Cost effectiveness of treatment strategies for high risk prostate cancer.

BACKGROUND: Patients with high-risk prostate cancer (HRPC) have multiple accepted treatment options. Because there is no overall survival benefit of one option over another, appropriate treatment must consider patient life expectancy, quality of life, and cost. METHODS: The authors compared quality-adjusted life years (QALYs) and cost effectiveness among treatment options for HRPC using a Markov model with three treatment arms: (1) external-beam radiotherapy (EBRT) delivered with 20 fractions, (2) EBRT with 23 fractions followed by low-dose-rate (LDR) brachytherapy boost, or (3) radical prostatectomy alone. An exploratory analysis considered a simultaneous integrated boost according to the FLAME trial (ClinicalTrials.gov identifier NCT01168479). RESULTS: Treatment strategies were compared using the incremental cost-effectiveness ratio (ICER). EBRT with LDR brachytherapy boost was a cost-effective strategy (ICER, $20,929 per QALY gained). These results were most sensitive to variations in the biochemical failure rate. However, the results still demonstrated cost effectiveness for the brachytherapy boost paradigm, regardless of any tested parameter ranges. Probabilistic sensitivity analysis demonstrated that EBRT with LDR brachytherapy was favored in 52% of 100,000 Monte Carlo iterations. In an exploratory analysis, EBRT with a simultaneous integrated boost was also a cost-effective strategy, resulting in an ICER of $62,607 per QALY gained; however, it was not cost effective compared with EBRT plus LDR brachytherapy boost. CONCLUSIONS: EBRT with LDR brachytherapy boost may be a cost-effective treatment strategy compared with EBRT alone and radical prostatectomy for HRPC, demonstrating high-value care. The current analysis suggests that a reduction in biochemical failure alone can result in cost-effective care, despite no change in overall survival.

Fluorescence depolarization dynamics of ionic strength sensors using time-resolved anisotropy.

Eukaryotic cells exploit dynamic and compartmentalized ionic strength to impact a myriad of biological functions such as enzyme activities, protein-protein interactions, and catalytic functions. Herein, we investigated the fluorescence depolarization dynamics of recently developed ionic strength biosensors (mCerulean3-linker-mCitrine) in Hofmeister salt (KCl, NaCl, NaI, and Na2SO4) solutions. The mCerulean3-mCitrine acts as a Förster resonance energy transfer (FRET) pair, tethered together by two oppositely charged α-helices in the linker region. We developed a time-resolved fluorescence depolarization anisotropy approach for FRET analyses, in which the donor (mCerulean3) is excited by 425-nm laser pulses, followed by fluorescence depolarization analysis of the acceptor (mCitrine) in KE (lysine-glutamate), arginine-aspartate, and arginine-glutamate ionic strength sensors with variable amino acid sequences. Similar experiments were carried out on the cleaved sensors as well as an E6G2 construct, which has neutral α-helices in the linker region, as a control. Our results show distinct dynamics of the intact and cleaved sensors. Importantly, the FRET efficiency decreases and the donor-acceptor distance increases as the environmental ionic strength increases. Our chemical equilibrium analyses of the collapsed-to-stretched conformational state transition of KE reveal that the corresponding equilibrium constant and standard Gibbs free energy changes are ionic strength dependent. We also tested the existing theoretical models for FRET analyses using steady-state anisotropy, which reveal that the angle between the dipole moments of the donor and acceptor in the KE sensor are sensitive to the ionic strength. These results help establish the time-resolved depolarization dynamics of these genetically encoded donor-acceptor pairs as a quantitative means for FRET analysis, which complement traditional methods such as time-resolved fluorescence for future in vivo studies.

Adjuvant chemoradiation in pancreatic cancer: impact of radiotherapy dose on survival.

