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Background De-intensified treatment strategies for early human papillomavirus-positive (HPV+) oropharynx cancer (OPC) rely on selecting patients with an excellent prognosis. The criterion for enrollment in current de-intensification trials is ≤10 pack-years. More nuance to the pack-year criteria may expand enrollment, improve patient outcomes, and prevent overtreatment. It was hypothesized that patients with more than 10 pack-years may experience favorable outcomes if smoking cessation has been achieved. Methods From an institutional review board-approved database, patients with HPV+ oropharyngeal squamous carcinoma treated definitively with radiation with or without chemotherapy were retrospectively identified. Patients with a history of smoking who were eligible for national de-intensification trials were included (cT1-2N1-2b or T3N0-2b [American Joint Committee on Cancer, seventh edition]). Cox regression with penalized smoothing splines was used to evaluate nonlinear effects of cessation. Recursive partitioning analysis (RPA) was used to objectively search for relationships between the 2 colinear variables (pack-years and time since cessation). Results Among 330 patients meeting the inclusion criteria, 130 (40%) were never smokers, 139 (42%) were former smokers, and 61 (18%) were current smokers. With standard therapy, all former smokers achieved a progression-free survival (PFS) rate higher than 91%, regardless of pack-year exposure. Nonlinear Cox regression demonstrated that more recent cessation was associated with significantly worse PFS even among those with ≤20 pack-years. RPA demonstrated that only current smokers experienced a 2-year PFS rate lower than 91%; former smokers, regardless of pack-years, experienced a 2-year PFS rate higher than 91%. Conclusions The 10-pack-year rule may not apply to all early HPV+ OPCs, particularly for former smokers. Future randomized de-intensification trials should consider a broader and more nuanced approach until the predictive role of smoking status is established.

Background Evidence supporting the efficacy of stereotactic body radiotherapy (SBRT) for localized prostate cancer is accumulating, but comparative studies of patient-reported quality of life (QOL) following SBRT versus conventionally fractionated external beam radiotherapy (EBRT) or active surveillance (AS) are limited. Objective To compare QOL of patients pursuing SBRT and EBRT versus AS. Design, setting, and participants A population-based cohort of 680 men with newly diagnosed localized prostate cancer was prospectively enrolled from 2011 to 2013. Intervention SBRT, EBRT without androgen deprivation therapy, or AS. Outcome measurements and statistical analysis QOL was prospectively assessed before treatment (baseline), and at 3, 12, and 24 mo after treatment using the validated Prostate Cancer Symptom Indices, which contain four domains: sexual dysfunction, urinary obstruction/irritation, urinary incontinence, and bowel problems. Propensity weighting via logistic regression models was used to balance baseline characteristics, and the mean QOL scores of EBRT and SBRT patients were compared against AS patients as the control group. Results and limitations Compared with AS patients, EBRT patients had worse urinary obstructive/irritative symptoms and sexual dysfunction at 3 mo, and worse bowel symptoms at 3 and 24 mo. SBRT patients had similar scores as AS patients in all domains and across all time points; however, due to small sample size, worse sexual function and urinary incontinence in SBRT patients cannot be ruled out. Further research is needed to assess long-term outcomes. Conclusions In a nonrandomized cohort of men with localized prostate cancer, SBRT appeared to result in favorable QOL results through 2 yr of follow-up, but worse sexual function and urinary incontinence compared with AS cannot be ruled out completely. Larger studies with longer follow-up are needed to confirm these findings. Patient summary Stereotactic body radiotherapy (SBRT) and active surveillance appear to have similar quality of life outcomes through 2 yr, although worse sexual function and urinary incontinence from SBRT cannot be ruled out completely.

