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Multidistrict litigation (MDL) has long been dogged by worries about illegitimate or even fraudulent claims. These claims, and public concern about them, damage the system; they erode confidence in judicial processes, increase costs, and contribute to rising caseloads. But while many have noted the problem, and some have even sought to address it, so far, judges' arsenals have been limited. Some judicial efforts (such as Lone Pine orders) amount to overkill: The entry of a Lone Pine order threatens to chill the vindication of important rights, not merely the initiation of bogus claims. Other efforts, such as plaintiff fact sheets and census orders, suffer from the opposite problem: Because they often lack teeth, these orders can encourage a game of judicial whack-a-mole, as some nonmeritorious claims may be rooted out even as more such claims are ushered in. Against that backdrop, we offer an innovative and practical solution to address this problem head-on. In particular, we explain how MDL transferee judges can harness common benefit fees to induce plaintiffs' lawyers to improve their screening practices, encouraging lawyers to cull invalid claims before they are filed. By assessing common benefit fees on a sliding scale, judges can financially reward those lawyers who meaningfully vet would-be clients and penalize those who don't. Over time, through tailored and targeted efforts, judges can ensure that attorneys are properly incentivized to review the factual basis of suits while also keeping courts open to claims of uncertain-but-possible merit. [ABSTRACT FROM AUTHOR]

Despite recent advances in the management of colorectal cancer, metastatic disease remains challenging, and patients are rarely cured. However, a better understanding of the pathways implicated in the evolution and proliferation of cancer cells has led to the development of targeted therapies, that is, agents with action directed at these pathways/features. This approach is more specific to cells within which these pathways, such as epidermal growth factor receptor (EGFR), are overactive; this is in contrast to the relatively indiscriminate mechanism by which cytotoxic chemotherapy tends to affect rapidly dividing cells, regardless of their role. Although factors unique to a given patient, such as the location of the primary tumor (sidedness) or the presence of mutations that confer resistance, may limit the utility of these agents, targeted therapies are now a part of the treatment paradigm for metastatic colorectal cancer, and survival outcomes have significantly improved. This review provides an overview of the role of targeted therapy in the management of patients with colorectal cancer metastases as well as a discussion of issues in patient selection, with a focus on inhibitors of angiogenesis, EGFR-targeted therapy, BRAF mutation-targeted therapies, and other novel strategies, including immunotherapy. [ABSTRACT FROM AUTHOR]

Importance: Combining biologic monoclonal antibodies with chemotherapeutic cytotoxic drugs provides clinical benefit to patients with advanced or metastatic colorectal cancer, but the optimal choice of the initial biologic therapy in previously untreated patients is unknown.Objective: To determine if the addition of cetuximab vs bevacizumab to the combination of leucovorin, fluorouracil, and oxaliplatin (mFOLFOX6) regimen or the combination of leucovorin, fluorouracil, and irinotecan (FOLFIRI) regimen is superior as first-line therapy in advanced or metastatic KRAS wild-type (wt) colorectal cancer.Design, Setting, and Participants: Patients (≥18 years) enrolled at community and academic centers throughout the National Clinical Trials Network in the United States and Canada (November 2005-March 2012) with previously untreated advanced or metastatic colorectal cancer whose tumors were KRAS wt chose to take either the mFOLFOX6 regimen or the FOLFIRI regimen as chemotherapy and were randomized to receive either cetuximab (n = 578) or bevacizumab (n = 559). The last date of follow-up was December 15, 2015.Interventions: Cetuximab vs bevacizumab combined with either mFOLFOX6 or FOLFIRI chemotherapy regimen chosen by the treating physician and patient.Main Outcomes and Measures: The primary end point was overall survival. Secondary objectives included progression-free survival and overall response rate, site-reported confirmed or unconfirmed complete or partial response.Results: Among 1137 patients (median age, 59 years; 440 [39%] women), 1074 (94%) of patients met eligibility criteria. As of December 15, 2015, median follow-up for 263 surviving patients was 47.4 months (range, 0-110.7 months), and 82% of patients (938 of 1137) experienced disease progression. The median overall survival was 30.0 months in the cetuximab-chemotherapy group and 29.0 months in the bevacizumab-chemotherapy group with a stratified hazard ratio (HR) of 0.88 (95% CI, 0.77-1.01; P = .08). The median progression-free survival was 10.5 months in the cetuximab-chemotherapy group and 10.6 months in the bevacizumab-chemotherapy group with a stratified HR of 0.95 (95% CI, 0.84-1.08; P = .45). Response rates were not significantly different, 59.6% vs 55.2% for cetuximab and bevacizumab, respectively (difference, 4.4%, 95% CI, 1.0%-9.0%, P = .13).Conclusions and Relevance: Among patients with KRAS wt untreated advanced or metastatic colorectal cancer, there was no significant difference in overall survival between the addition of cetuximab vs bevacizumab to chemotherapy as initial biologic treatment.Trial Registration: clinicaltrials.gov identifier: NCT00265850. [ABSTRACT FROM AUTHOR]