BACKGROUND: To evaluate the impact of radiation dose on overall survival (OS) in patients treated with adjuvant chemoradiation (CRT) for pancreatic ductal adenocarcinoma (PDAC). METHODS: A multicenter retrospective analysis on 514 patients with PDAC (T1-4; N0-1; M0) treated with surgical resection with macroscopically negative margins (R0-1) followed by adjuvant CRT was performed. Patients were stratified into 4 groups based on radiotherapy doses (group 1: < 45 Gy, group 2: ≥ 45 and < 50 Gy, group 3: ≥ 50 and < 55 Gy, group 4: ≥ 55 Gy). Adjuvant chemotherapy was prescribed to 141 patients. Survival functions were plotted using the Kaplan-Meier method and compared through the log-rank test. RESULTS: Median follow-up was 35 months (range: 3-120 months). At univariate analysis, a worse OS was recorded in patients with higher preoperative Ca 19.9 levels (≥ 90 U/ml; p < 0.001), higher tumor grade (G3-4, p = 0.004), R1 resection (p = 0.004), higher pT stage (pT3-4, p = 0.002) and positive nodes (p < 0.001). Furthermore, patients receiving increasing doses of CRT showed a significantly improved OS. In groups 1, 2, 3, and 4, median OS was 13.0 months, 21.0 months, 22.0 months, and 28.0 months, respectively (p = 0.004). The significant impact of higher dose was confirmed by multivariate analysis. CONCLUSIONS: Increasing doses of CRT seems to favorably impact on OS in adjuvant setting. The conflicting results of randomized trials on adjuvant CRT in PDAC could be due to < 45 Gy dose generally used.

Effect of Doxepin Mouthwash or Diphenhydramine-Lidocaine-Antacid Mouthwash vs Placebo on Radiotherapy-Related Oral Mucositis Pain: The Alliance A221304 Randomized Clinical Trial.

Importance: Oral mucositis causes substantial morbidity during head and neck radiotherapy. In a randomized study, doxepin mouthwash was shown to reduce oral mucositis-related pain. A common mouthwash comprising diphenhydramine-lidocaine-antacid is also widely used. Objective: To evaluate the effect of doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash for the treatment of oral mucositis-related pain. Design, Setting, and Participants: A phase 3 randomized trial was conducted from November 1, 2014, to May 16, 2016, at 30 US institutions and included 275 patients who underwent definitive head and neck radiotherapy, had an oral mucositis pain score of 4 points or greater (scale, 0-10), and were followed up for a maximum of 28 days. Interventions: Ninety-two patients were randomized to doxepin mouthwash (25 mg/5 mL water); 91 patients to diphenhydramine-lidocaine-antacid; and 92 patients to placebo. Main Outcome and Measures: The primary end point was total oral mucositis pain reduction (defined by the area under the curve and adjusted for baseline pain score) during the 4 hours after a single dose of doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash compared with a single dose of placebo. The minimal clinically important difference was a 3.5-point change. The secondary end points included drowsiness, unpleasant taste, and stinging or burning. All scales ranged from 0 (best) to 10 (worst). Results: Among the 275 patients randomized (median age, 61 years; 58 [21%] women), 227 (83%) completed treatment per protocol. Mucositis pain during the first 4 hours decreased by 11.6 points in the doxepin mouthwash group, by 11.7 points in the diphenhydramine-lidocaine-antacid mouthwash group, and by 8.7 points in the placebo group. The between-group difference was 2.9 points (95% CI, 0.2-6.0; P = .02) for doxepin mouthwash vs placebo and 3.0 points (95% CI, 0.1-5.9; P = .004) for diphenhydramine-lidocaine-antacid mouthwash vs placebo. More drowsiness was reported with doxepin mouthwash vs placebo (by 1.5 points [95% CI, 0-4.0]; P = .03), unpleasant taste (by 1.5 points [95% CI, 0-3.0]; P = .002), and stinging or burning (by 4.0 points [95% CI, 2.5-5.0]; P < .001). Maximum grade 3 adverse events for the doxepin mouthwash occurred in 3 patients (4%); diphenhydramine-lidocaine-antacid mouthwash, 3 (4%); and placebo, 2 (2%). Fatigue was reported by 5 patients (6%) in the doxepin mouthwash group and no patients in the diphenhydramine-lidocaine-antacid mouthwash group. Conclusions and Relevance: Among patients undergoing head and neck radiotherapy, the use of doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash vs placebo significantly reduced oral mucositis pain during the first 4 hours after administration; however, the effect size was less than the minimal clinically important difference. Further research is needed to assess longer-term efficacy and safety for both mouthwashes. Trial Registration: ClinicalTrials.gov Identifier: NCT02229539.