Salivary gland tumors represent a heterogeneous group of neoplasms characterized by varied histologies and disease outcomes. Initial treatment for the primary and gross nodal disease is usually surgery. Management of the clinically node-negative neck depends upon the risk of lymph nodal involvement. This is usually determined by the AJCC “T” stage and histology. Both surgery and radiation may be utilized to address the lymph nodes at risk. This is especially important for minor salivary gland tumors. Radiation plays an important role in the adjuvant management of salivary gland tumors by reducing the risk of locoregional recurrence. Certain histologies like adenoid cystic carcinoma have a predilection for neurotropic spread to the skull base. Radiation is particularly important in controlling disease at the skull base. The role of concurrent chemotherapy in the adjuvant treatment of salivary gland tumors is not established and remains an area of active research. Certain histologies like salivary duct carcinoma exhibit readily identifiable molecular targets amenable to targeted therapy. Finally, advanced testing of these tumors using next-generation sequencing can also potentially identify molecular targets amenable to therapy. While useful in the management of metastatic disease, the role of these therapies in the adjuvant setting remains unknown.

Although radical cystectomy is considered the gold standard approach for patients with muscle-invasive bladder cancer, tri-modal therapy (TMT) is a well-tolerated and efficacious alternative to radical cystectomy that is underutilized in inoperable patients and rarely offered to cystectomy candidates in the USA. Retrospective data suggest similar outcomes between radical cystectomy and TMT after adjusting for patient selection and other confounding factors. Nearly 70–80% of patients can keep their native bladder with favorable post-treatment quality of life metrics. Current trials are investigating novel combination strategies including immune checkpoint inhibition along with chemoradiation or radiation. Emerging techniques for improved patient selection and risk stratification include incorporating MP-MRI, and novel biomarkers such as inflammatory, stromal, and DNA damage response gene signatures may guide patient selection and expand the landscape of bladder preservation options available to patients in the future.

Due to its relatively indolent disease course, the sensitivity of PSA testing, and the emergence of novel PET imaging, metastatic prostate cancer is particularly likely to present with a limited volume of disease. Patients with up to five metastatic lesions should be considered for an oligometastatic treatment approach. Systemic therapy remains the cornerstone of treatment for these patients. The optimal type and duration are unknown; however, the addition of a second agent to ADT appears to be beneficial. Multiple recent studies have found significant benefits to the integration of systemic therapy and local metastasis-directed therapies (MDT), including radiation and surgery, to the prostate and metastatic sites. MDT may also be used in select patients wishing to delay the initiation of systemic therapy. For patients with isolated regional nodal recurrences, whole pelvic radiotherapy or extensive lymphadenectomy is preferred, in combination with ADT.

The objective of this study is to evaluate locoregional and distant failure for human papillomavirus-associated (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) using American Joint Committee on Cancer eighth edition (AJCC 8) staging.Retrospective cohort study of 457 patients with HPV + OPSCC, treated with platinum-based chemoradiation from 2002 to 2018, followed for a median of 4.3 years. Time to locoregional failure (TTLRF) and distant failure (TTDF) were estimated by Kaplan-Meier method. Log-rank, recursive partitioning analysis (RPA), and multivariable Cox proportional hazards were used to evaluate associated factors and stratify risk.Rates of five-year locoregional control (LRC) and distant control (DC) were 92% (95% CI, 90-95%) and 89% (95% CI, 85-92%), respectively. Smoking, T4, N3, and stage III were associated with significantly worse TTLRF. RPA identified three distinct locoregional failure groups: cT1-3 and 19 pack-years vs. cT1-3 with ≥19 pack-years vs. cT4 (five-year LRC: 97% vs. 90% vs. 82%, P .0001). The only factor associated with significantly worse TTDF was smoking status, while stage was not correlated. RPA identified two prognostic groups: former or never smokers vs. current smokers (five-year DC: 92% vs. 77%, P = .0003).In the largest evaluation of HPV + OPSCC after platinum-based chemoradiation using AJCC 8, risk for locoregional recurrence was stratified by smoking, T category, N category, and overall stage. Risk of distant recurrence was only stratified by smoking status and not related to stage. This has implications for surveillance and clinical trial design.

