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There are many design options for toxicity-driven phase 1 dose-finding in oncology drug development. Ultimately, if the target DLT-rate is 25%, the most commonly selected target, do the physicians need to have an acceptable interval of 0.16 to 0.33 or would it be just as reasonable to set the range as 0% to 33% DLT rate for the permissible doses? For the BLRM or related methods, this includes the DLT definition, the DLT-target, and the DLT-target acceptable range which are all very related. There are methods that are simple, traditional and transparent, such as the 3 + 31 or rolling 6 design2 that do not target a dose limiting toxicity (DLT)-rate and are focused on exploring escalating doses subject to limits on patient risk. [Extracted from the article]

Background: The objective of this study was to determine the effects of National Comprehensive Cancer Network (NCCN) guideline-adherent initiation of postoperative radiation therapy (PORT) and different time-to-PORT intervals on the overall survival (OS) of patients with head and neck squamous cell carcinoma (HNSCC).Methods: The National Cancer Data Base was reviewed for the period of 2006-2014, and patients with HNSCC undergoing surgery and PORT were identified. Kaplan-Meier survival estimates, Cox regression analysis, and propensity score matching were used to determine the effects of initiating PORT within 6 weeks of surgery and different time-to-PORT intervals on survival.Results: This study included 41,291 patients. After adjustments for covariates, starting PORT >6 weeks postoperatively was associated with decreased OS (adjusted hazard ratio [aHR], 1.13; 99% confidence interval [CI], 1.08-1.19). This finding remained in the propensity score-matched subset (hazard ratio, 1.21; 99% CI, 1.15-1.28). In comparison with starting PORT 5 to 6 weeks postoperatively, initiating PORT earlier was not associated with improved survival (aHR for ≤ 4 weeks, 0.93; 99% CI, 0.85-1.02; aHR for 4-5 weeks, 0.92; 99% CI, 0.84-1.01). Increasing durations of delay beyond 7 weeks were associated with small, progressive survival decrements (aHR, 1.09, 1.10, and 1.12 for 7-8, 8-10, and >10 weeks, respectively).Conclusions: Nonadherence to NCCN guidelines for initiating PORT within 6 weeks of surgery was associated with decreased survival. There was no survival benefit to initiating PORT earlier within the recommended 6-week timeframe. Increasing durations of delay beyond 7 weeks were associated with small, progressive survival decrements. Cancer 2017;123:4841-50. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Adherence to evidence-based treatment guidelines has been proposed as a measure of cancer care quality. The objective of this study was to determine the rate and predictors of care that does not adhere to National Comprehensive Cancer Network guidelines regarding commencing postoperative radiation therapy (PORT) within 6 weeks of surgery for patients with head and neck squamous cell carcinoma (HNSCC).Methods: The National Cancer Data Base was reviewed from 2006 to 2014, and patients with HNSCC who underwent curative-intent surgery followed by PORT were identified. Multivariable logistic regression analysis was used to determine the factors associated with nonadherence to guidelines regarding the timing of initiating PORT.Results: In total, 47,273 patients were included in the study. 55.7% of patients (26,340/47,273) failed to commence PORT within 6 week of surgery. The percentage of patients who failed to initiate PORT within 6 week of surgery increased over time. On multivariable analysis, the factors associated with failure to initiate timely, guideline-adherent PORT included black race, public insurance [Medicare, Medicaid] or uninsured status, lower levels of education, increased severity of comorbidity, increased postoperative length of stay, 30-day unplanned hospital readmission, treatment at an academic medical center, and the receipt of surgery and PORT at different facilities.Conclusions: Over 50% of patients with HNSCC who undergo surgery and PORT receive care that does not adhere to National Comprehensive Cancer Network guidelines with regard to initiating PORT within 6 weeks of surgery. Sociodemographic, oncologic, treatment, and hospital factors are all associated with failure to receive guideline-directed care and should be explored in future studies. Cancer 2017;123:2651-60. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Comparisons of crude incidence and mortality rates for acute myeloid leukemia cannot be used to determine whether cancer clusters exist. Geographic data should be analyzed via spatial modeling with appropriate adjustments for known prognostic factors. [ABSTRACT FROM AUTHOR]