Percutaneous revascularization in patients treated with thoracic radiation for cancer.

OBJECTIVES: To assess coronary revascularization outcomes in patients with previous thoracic radiation therapy (XRT). BACKGROUND: Previous chest radiation has been reported to adversely affect long term survival in patients with coronary disease treated with percutaneous coronary interventions (PCI). METHODS: Retrospective, single center cohort study of patients previously treated with thoracic radiation and PCI. Patients were propensity matched against control patients without radiation undergoing revascularization during the same time period. RESULTS: We identified 116 patients with radiation followed by PCI (XRT-PCI group) and 408 controls. Acute procedural complications were similar between groups. There were no differences in all-cause and cardiac mortality between groups (all-cause mortality HR 1.31, P=.078; cardiac mortality 0.78, P=.49). CONCLUSION: Patients with prior thoracic radiation and coronary disease treated with PCI have similar procedural complications and long term mortality when compared to control subjects.

Repeated measures analyses of dermatitis symptom evolution in breast cancer patients receiving radiotherapy in a phase 3 randomized trial of mometasone furoate vs placebo (N06C4 [alliance]).

PURPOSE: Radiotherapy-related dermatological toxicities over time have not been well quantified. We examined during and immediately following radiation therapy skin toxicities over time in a randomized study of mometasone furoate vs placebo during breast radiotherapy. MATERIAL AND METHODS: Patients with breast cancer undergoing radiotherapy to the breast or chest wall were randomized. Symptoms related to skin toxicity were addressed weekly using provider-reported Common Terminology Criteria for Adverse Events (CTCAE v3.0) and 4 patient-reported outcomes (PRO) surveys. We applied repeated measures and risk analysis methodologies. RESULTS: One hundred seventy-six patients were enrolled. By CTCAE, significant differences favoring mometasone were detected over time in all toxicities except skin striae, atrophy, and infection. Statistically significant differences between arms at baseline but not over time occurred for all Linear Analog Self-Assessment. Statistically significant differences occurred for all symptoms in the temporal profile of symptoms as measured by PRO surveys (all P < .001). CONCLUSIONS: The use of longitudinal methods enhanced the ability of PRO tools to detect differences between study arms. Our results strengthened the conclusions of the original report that mometasone reduced acute skin toxicities. PRO surveys can accurately assess patients' experiences of symptom type and intensity over time and should be included in future clinical trials. For radiotherapy-related dermatological toxicity, we hypothesized that clinically significant differences over time, if any, can be found by repeated measures. We examined the acute skin toxicities in a randomized study of mometasone vs placebo during breast radiotherapy. For secondary end points, we showed that longitudinal methods enhanced the detection of differences between study arms and strengthened the conclusions from the original report. Frequent patient-reported outcome surveys over time should be included in future clinical trials.

Evaluation of Adjuvant Radiation Therapy for Resected Gallbladder Carcinoma: A Multi-institutional Experience.

PURPOSE: The role of adjuvant radiation for gallbladder carcinoma (GBC) is uncertain. We combine the experience of six National Cancer Institute-designated cancer centers to explore the impact of adjuvant radiation following oncologic resection of GBC. METHODS: Patients who underwent extended surgery for GBC at Johns Hopkins, Mayo Clinic, Duke University, Oregon Health & Science University, University of Michigan, and University of Texas MD Anderson between 1985 and 2008 were reviewed. Patients with metastatic disease at surgery, gross residual disease, or missing pathologic information were excluded. RESULTS: Of the 112 patients identified, 61 % received adjuvant radiation, 93 % of whom received concurrent chemotherapy. Median follow-up of surviving patients was 47.3 (range 2.2-167.7) months. Patients who received adjuvant radiation had a higher rate of advanced T-stage (57 vs. 16 %, p < 0.01), lymph node involvement (63 vs. 18 %, p < 0.01), and positive microscopic margins (37 vs. 9 %, p < 0.01) compared with patients managed with surgery alone, but overall survival (OS) was comparable between the two cohorts (5-year OS: 49.7 vs. 52.5 %, p = 0.20). Lymph node involvement had the strongest association with poor OS (p < 0.01). Adjuvant radiation was associated with decreased isolated local failure (hazard ratio 0.17, 95 % confidence interval 0.05-0.63, p = 0.01). However, 71 % of recurrences included distant failure. CONCLUSIONS: Following oncologic resection for GBC, adjuvant radiation may offer improved local control compared with observation. The benefit of adjuvant radiation beyond chemotherapy alone should therefore be explored. Certainly, the high rate of distant failure highlights the need for more effective systemic therapy.