Purpose/objective(s) Stereotactic body radiation therapy (SBRT) is increasingly utilized for treatment of patients with recurrent and metastatic tumors. Considering the relative radioresistance of some sarcoma histologies, SBRT may allow for higher biological effectiveness compared to conventional radiotherapy. We report local control outcomes after SBRT based on radiation dose and histology. Materials/methods From our IRB-approved single-institution registry, all patients treated with SBRT for metastatic sarcoma between 2014 and 2020 were identified. Kaplan-Meier analysis was used to estimate local control and overall survival at 1 year. Univariate and multivariable Cox proportional hazard model analyses were performed to determine association between SBRT dose, histology, and local control. Small round blue cell sarcomas were classified as more radiosensitive and others as radioresistant histologies. A receiver operating characteristic (ROC) curve was generated to determine optimal biologically effective dose (BED) using a/β of 3 Gy. Local control was compared by SBRT dose using the BED cut point and histology. Results Forty-two patients with a total of 138 lesions met inclusion criteria. Median follow up was 9.7 months (range 0.5-34.5). Patients were heavily pre-treated with systemic therapy. Median SBRT prescription was 30 Gy (range 15-60) in 4 fractions (range 1-5). Sixty-two lesions met criteria for radiosensitive histology while 75 lesions were considered radioresistant. Local control for all lesions was 66.7% (95% CI, 56.6-78.5) at 1 year and 50.2% (95% CI, 38.2-66.1) at 2 years. Stratifying by histology, 1-year local control was 65.3% for radiosensitive and 68.6% for radioresistant histologies (P = 0.49). The ROC cut point for BED was 95 Gy. Local control at 1-year was 75% for lesions receiving ≥ 95 Gy BED, and 46.2% for lesions receiving Conclusion For patients undergoing stereotactic body radiotherapy for metastatic sarcoma, local control was significantly improved when BED was ≥ 95 Gy for radiosensitive histologies, but was not significant for radioresistant histologies. Further investigation into the dose-response relationship is warranted to maximize the therapeutic index.

Background Men with early-stage prostate cancer have multiple options that have similar oncologic efficacy but vary in terms of their impact on quality of life. In low-risk cancer, active surveillance is the option that best preserves patients' sexual function, but it is unknown if patient preference affects treatment selection. Our objectives were to identify patient characteristics associated with a strong preference to preserve sexual function and to determine whether patient preference and baseline sexual function level are associated with receipt of active surveillance in low-risk cancer. Methods In this population-based cohort of men with localized prostate cancer, baseline patient-reported sexual function was assessed using a validated instrument. Patients were also asked whether preservation of sexual function was very, somewhat, or not important. Prostate cancer disease characteristics and treatments received were abstracted from medical records. A modified Poisson regression model with robust standard errors was used to compute adjusted risk ratio (aRR) estimates. All statistical tests were two-sided. Results Among 1194 men, 52.6% indicated a strong preference for preserving sexual function. Older men were less likely to have a strong preference (aRR = 0.98 per year, 95% confidence interval [CI] = 0.97 to 0.99), while men with normal sexual function were more likely (vs poor function, aRR = 1.59, 95% CI = 1.39 to 1.82). Among 568 men with low-risk cancer, there was no clear association between baseline sexual function or strong preference to preserve function with receipt of active surveillance. However, strong preference may differnetially impact those with intermediate baseline function vs poor function (Pinteraction = .02). Conclusions Treatment choice may not always align with patients' preferences. These findings demonstrate opportunities to improve delivery of patient-centered care in early prostate cancer.

Historically, stage IV prostate cancer was considered incurable. Although node-positive and oligometastatic prostate cancers are both classified as stage IV, these likely represent distinct clinical groups, and some patients may be curable with aggressive multimodality treatments. There is a lack of randomized evidence, but retrospective studies suggest that radical prostatectomy or radiotherapy may improve survival in these patients. This is an area of great current research interest and prospective randomized trials are needed to help define the optimal treatments for these patients.