Background: The availability of safe and effective COVID‐19 vaccines has enabled protections against serious COVID‐19 outcomes, which are particularly important for patients with cancer. The American Society of Clinical Oncology Registry enabled the study of COVID‐19 vaccine uptake in patients with cancer who were positive for severe acute respiratory syndrome‐coronavirus 2. Methods: Medical oncology practices entered data on patients who were in cancer treatment. The cohort included patients who had severe acute respiratory syndrome‐coronavirus 2 infection in 2020 and had visits and vaccine data after December 31, 2020. The primary end point was the time to first vaccination from January 1, 2021. Cumulative incidence estimates and Cox regression with death as a competing risk were used to describe the time to vaccine uptake and factors associated with vaccine receipt. Results: The cohort included 1155 patients from 56 practices. Among 690 patients who received the first vaccine dose, 92% received the second dose. The median time to vaccine was 99 days. After adjustment, older patients were associated with a higher likelihood of vaccination compared with patients younger than 50 years in January through March 2021, and age exhibited a linear effect, with older patients showing higher rates of vaccination. Metastatic solid tumors (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.73–0.98) or non–B‐cell hematologic malignancies (HR, 0.71; 95% CI, 0.54–0.93) compared with nonmetastatic solid tumors, and any comorbidity (HR, 0.83; 95% CI, 0.73–0.95) compared with no comorbidity, were associated with lower vaccination rates. Area‐level social determinants of health (lower education attainment and higher unemployment rates) were associated with lower vaccination rates. Conclusions: Patient age, cancer type, comorbidity, area‐level education attainment, and unemployment rates were associated with differential vaccine uptake rates. These findings should inform strategies to communicate about vaccine safety and efficacy to patients with cancer. Among patients who had cancer and severe acute respiratory syndrome‐coronavirus 2 infection before vaccine availability (e.g., before January 1, 2021), significant variation in vaccine uptake was noted depending on age, cancer type, comorbidity, and two area‐level social determinant of health variables (based on patients' home zip codes)—specifically, the percentage of residents aged 25 years and older with only a high school diploma and the unemployment rate. In the face of ongoing surges of COVID‐19, the emergence of variants, and the evolving role of additional vaccine doses and boosters, the findings—including the identification of subgroups of patients with cancer who remain unvaccinated—should be used to inform strategies to communicate information about vaccine safety and efficacy and vaccine recommendations to these patients. [ABSTRACT FROM AUTHOR]