Concurrent MCL1 and JUN amplification in pseudomyxoma peritonei: a comprehensive genetic profiling and survival analysis.

Pseudomyxoma peritonei (PMP) is a rare abdominal malignancy. We hypothesized that next-generation exomic sequencing would identify recurrent mutations that may have prognostic or therapeutic implications. Ten patients were selected on the basis of availability of tissue and adequate follow-up. They were treated at our institution between September 2002 and August 2004. Using next-generation exomic sequencing, we tested for mutations in 236 cancer-related genes in formalin-fixed paraffin-embedded slides. MCL1 amplification was additionally tested with immunohistochemical staining. Detectable mutations were found in 8 patients (80%). Seven patients harbored a KRAS mutation, most commonly involving codon 12. Four GNAS mutations (R201H/R201C substitutions) were also detected. MCL1 and JUN were concurrently amplified in three patients. One patient with MCL1 and JUN amplification had concurrent amplification of MYC and NFKBIA. ZNF703 was amplified in one patient. Patients with MCL1 amplification were also found to express MCL1 with immunohistochemistry, but MCL1 expression was also detected in some patients without amplification. To our knowledge, we are the first to report MCL1 and JUN coamplification in PMP. Expression of MCL1 may not be completely dependent on amplification. The prognostic and therapeutic implications of these recurrent mutational events are the subject of ongoing investigation.

Incidence and outcomes of chemotherapy and radiation in morbidly obese patients with locally advanced lung and esophageal cancers: a single-institution experience.

BACKGROUND: In 2012, the American Society of Clinical Oncology issued a guideline urging health care professionals to "routinely use an obese patient's actual body weight, rather than an ideal body weight or other estimate, to calculate the appropriate dose of nearly all chemotherapy drugs. " This guideline does not address dosages for patients who are morbidly obese (body mass index ≥ 40) and receiving concomitant chemotherapy and radiation. METHODS: This report describes a single-institution experience intended to address the issue of appropriate dosages for this patient population. RESULTS: Among 1,886 cancer patients who received curative thoracic radiation at the Mayo Clinic, 16 (0.8%) were morbidly obese and received concomitant chemotherapy and radiation. Charlson morbidity scores for the cohort ranged from 2 to 9, and 10 patients had esophageal cancer. Ten of 16 patients received an initial chemotherapy dose reduction, and 4 of these patients experienced major adverse events, including 1 death. Similarly, among the 6 patients who received full-dose chemotherapy at the beginning of treatment, 2 had major adverse events. Nine patients went on to have their cancers resected, but no differences in survival were apparent among patients who received initial dose reductions and those who did not. CONCLUSIONS: This single-institution experience remains limited. However, in view of the severe toxicity observed in this cohort, chemotherapy dose reductions seem appropriate in specific instances. Clinicians should also consider prescribing newer chemotherapy regimens that may be better tolerated in morbidly obese patients with cancer.

Multimodality therapy including salvage surgical resection and intraoperative radiotherapy for patients with squamous-cell carcinoma of the anus with residual or recurrent disease after primary chemoradiotherapy.