To identify risk factors for progression-free survival (PFS) in the molecular era among patients with low-grade glioma (LGG) who undergo gross total resection (GTR) followed by initial observation.We reviewed patients with World Health Organization grade 2 LGG treated at a single institution. We included only those who underwent magnetic resonance imaging (MRI)-confirmed GTR followed by initial observation. Molecular classification was obtained at either the time of diagnosis or pathology review. Cox proportional hazards regression, the Kaplan-Meier method, and the log-rank test were used. P values.05 were considered statistically significant.We included 144 patients who underwent MRI-confirmed GTR between 1994 and 2014 followed by initial observation. Median age was 29 years (interquartile range [IQR], 18-41), median tumor size was 2.7 cm (IQR, 1.8-4.0), and median follow-up was 81 months (IQR, 36-132). Molecular classification was 13% IDH-mutant 1p19q-codeleted; 21% IDH-mutant 1p19q-intact; 39% IDH1-R132H-wildtype; and 28% undetermined. For the entire cohort, 5- and 10-year PFS and overall survival were 71% and 53%, and 98% and 90%, respectively. On multivariate analysis, factors associated with worse PFS included increasing age at diagnosis (hazard ratio [HR], 1.05; 95% CI, 1.00-1.09; P = .03), increasing preoperative tumor size (HR, 1.07; 95% CI, 1.04-1.10; P .0001), and IDH-mutant 1p19q-intact classification (HR, 3.18; 95% CI, 1.15-8.74, P = .025). Median PFS for patients with IDH-mutant 1p19q-codeleted, IDH-mutant 1p19q-intact, and IDH1-R132H-wildtype tumors were 113 months, 56 months, and not reached, respectively. Molecular classification was significantly associated with PFS (P .0001) but not overall survival (P = .20).Among patients with LGG who undergo MRI-confirmed GTR and initial observation in the molecular era, increasing age, increasing tumor size, and IDH-mutant 1p19q-intact classification are associated with worse PFS. Because tumor progression is associated with adverse health-related quality of life, these factors may aid clinicians and patients in the shared decision-making process regarding goals of surgery and timing of postoperative therapy. Further study is required to elucidate why IDH-mutant 1p19q-intact LGGs are at higher risk for early progression.

Importance Patients diagnosed with localized prostate cancer have to decide among treatment strategies that may differ in their likelihood of adverse effects. Objective To compare quality of life (QOL) after radical prostatectomy, external beam radiotherapy, and brachytherapy vs active surveillance. Design, Setting, and Participants Population-based prospective cohort of 1141 men (57% participation among eligible men) with newly diagnosed prostate cancer were enrolled from January 2011 through June 2013 in collaboration with the North Carolina Central Cancer Registry. Median time from diagnosis to enrollment was 5 weeks, and all men were enrolled with written informed consent prior to treatment. Final follow-up date for current analysis was September 9, 2015. Exposures Treatment with radical prostatectomy, external beam radiotherapy, brachytherapy, or active surveillance. Main Outcomes and Measures Quality of life using the validated instrument Prostate Cancer Symptom Indices was assessed at baseline (pretreatment) and 3, 12, and 24 months after treatment. The instrument contains 4 domains—sexual dysfunction, urinary obstruction and irritation, urinary incontinence, and bowel problems—each scored from 0 (no dysfunction) to 100 (maximum dysfunction). Propensity-weighted mean domain scores were compared between each treatment group vs active surveillance at each time point. Results Of 1141 enrolled men, 314 pursued active surveillance (27.5%), 469 radical prostatectomy (41.1%), 249 external beam radiotherapy (21.8%), and 109 brachytherapy (9.6%). After propensity weighting, median age was 66 to 67 years across groups, and 77% to 80% of participants were white. Across groups, propensity-weighted mean baseline scores were 41.8 to 46.4 for sexual dysfunction, 20.8 to 22.8 for urinary obstruction and irritation, 9.7 to 10.5 for urinary incontinence, and 5.7 to 6.1 for bowel problems. Compared with active surveillance, mean sexual dysfunction scores worsened by 3 months for patients who received radical prostatectomy (36.2 [95% CI, 30.4-42.0]), external beam radiotherapy (13.9 [95% CI, 6.7-21.2]), and brachytherapy (17.1 [95% CI, 7.8-26.6]). Compared with active surveillance at 3 months, worsened urinary incontinence was associated with radical prostatectomy (33.6 [95% CI, 27.8-39.2]); acute worsening of urinary obstruction and irritation with external beam radiotherapy (11.7 [95% CI, 8.7-14.8]) and brachytherapy (20.5 [95% CI, 15.1-25.9]); and worsened bowel symptoms with external beam radiotherapy (4.9 [95% CI, 2.4-7.4]). By 24 months, mean scores between treatment groups vs active surveillance were not significantly different in most domains. Conclusions and Relevance In this cohort of men with localized prostate cancer, each treatment strategy was associated with distinct patterns of adverse effects over 2 years. These findings can be used to promote treatment decisions that incorporate individual preferences.