Background: The current study was conducted to determine the effect of postoperative radiotherapy (PORT) on overall survival in patients with surgically managed pT3-T4aN0 laryngeal squamous cell carcinoma (SCC).Methods: A review of the National Cancer Data Base from 2004 through 2013 was performed. Patients with surgically managed pT3-4aN0 laryngeal SCC with negative surgical margins were included. Univariable and multivariable Cox regression analyses were used to determine factors associated with survival.Results: A total of 1460 patients were included, 46.2% of whom had pT3N0 disease (674 patients) and 53.8% of whom had pT4aN0 disease (786 patients). Approximately 72.0% of the patients with pT3N0 disease (485 patients) and 50.1% of the patients with pT4aN0 disease (394 patients) received PORT. PORT was not found to be associated with improved overall survival on univariable analysis for patients with pT3N0 disease (hazard ratio [HR], 0.84; 95% confidence interval [95% CI], 0.62-1.14), but was for patients with pT4aN0 disease (HR, 0.57; 95% CI, 0.45-0.71). For patients with pT3N0 SCC of the larynx, in a multivariable Cox regression analysis adjusting for age >65 years, severity of comorbidities, larynx subsite, extent of laryngectomy, and number of lymph nodes removed, PORT was not found to be associated with improved survival (adjusted HR, 0.88; 95% CI, 0.64-1.21). For patients with pT4aN0 disease, the administration of PORT was associated with improved survival on multivariable analysis adjusting for age >65 years, severity of comorbidities, larynx subsite, number of lymph nodes removed, and type of hospital (adjusted HR, 0.58; 95% CI, 0.46-0.73).Conclusions: For patients with surgically managed pT3N0 laryngeal SCC with negative margins, PORT does not appear to be associated with improved survival. Despite a survival benefit, nearly 50% of patients with pT4aN0 laryngeal SCC and negative surgical margins do not receive standard-of-care PORT. Cancer 2017;123:2248-2257. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: The American Society of Clinical Oncology (ASCO) surveyed cancer patients to assess practice patterns related to weight, diet, and exercise as a part of cancer care. Methods: An online survey was distributed between March and June 2020 through ASCO channels and patient advocacy organizations. Direct email communication was sent to more than 25,000 contacts, and information about the survey was posted on Cancer.Net. Eligibility criteria included being aged at least 18 years, living in the United States, and having been diagnosed with cancer. Logistic regression was used to determine factors associated with recommendation and referral patterns. Results: In total, 2419 individuals responded to the survey. Most respondents were female (60.1%), 61.1% had an early‐stage malignancy, and 48.4% were currently receiving treatment. Breast cancer was the most common cancer (35.7%). The majority of respondents consumed ≤2 servings of fruits and vegetables/d (50.5%) and exercised ≤2 times/wk (50.1%). Exercise was addressed at most or some oncology visits in 56.8% of respondents, diet in 50.1%, and weight in 28.0%. Respondents whose oncology provider provided diet and/or exercise recommendations were more likely to report changes in these behaviors vs. those whose oncology provider did not (exercise: 79.6% vs 69.0%, P <.001; diet 81.1% vs 71.3%, P <.001; weight 81.0% vs 73.3%, P =.003). Conclusions: In a national survey of oncology patients, slightly more than one‐half reported attention to diet and exercise during oncology visits. Provider recommendations for diet, exercise, and weight were associated with positive changes in these behaviors, reinforcing the importance of attention to these topics as a part of oncology care. In a national survey of 2419 oncology patients conducted by the American Society of Clinical Oncology, slightly more than one‐half of respondents reported attention to diet and exercise during oncology visits. Provider recommendations for diet, exercise, and weight were associated with positive changes in these behaviors, reinforcing the importance of attention to these topics as part of oncology care. [ABSTRACT FROM AUTHOR]

Background: An ASCO taskforce comprised of representatives of oncology clinicians, the American Cancer Society National Lung Cancer Roundtable (NLCRT), LUNGevity, the GO2 Foundation for Lung Cancer, and the ROS1ders sought to: characterize U.S. oncologists' biomarker ordering and treatment practices for advanced non‐small‐cell lung cancer (NSCLC); ascertain barriers to biomarker testing; and understand the impact of delays on treatment decisions. Methods: We deployed a survey to 2374 ASCO members, targeting U.S. thoracic and general oncologists. Results: We analyzed 170 eligible responses. For non‐squamous NSCLC, 97% of respondents reported ordering tests for EGFR, ALK, ROS1, and BRAF. Testing for MET, RET, and NTRK was reported to be higher among academic versus community providers and higher among thoracic oncologists than generalists. Most respondents considered 1 (46%) or 2 weeks (52%) an acceptable turnaround time, yet 37% usually waited three or more weeks to receive results. Respondents who waited ≥3 weeks were more likely to defer treatment until results were reviewed (63%). Community and generalist respondents who waited ≥3 weeks were more likely to initiate non‐targeted treatment while awaiting results. Respondents <5 years out of training were more likely to cite their concerns about waiting for results as a reason for not ordering biomarker testing (42%, vs. 19% with ≥6 years of experience). Conclusions: Respondents reported high biomarker testing rates in patients with NSCLC. Treatment decisions were impacted by test turnaround time and associated with practice setting and physician specialization and experience. [ABSTRACT FROM AUTHOR]