BACKGROUND: For patients with residual or recurrent squamous-cell carcinoma of the anus after primary chemoradiotherapy, the standard treatment is surgical salvage. Patients with unresectable or borderline unresectable disease have poor outcomes, thus adjunctive treatments should be explored. OBJECTIVE: The aim of this study is to report outcomes for patients with residual/recurrent anal cancer treated with multimodality therapy including salvage surgical resection and intraoperative radiotherapy. DESIGN: This is an observational study. SETTINGS: This study was conducted at a tertiary referral center. PATIENTS: Thirty-two patients were treated between 1993 and 2012. Median age was 53 years (range, 34-87). Salvage treatment was performed for residual disease (n = 9), first recurrence (n = 17), or second recurrence (n = 6) after primary chemoradiotherapy. INTERVENTIONS: Patients with recurrent disease received preoperative external beam reirradiation with concurrent chemotherapy. All patients underwent salvage surgical resection and intraoperative radiotherapy. Extent of surgical resection was R0 (negative margins, n = 16), R1 (microscopic residual, n = 13), or R2 (macroscopic residual, n = 3). The median intraoperative radiotherapy dose was 12.5 Gy. MAIN OUTCOME MEASURES: Treatment-related adverse events were classified according to the National Cancer Institute - Common Toxicity Criteria. Overall and disease-free survival were estimated by using the Kaplan-Meier technique. Central, local-regional, and distant failure were estimated by the use of the cumulative incidence method. RESULTS: Median length of hospital stay was 9 days. Mortality at 30 days after surgery and intraoperative radiotherapy was 0%. Fifteen patients (47%) experienced a total of 16 grade 3 treatment-related adverse events (wound complication (n = 6), bowel obstruction (n = 5), and ureteral obstruction (n = 3)). The 5-year estimates of overall and disease-free survival were 23% and 17%. The 5-year estimates of central, local-regional, and distant failure were 21%, 51%, and 40%. LIMITATIONS: This was a single-institution observational study with limited patient numbers. CONCLUSIONS: In this heavily pretreated, high-risk patient population, multimodality therapy including salvage surgery and intraoperative radiotherapy was associated with long-term survival in a small, but significant subset of patients.

Influence of patient's physiologic factors and immobilization choice with stereotactic body radiotherapy for upper lung tumors.

The purpose of the present study was to compare the impact of pulmonary function, body habitus, and stereotactic body radiation therapy (SBRT) immobilization on setup and reproducibility for upper lung tumor. From 2008 through 2011, our institution's prospective SBRT database was searched for patients with upper lung tumors. Two SBRT immobilization strategies were used: full-length BodyFIX and thermoplastic S-frame. At simulation, free-breathing, four-dimensional computed tomography was performed. For each treatment, patients were set up to isocenter with in-room lasers and skin tattoos. Shifts from initial and subsequent couch positions with cone-beam computed tomography (CBCT) were analyzed. Accounting for setup uncertainties, institutional tolerance of CBCT-based shifts for treatment was 2, 2, and 4 mm in left-right, anterior-posterior, and cranial-caudal directions, respectively; shifts exceeding these limits required reimaging. Each patient's pretreatment pulmonary function test was recorded. A multistep, multivariate linear regression model was performed to elucidate intervariable dependency for three-dimensional calculated couch shift parameters. BodyFIX was applied to 76 tumors and S-frame to 17 tumors. Of these tumors, 41 were non-small cell lung cancer and 15 were metastatic from other sites. Lesions measured < 1 (15%), 1.1 to 2 (50%), 2.1 to 3 (25%), and > 3 (11%) cm. Errors from first shifts of first fractions were significantly less with S-frame than BodyFIX (p < 0.001). No difference in local control (LC) was found between S-frame and BodyFIX (p = 0.35); two-year LC rate was 94%. Multivariate modeling confirmed that the ratio of forced expiratory volume in the first second of expiration to forced vital capacity, body habitus, and the immobilization device significantly impacted couch shift errors. For upper lung tumors, initial setup was more consistent with S-frame than BodyFIX, resulting in fewer CBCT scans. Patients with obese habitus and poor lung function had more SBRT setup uncertainty; however, outcome and probability for LC remained excellent.

Radiotherapy for aseptic granulomatous dermatitis: A case report.