Objective Sarcopenia is the age-related loss of muscle mass, strength, and function. It is a common finding in older patients and is associated with decreased life expectancy and potentially higher susceptibility to chemotherapy toxicity. This study describes the prevalence of sarcopenia in older adults with early stage colorectal cancer. Materials and Methods Patients ≥ 70 years old who underwent surgical resection for stage I–III colorectal cancer between 2008 and 2013 were identified from the medical record. Sarcopenia was assessed by measuring the total muscle area on computerized tomography (CT) images obtained prior to surgery. Total muscle area was measured at the level of L3 and normalized using each patient’s height to produce a skeletal muscle index (SMI). Sarcopenia was defined using sex- and body mass index (BMI)–specific threshold values of SMI. Results Eighty-seven patients were included, with a median age of 77 years (70–96). Twenty-five men (60% of 42) and 25 women (56% of 45) had sarcopenia. Sarcopenic patients had significantly lower BMI ( p = 0.03) compared to non-sarcopenic patients. There was a positive correlation between BMI and SMI for both men ( r = 0.44) and women ( r = 0.16). Conclusion Sarcopenia is highly prevalent among older patients with early stage colorectal cancer. BMI alone is a poor indicator of lean body mass and improved methods of screening for sarcopenia are necessary. CT scans are a viable option for identifying sarcopenic patients in whom timely interventions may improve survival, quality of life, and functional outcomes.

We appreciate the opportunity to respond to Drs. Safer and Binay Saferregarding ourrecentstudy which utilizedcomputed tomography (CT) imaging to determine the prevalence of sarcopenia in older adults with colorectal cancer. The authors inquired about the usage of single-slice CT imaging to determine total body muscle mass and our functioning definition of sarcopenia.

Researchers need an available and easy-to-use model of the human intestine to better understand human intestinal physiology and pathophysiology of diseases, and to offer an enhanced platform for developing drug therapy. Our work employs human enteroids derived from each of the major intestinal sections to advance understanding of several diarrheal diseases, including those caused by cholera, rotavirus and enterohemorrhagic Escherichia coli. An enteroid bank is being established to facilitate comparison of segmental, developmental, and regulatory differences in transport proteins that can influence therapy efficacy. Basic characterization of major ion transport protein expression, localization and function in the human enteroid model sets the stage to study the effects of enteric infection at the transport level, as well as to monitor potential responses to pharmacological intervention.

e18093Background: Prostate cancer patients face several treatment options which vary in their impact on sexual function: active surveillance (least), radiotherapy, and radical prostatectomy (most)....

Cystic fibrosis (CF), an inherited disease characterized by defective epithelial Cl−transport, damages lungs via chronic inflammation and oxidative stress. Glutathione, a major antioxidant in the epithelial lung lining fluid, is decreased in the apical fluid of CF airway epithelia due to reduced glutathione efflux (Gao L, Kim KJ, Yankaskas JR, and Forman HJ. Am J Physiol Lung Cell Mol Physiol 277: L113–L118, 1999). The present study examined the question of whether restoration of chloride transport would also restore glutathione secretion. We found that a Cl−channel-forming peptide (N-K4-M2GlyR) and a K+channel activator (chlorzoxazone) increased Cl−secretion, measured as bumetanide-sensitive short-circuit current, and glutathione efflux, measured by high-performance liquid chromatography, in a human CF airway epithelial cell line (CFT1). Addition of the peptide alone increased glutathione secretion (181 ± 8% of the control value), whereas chlorzoxazone alone did not significantly affect glutathione efflux; however, chlorzoxazone potentiated the effect of the peptide on glutathione release (359 ± 16% of the control value). These studies demonstrate that glutathione efflux is associated with apical chloride secretion, not with the CF transmembrane conductance regulator per se, and the defect of glutathione efflux in CF can be overcome pharmacologically.