Background: Therapeutic options for patients with advanced soft‐tissue sarcoma (STS) are limited. The goal of the current phase 2 study was to examine the clinical activity and safety of the combination of gemcitabine plus pazopanib, a multityrosine kinase inhibitor with activity in STS. Methods: The current randomized, phase 2 trial enrolled patients with advanced nonadipocytic STS who had received prior anthracycline‐based therapy. Patients were assigned 1:1 to receive gemcitabine at a dose of 1000 mg/m2 on days 1 and 8 with pazopanib at a dose of 800 mg daily (G+P) or gemcitabine at a dose of 900 mg/m2 on days 1 and 8 and docetaxel at a dose of 100 mg/m2 on day 8 (G+T) every 3 weeks. Crossover was allowed at the time of disease progression. The study used a noncomparative statistical design based on the precision of 95% confidence intervals for reporting the primary endpoints of median progression‐free survival (PFS) and rate of grade ≥3 adverse events (AEs) for these 2 regimens based on the intent‐to‐treat patient population (AEs were graded using version 4.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events). Results: A total of 90 patients were enrolled: 45 patients on each treatment arm. The median PFS was 4.1 months for each arm (P =.3, log‐rank test). The best overall response of stable disease or better (complete response + partial response + stable disease) was the same for both treatment arms (64% for both the G+T and G+P arms). The rate of related grade ≥3 AEs was 82% for the G+T arm and 78% for the G+P arm. Related grade ≥3 AEs occurring in ≥10% of patients in the G+T and G+P arms were anemia (36% and 20%, respectively), fatigue (29% and 13%, respectively), thrombocytopenia (53% and 49%, respectively), neutropenia (20% and 49%, respectively), lymphopenia (13% and 11%, respectively), and hypertension (2% and 20%, respectively). Conclusions: The data from the current study have demonstrated the safety and efficacy of G+P as an alternative to G+T for patients with nonadipocytic STS. The results of the current trial suggest similar efficacy and tolerability when comparing the gemcitabine and pazopanib (G+P) regimen with the gemcitabine and docetaxel (G+T) regimen. In patients who are not suitable for treatment with G+T, the G+P regimen is a reasonable alternate for the second‐line treatment of patients with metastatic nonadipocytic sarcomas. [ABSTRACT FROM AUTHOR]

Background and Aims: Within the context of busy clinical settings, health‐care providers need practical, evidence‐based options to engage smokers in quitting. Sampling of nicotine replacement therapy [i.e. provision of nicotine replacement therapy (NRT starter kits)] is a brief, pragmatic strategy to address this need. We aimed to compare the effects of NRT sampling plus standard care (SC), relative to SC alone, provided by primary care providers during routine clinic visits. Design Cluster‐randomized clinical trial. Setting: Twenty‐two primary care clinics in South Carolina, USA. Participants: Adult smokers [n = 1245; 61% female, mean age = 50.7, standard deviation (SD) = 13.5] both motivated and unmotivated to quit, seen during routine clinical visit. Interventions were provider‐delivered SC (n = 652, 12 clinics) cessation advice or SC + a 2‐week supply of both nicotine patch and lozenge, with minimal instructions on use (n = 593; 10 clinics). Measurements The primary outcome was 7‐day point prevalence smoking abstinence at 6‐month follow‐up, using intent‐to‐treat. Additional outcomes included NRT use and quit attempts, assessed at 1, 3 and 6 months following baseline. Findings Seven‐day point prevalence abstinence rates were significantly higher in the NRT sampling group throughout follow‐up, including at 6 months [12 versus 8%, odds ratio (OR) = 1.5, 95% confidence interval (CI) = 1.0–2.4]. NRT sampling increased prevalence of any use of NRT (65 versus 25%, OR = 5.8, 95% CI = 4.3–7.7), with higher prevalence of use at 6 months (25 versus 14%, OR = 2.0, 95% CI = 1.5–2.7). NRT sampling increased the rate of quit attempts in the initial month (24 versus 18%, OR = 1.5, 95% CI = 1.0–2.3) but had no significant effect on overall rate of quit attempts (48 versus 45%, OR = 1.2, 95% CI = 0.8–1.7). Conclusion: Providing smokers with a free 2‐week starter kit of nicotine replacement therapy increased quit attempts, use of stop smoking medications and smoking abstinence compared with standard care in a primary care setting. [ABSTRACT FROM AUTHOR]