Granulomatous dermatitis is a common tissue reaction pattern seen in the skin or systematically in various presentations. Granulomatous dermatitis can be subclassified into infectious and non-infectious categories. This article focuses on a patient with non-infectious granulomatous dermatitis followed for many years. Past medical history included bilateral total shoulder arthroplasty complicated by prosthetic joint infections. In its early stages, the axillary rash was painful and had many fluid-filled blisters. Ultimately, the histology of the rash deemed the lesion non-infectious and mostly due to an inflammatory process. Specifically, ionizing radiation was used for this patient. The category of granulomatous processes is broad and there are many subtypes. Other treatment options for non-infectious granulomatous processes may include corticosteroids, phototherapy, and interferon-gamma injections. The differential for granulomatous processes is extensive and treatment should be decided on a case-by-case basis.

Non-Fungible Tokens for Organoids: Decentralized Biobanking to Empower Patients in Biospecimen Research.

Introduction: Scientists use donated biospecimens to create organoids, which are miniature copies of patient tumors that are revolutionizing precision medicine and drug discovery. However, biobanking platforms remove donor identifiers to protect privacy, precluding patients from benefiting from their contributions or sharing information that may be relevant to research outcomes. Decentralized biobanking (de-bi) leverages blockchain technology to empower patient engagement in biospecimen research. We describe the creation of the first de-bi prototype for an organoid biobanking use case. Methods: We designed and developed a proof-of-concept non-fungible tokens (NFTs) framework for an organoid research network of patients, physicians, and scientists within a synthetic dataset modeled on a real-world breast cancer organoid ecosystem. Our implementation deployed multiple smart contracts on Ethereum test networks, minting NFTs representing each stakeholder, biospecimen, and organoid. The system architecture was designed to be composable with established biobanking programs. Results: Our de-bi prototype demonstrated how NFTs representing patients, physicians, scientists, and organoids may be united in a privacy-preserving platform that builds upon relationships and transactions of existing biobank research networks. The mobile application simulated key features, enabling patients to track their biospecimens, view organoid images and research updates from scientists, and allow physicians to participate in peer-to-peer communications with basic scientists and patients alike, all while ensuring compliance with de-identification requirements. Discussion: We demonstrate proof-of-concept for a web3 platform engaging patients, physicians, and scientists in a dynamic research community, unlocking value for a model organoid ecosystem. This initial prototype is a critical first step for advancing paradigm-shifting de-bi technology that provides unprecedented transparency and suggests new standards for equity and inclusion in biobanking. Further research must address feasibility and acceptability considering the ethical, legal, economic, and technical complexities of organoid research and clinical translation.

A Longitudinal Metagenomic Comparative Analysis of Oral Microbiome Shifts in Patients Receiving Proton Radiation versus Photon Radiation for Head and Neck Cancer.

Introduction: Due to the radiation-sparing effects on salivary gland acini, changes in the composition of the oral microbiome may be a driver for improved outcomes in patients receiving proton radiation, with potentially worse outcomes in patients exposed to photon radiation therapy. To date, a head-to-head comparison of oral microbiome changes at a metagenomic level with longitudinal sampling has yet to be performed in these patient cohorts. Methods and Materials: To comparatively analyze oral microbiome shifts during head and neck radiation therapy, a prospective pilot cohort study was performed at the Maryland Proton Treatment Center and the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center. A longitudinal metagenomic comparative analysis of oral microbiome shifts was performed at three time points (pre-radiation, during radiation, and immediately post-radiation). Head and neck cancer patients receiving proton radiation (n = 4) were compared to photon radiation (n = 4). Additional control groups included healthy age- and sex-matched controls (n = 5), head and neck cancer patients who never received radiation therapy (n = 8), and patients with oral inflammatory disease (n = 3). Results: Photon therapy patients presented with lower microbial alpha diversity at all timepoints, and there was a trend towards reduced species richness as compared with proton therapy. Healthy controls and proton patients exhibited overall higher and similar diversity. A more dysbiotic state was observed in patients receiving photon therapy as compared to proton therapy, in which oral microbial homeostasis was maintained. Mucositis was observed in 3/4 photon patients and was not observed in any proton patients during radiation therapy. The bacterial de novo pyrimidine biosynthesis pathway and the nitrate reduction V pathway were comparatively higher following photon exposure. These functional changes in bacterial metabolism may suggest that photon exposure produces a more permissive environment for the proliferation of pathogenic bacteria. Conclusion: Oral microbiome dysbiosis in patients receiving photon radiation may be associated with increased mucositis occurrence. Proton radiation therapy for head and neck cancer demonstrates a safer side effect profile in terms of oral complications, oral microbiome dysbiosis, and functional metabolic status.

