-cereal combination (n = 45) from 4 to 9 mo or no intervention (control group; n = 59). The interventions provided 7.0-7.5 mg ferrous sulfate/d. Infants were enrolled at 1 mo and were followed to 2 y. Iron-status indicators were determined periodically, stool characteristics were recorded, and growth was monitored., Results: The regular provision of iron led to improved iron status during and for some months after the intervention. Both sources of iron were about equally effective. Iron affected stool color but had no effect on feeding-related behavior. However, medicinal iron was associated with a small but significant reduction in length gain and a trend toward reduced weight gain. ID anemia was observed in 4 infants (2.3%), most of whom had a low birth iron endowment. Mild ID was common in the second year of life., Conclusions: Regular provision of medicinal iron or iron-fortified cereal improves the iron status of breastfed infants and may prevent ID. Both modalities are equally effective, but medicinal iron leads to somewhat reduced growth. This trial was registered at ClinicalTrials.gov as NCT00760890.

Background: In breastfed infants, iron deficiency at <6 mo of life, although uncommon, is observed in industrialized countries. Iron supplementation starting at an early age may prevent iron deficiency., Objective: The study assessed the effect of early iron supplementation of breastfed infants and tested the hypothesis that iron supplementation enhances iron status. Potential adverse effects (tolerance and growth) were monitored., Design: The prospective, placebo-controlled study involved exclusively breastfed infants who were randomly assigned at 1 mo of age to iron (n = 37) or placebo (n = 38). Iron (7 mg/d as multivitamin preparation with ferrous sulfate) or placebo (multivitamin preparation without iron) was given from 1 to 5.5 mo of age. Complementary foods were allowed at >4 mo. Infants were followed to 18 mo. Blood concentrations of ferritin, transferrin receptor, hemoglobin, and red cell indexes were determined at bimonthly intervals. Stool consistency and color and feeding behavior were recorded., Results: Iron supplementation caused modest augmentation of iron status during the intervention at 4 and 5.5 mo but not thereafter. Iron supplements were well tolerated and had no measurable effect on growth. One infant developed iron deficiency anemia by 5.5 mo of age. Plasma ferritin and hemoglobin tracked over time., Conclusion: Early iron supplementation of breastfed infants is feasible and transiently increases iron status but not hematologic status. Iron is tolerated by most infants. The prevalence of iron deficiency anemia is low (3%) among unsupplemented breastfed infants in the first 6 mo of life.

Background: Bisphosphonates are medications that impact bone reformation by inhibiting osteoclast function. Osteonecrosis of the jaw has been reported among patients receiving these medications. It is unclear if the risk factors associated with osteonecrosis of the jaw among cancer patients taking bisphosphonates also are possible risk factors among patients receiving these medications for other indications., Methods: A systematic review search strategy was used to identify cases of osteonecrosis of the jaw among patients taking bisphosphonates for an indication other than cancer to identify potential contributing factors. Data were analyzed according to previous models to develop a more expanded model that may explain possible mechanisms for the development of osteonecrosis of the jaw among patients without cancer., Results: Ninety-nine cases of osteonecrosis of the jaw were identified among patients who were prescribed a bisphosphonate for an indication other than cancer. These cases included 85 osteoporosis patients, 10 patients with Paget's disease, 2 patients with rheumatoid arthritis, 1 patient with diabetes, and 1 patient with maxillary fibrous dysplasia. The mean age was 69.4 years, 87.3% were female, and 83.3% were receiving oral, but not intravenous, bisphosphonates. Of the 63 patients reporting dental care information, 88.9% had a dental procedure before the onset of osteonecrosis of the jaw. Of all cases providing medical information, 71% were taking at least one medication that affects bone turnover in addition to the bisphosphonate, and 81.3% reported additional underlying health conditions., Conclusions: The case details suggest a multiplicity of factors associated with this condition and provide the foundation for a model outlining the potential mechanism for the development of osteonecrosis of the jaw among patients taking bisphosphonates for an indication other than cancer.

Objective: The purpose of this work was to assess the vitamin D status of breastfed infants living in Iowa (latitude: 41 degrees N)., Methods: Blood samples and dietary records from 84 breastfed infants participating in another study were used for a survey of vitamin D status at 280 days of age. The vitamin D status of those (35 infants) who did not receive preformed vitamin D at 280 days of age (unsupplemented infants) was assessed longitudinally between 112 days and 15 months of age. Plasma 25-hydroxyvitamin D and, in most cases, parathyroid hormone and alkaline phosphatase were determined., Results: At 280 days of age, 10% of breastfed infants were vitamin D deficient (25-hydroxyvitamin D < 11 ng/mL). Deficiency was significantly more prevalent among dark-skinned infants and during winter and occurred exclusively in unsupplemented infants. During winter, 78% of unsupplemented infants were vitamin D deficient. During summer, only 1 infant who had dark skin pigmentation was vitamin D deficient. Longitudinal assessment of unsupplemented infants similarly showed that the majority of breastfed infants were vitamin D deficient during winter. Severe deficiency (25-hydroxyvitamin D < 5 ng/mL) was common and was accompanied by elevation of parathyroid hormone and alkaline phosphatase. The prevalence of vitamin D deficiency decreased with age but was still 12% at 15 months of age if no preformed vitamin D was received., Conclusions: Vitamin D deficiency, including severe deficiency, was common among breastfed infants in Iowa who did not receive preformed vitamin D. Deficiency occurred mostly during winter but was not completely absent during summer. It affected infants with light as well as dark skin pigmentation. Consumption of preformed vitamin D from vitamin supplements or formula is effective in preventing vitamin D deficiency. Vitamin D supplementation should be provided to all breastfed infants.

Approximately 6% of colorectal cancers can be attributed to recognizable heritable germline mutations. Familial adenomatous polyposis is an autosomal dominant syndrome classically presenting with hundreds to thousands of adenomatous colorectal polyps that are caused by mutations in the APC gene. Adenomas typically develop in the midteens in these patients, and colorectal cancer is a virtual certainty if this condition is untreated. A low-penetrance susceptibility allele that is common in Jews from Eastern Europe, APC 11307K, confers a two-fold increased risk of colorectal cancer without the full expression of familial adenomatous polyposis. Biallelic mutations in the MYH gene are associated with an attenuated familial adenomatous polyposis phenotype. Lynch syndrome (hereditary nonpolyposis colorectal cancer) is an autosomal dominant disorder characterized by early onset of colorectal cancer with microsatellite instability. Mutations in mismatch repair genes lead to a lifetime colon cancer risk of 85% in these patients; carcinomas of the endometrium, ovary, and other organs also occur with increased frequency. Although adenomas are not characteristic of the hamartomatous polyp syndromes such as juvenile polyposis and Peutz-Jeghers syndrome, individuals with these diseases have a markedly increased risk of colorectal cancer relative to the general population. In this review, we will describe the phenotypes, genotypes, diagnosis, and management of hereditary colon cancer syndromes.