To study the contribution of T‐cell receptors (TCR) to resulting T‐cell responses, we studied three different human αβ TCRs, reactive to the same gp100‐derived peptide presented in the context of HLA‐A*0201. When expressed in primary CD8 T cells, all receptors elicited classic antigen‐induced IFN‐γ responses, which correlated with TCR affinity for peptide–MHC in the order T4H2 > R6C12 > SILv44. However, SILv44 elicited superior IL‐17A release. Importantly, in vivo, SILv44‐transgenic T cells mediated superior antitumor responses to 888‐A2 + human melanoma tumor cells upon adoptive transfer into tumor‐challenged mice while maintaining IL‐17 expression. Modeling of the TCR ternary complexes suggested architectural differences between SILv44 and the other complexes, providing a potential structural basis for the observed differences. Overall, the data reveal a more prominent role for the T‐cell receptor in defining host T‐cell physiology than traditionally assumed, while parameters beyond IFN‐γ secretion and TCR affinity ultimately determine the reactivity of tumor‐reactive T cells. [ABSTRACT FROM AUTHOR]

To generate a mouse model of spontaneous epidermal depigmentation, parental h3 TA2 mice, expressing both a human-derived, tyrosinase-reactive T-cell receptor on T cells and the matching HLA-A2 transgene, were crossed to keratin 14-promoter driven, stem cell factor transgenic (K14- SCF) mice with intra-epidermal melanocytes. In resulting Vitesse mice, spontaneous skin depigmentation precedes symmetrical and sharply demarcated patches of graying hair. Whereas the SCF transgene alone dictates a greater retinoic acid receptor-related orphan receptor gamma ( RORγt)+ T-cell compartment, these cells displayed markedly increased IL-17 expression within Vitesse mice. Similar to patient skin, regulatory T cells were less abundant compared with K14- SCF mice, with the exception of gradually appearing patches of repigmenting skin. The subtle repigmentation observed likely reflects resilient melanocytes that coexist with skin-infiltrating, melanocyte-reactive T cells. Similar repigmenting lesions were found in a different TCR transgenic model of vitiligo developed on an SCF transgenic background, supporting a role for SCF in repigmentation. [ABSTRACT FROM AUTHOR]

Hematopoietic stem cell graft cellular composition has been generally accepted to impact outcomes. Recent studies question this hypothesis. We conducted a single‐center retrospective study of sixty‐one pediatric BMT recipients for malignant (68%) and nonmalignant diseases (32%) examining effects of graft composition on engraftment, acute GVHD, chronic GVHD, and survival at day 100 and 1 year. Grafts contained a median of 3.63 x  08TNC/kg (range: 0.031‐10.31 x 108TNC/kg) and 4.09 x 106CD34+/kg (range: 0.76‐24.15 x 106CD34+/kg) with median neutrophil and platelet engraftment times of 17 and 29 days, respectively. A univariate analysis showed a trend for increasing TNC and increasing time to neutrophil engraftment HR: 0.875; CI: 0.075‐1.001). Increasing CD34+ counts shortened time to platelet engraftment (HR: 1.085; CI: 1.015‐1.161). No significant relationship was found between TNC, CD34+, or CD3+ and acute or chronic GVHD. TNC or CD34+ did not affect day 100, 1‐year survival, or 2‐year survival. Increasing CD3+ counts demonstrated a negative trend on day 100 survival (HR: 1.108; CI: 1.001‐1.036) but not 1‐year survival or 2‐year survival. These results add additional data questioning the effect of graft composition on outcomes in pediatric BMT patients with important ramifications for the management of donors. [ABSTRACT FROM AUTHOR]