Assessment of patient-reported measures of bowel function before and after pelvic radiotherapy: an ancillary study of the North Central Cancer Treatment Group study N00CA.

PURPOSE: The Bowel Function Questionnaire (BFQ) has been used in clinical trials to assess symptoms during and after pelvic radiotherapy (RT). This study evaluated the importance of symptoms in the BFQ from a patient perspective. METHODS: Patients reported presence or absence of symptoms and rated importance of symptoms at baseline, 4 weeks after completion of pelvic RT, and 12 and 24 months after RT. The BFQ measured overall quality of life (QOL) and symptoms of nocturnal bowel movements, incontinence, clustering, need for protective clothing, inability to differentiate stool from gas, liquid bowel movements, urgency, cramping, and bleeding. Bowel movement frequency also was recorded. A content validity questionnaire (CVQ) was used to rate symptoms as "not very important," "moderately unimportant," "neutral," "moderately important," or "very important." RESULTS: Most of the 125 participating patients rated all symptoms as moderately or very important. Generally, patients gave similar ratings for symptom importance at all study points, and ratings were independent of whether the patient experienced the symptom. Measures of greatest importance (moderately or very important) at baseline were ability to control bowel movements (94 %), not having to wear protective clothing (90 %), and not having rectal bleeding (94 %). With the exception of need for protective clothing, the presence of a symptom at 4 weeks was associated with significantly worse QOL (P < .01 for all). CONCLUSIONS: The BFQ has excellent content validity. Patients rated most symptoms as moderately or very important, indicating the BFQ is an appropriate tool for symptom assessment during and after pelvic RT.

Incidence of Brain Metastasis as First Event in Patients with Esophageal Carcinoma: a Report from Three Prospective Alliance Clinical Trials.

PURPOSE: Historically, reported incidence of brain metastasis secondary to esophageal carcinoma is low. We sought to determine the incidence of brain metastasis in a contemporary cohort of patients with carcinoma of the esophagus. METHODS: Data from patients with localized esophageal carcinoma prospectively enrolled on three curative intent Alliance treatment trials (N0044, N0342, N044E) were reviewed including time to diagnosis of first progression event (brain versus other site) and overall survival. RESULTS: Eighty-five patients comprised the cohort of which 85% were male and 86% had adenocarcinoma primary tumor histology. Thirty-nine of the 85 patients had documented progression to any site, and of those, brain metastasis occurred as the first event in 15% (6 of 39). Adenocarcinoma was the primary histology in all 6 patients and tumor grade was high (3 or 4) in 5 of the 6 patients (one not documented). Median time to brain metastasis (9.6 months) versus non-brain metastasis (12.4 months) and median survival after first progression (5.4 months versus 8.1 months, respectively) were not statistically different. CONCLUSION: In this prospective cohort of patients with esophageal carcinoma, those with high-grade adenocarcinoma appear to have a higher incidence of brain metastasis than historically reported. The pattern of brain metastases corroborates recent findings in terms of incidence, predominance of adenocarcinoma primary tumor histology, timing after diagnosis, and overall survival. Further study to confirm these findings, as well as the value of baseline, restaging and follow-up cranial imaging for brain metastasis is recommended. GOV IDENTIFIERS: NCT00022139 (NCCTG N0044), NCT00100945 (NCCTG N0342), and NCT00100945 (NCCTG N044E).

Using the Skindex-16 and Common Terminology Criteria for Adverse Events to assess rash symptoms: results of a pooled-analysis (N0993).

BACKGROUND: Historically, skin toxicity has been assessed in prospective clinical trials using the clinician-reported National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE). The patient-reported Skindex-16 measures symptoms and perceptions of toxicity. This study was designed to compare information provided by these two measures. METHODS: Data were compiled from three placebo-controlled North Central Cancer Treatment Group studies (N06C4, N03CB, N05C4) having rash prevention as the primary objective. All used the Skindex-16 and CTCAE at baseline, weekly during treatment and during a minimum 2-week follow-up period. Statistical procedures, including Pearson correlations, were utilized to determine relationships between adverse event (AE) grades and Skindex-16 scores. RESULTS: Four hundred and twelve individual patients provided data (median age, 61; 134 male). Patients' Skindex-16 score results show a 0.9 overall mean (range 0-6 with 6 being worse symptoms), a 0.4 baseline mean (range, 0-4.3) and a 1.3 end-of-treatment mean (range, 0-5.9). Ninety-three, 142 and 177 patients experienced a grade 0, 1 and 2+ CTCAE skin toxicity, respectively. Baseline Skindex-16 scores had relatively low correlation with CTCAE grades. The correlation of rash grade with Skindex-16 scores ranged from r = 0.49 with the function subscale to r = 0.62 with the symptom subscale. The highest correlations of the maximum grade of any dermatological AE with the Skindex-16 were r = 0.48 for the total score and r = 0.55 for the symptom subscale. CONCLUSIONS: The data reported support the decision to include both measures in a clinical trial to assess the patient experience, as each measure may specifically target varying symptoms and intensities.

Psychosocial Impact of the War in Ukraine on Pediatric Cancer Patients and Their Families Receiving Oncological Care Outside Their Country at the Onset of Hostilities.

Psychosocial care of pediatric cancer patients and their families is as critical as the medical and surgical components of their therapies. Strains on family communication and structure and financial need are linked to poorer psychological outcomes for both patients and families. It is critical that children remain as connected as possible to their communities and extended families during therapy. For Ukrainian pediatric cancer patients receiving care outside of their nation's borders on February 24, 2022, the Russian invasion of Ukraine compounded these problems. Based on conversations with patients and parents, we evaluated the psychosocial impact of war on pediatric Ukrainian cancer patients and their families who had left their country before the onset of the conflict to undergo treatment of pediatric malignancies at our medical center. These families shared with us the problems they have experienced after the Russian invasion of Ukraine. Their concerns can be summarized in 4 categories: (1) emotional stress experienced by the patients, families and relatives related to the dangers of war; (2) difficulties in obtaining previous hospital records in Ukraine; (3) medical expenses; and (4) uncertainty regarding the patient's and their family's future and the ability of the children to ever return to their homes. Psychosocial distress relating to the violence of war will hopefully pass in near future, but our pediatric patients and their families will continue to face stressors related to displacement and financial concerns for some time to come.

Respect, justice and learning are limited when patients are deidentified data subjects.

Introduction: Critical for advancing a Learning Health System (LHS) in the U.S., a regulatory safe harbor for deidentified data reduces barriers to learning from care at scale while minimizing privacy risks. We examine deidentified data policy as a mechanism for synthesizing the ethical obligations underlying clinical care and human subjects research for an LHS which conceptually and practically integrates care and research, blurring the roles of patient and subject. Methods: First, we discuss respect for persons vis-a-vis the systemic secondary use of data and tissue collected in the fiduciary context of clinical care. We argue that, without traditional informed consent or duty to benefit the individual, deidentification may allow secondary use to supersede the primary purpose of care. Next, we consider the effectiveness of deidentification for minimizing harms via privacy protection and maximizing benefits via promoting learning and translational care. We find that deidentification is unable to fully protect privacy given the vastness of health data and current technology, yet it imposes limitations to learning and barriers for efficient translation. After that, we evaluate the impact of deidentification on distributive justice within an LHS ethical framework in which patients are obligated to contribute to learning and the system has a duty to translate knowledge into better care. Such a system may permit exacerbation of health disparities as it accelerates learning without mechanisms to ensure that individuals' contributions and benefits are fair and balanced. Results: We find that, despite its established advantages, system-wide use of deidentification may be suboptimal for signaling respect, protecting privacy or promoting learning, and satisfying requirements of justice for patients and subjects. Conclusions: Finally, we highlight ethical, socioeconomic, technological and legal challenges and next steps, including a critical appreciation for novel approaches to realize an LHS that maximizes efficient, effective learning and just translation without the compromises of deidentification.