Purpose: No standard of care exists for patients with metastatic pancreatic cancer following progression on first-line chemotherapy. Based on potential for additive or synergistic activity by concurrent inhibition of VEGF and EGFR, we conducted a phase II study evaluating the combination of bevacizumab plus erlotinib in this patient population. Methods: Patients with metastatic pancreatic adenocarcinoma, ECOG performance status 0-1, and previous exposure to 1-3 systemic therapies (at least one gemcitabine-based) were eligible. Treatment consisted of bevacizumab 15 mg/kg every 21 days plus erlotinib 150 mg daily. Results: Thirty-six patients were enrolled, including eight who had previously received VEGF-targeted therapy and nine prior erlotinib. Median number of treatment cycles was 2 (range, 1-7). Common toxicities included rash (72%), diarrhea (25%), venous thromboembolic events (15%), and hypertension (11%). One patient demonstrated partial response and seven others stable disease for >2 cycles. CA19-9 decline ≥25% was observed in 4/26 patients with baseline levels >2 x ULN. Estimated median time to progression was 40 days (95% CI, 35-41 days) and median survival 102 days (95% CI, 74-117 days), with a 6-month survival rate of 22%. Baseline concentration of circulating endothelial cells (CD45/CD34/CD31) was inversely associated with overall survival. Conclusions: The combination of bevacizumab and erlotinib is safe but relatively ineffective in patients with gemcitabine-refractory metastatic pancreatic cancer. Future studies should focus on refining subsets of patients in this challenging population likely to benefit from treatment beyond first-line. [ABSTRACT FROM AUTHOR]

The currents induced in long conductors such as guidewires by the radio-frequency (RF) field in magnetic resonance imaging (MRI) are responsible for potentially dangerous heating of surrounding media, such as tissue. This paper presents an optically coupled system with the potential to quantitatively measure the RF currents induced on these conductors. The system uses a self shielded toroid transducer and active circuitry to modulate a high speed light-emitting-diode transmitter. Plastic fiber guides the light to a photodiode receiver and transimpedance amplifier. System validation included a series of experiments with bare wires that compared wire tip heating by fluoroptic thermometers with the RF current sensor response. Validations were performed on a custom whole body 64 MHz birdcage test platform and on a 1.5 T MRI scanner. With this system, a variety of phenomena were demonstrated including cable trap current attenuation, lossy dielectric Q-spoiling and even transverse electromagnetic wave node patterns. This system should find applications in studies of MRI RF safety for interventional devices such as pacemaker leads, and guidewires. In particular, variations of this device could potentially act as a realtime safety monitor during MRI guided interventions. [ABSTRACT FROM AUTHOR]

The authors discuss an article by A. Mahipal and A. Grothey on the role of biologics in first-line treatment of metastatic colorectal cancer. Topics include explanation on why patients with metastatic colorectal cancer have derived less benefit than was expected from biologic agents, definition of the term biologics, and basis of using bevacizumab as treatment for colorectal cancer.

Combination therapy of two antitumor agents may provide treatment additivity or synergy. Phase I trials for combination therapy search for the maximum tolerated dose (MTD) for combined agents. The conventional approach is to preselect an escalation path, usually increasing the dose of one agent and then another, and to use the standard 3 + 3 design. However, this procedure may miss the optimum dose combination, prolong the time it takes, and increase the number of patients necessary to reach the MTD. In this study, we present strategies for a comprehensive search for MTD for a two-agent combination therapy. We evaluate algorithms based on two-stage and three-stage design as well as variations in cohort size. A two-dimensional isotonic estimation method for toxicity rate is provided. We use simulation methods to compare 2 + 1 + 3 vs. 3 + 3 cohort sizes. We conclude that the comprehensive search proposed in our study can be more practical and efficient in identifying the MTD in combination-therapy of two agents. [ABSTRACT FROM AUTHOR]

Despite important refinements of surgical technique and significant progress in perioperative care, esophageal cancer remains highly lethal. Therefore, hope for improvement in the prognosis of esophageal cancer lies largely in the use of additional therapy. Promising data from numerous Phase II trials and a single Phase III trial led to the widespread adoption of neoadjuvant chemoradiotherapy. However, subsequent randomized trials did not conclusively demonstrate a survival benefit with any of the current neoadjuvant protocols for patients with resectable esophageal cancer. Benefit, if any, exists only for complete pathologic responders. Neoadjuvant chemoradiation should not be used in patients with resectable esophageal cancer outside of the clinical trials. Future investigation must focus on the development of new biologic or chemotherapeutic agents, and the identification of biologic markers that might predict response to chemoradiation. [Copyright &y& Elsevier]

A letter to the editor is presented in response to an article about the use of imatinib for treating metastatic gastrointestinal stromal tumor during an economic downturn.

Purpose: Persistent gastrointestinal (GI) symptoms are frequently experienced by colon cancer survivors and may help identify patients with higher utilization of healthcare services. To assess the relationship between GI symptoms and specialty care utilization among colon cancer survivors. Methods: A prospective longitudinal cohort study at an academic medical center of 126 adults surgically treated for stage I–IV colon cancer between February 2017 and June 2022. Participants reported GI symptoms through the EORTC QLQ-C30 and QLQ-CR29 at enrollment and as frequently as every 6 months for 5 years. Main outcome measures were visits, telephone encounters, and secure messages with a medical provider within specialty oncology clinics within 6 months after each survey completion. Generalized linear mixed regression model for repeated measurements with random trajectory for each participant was performed to estimate the associations between symptoms and healthcare use. Models were adjusted for demographics, clinical and surgical factors, and timing in relation to onset of the COVID-19 pandemic. Results: In the 6 months after each survey time point, patients averaged 1.2 visits, 0.5 telephone encounters, and 3.2 patient-initiated messages. In adjusted models, those with any abdominal pain (RR 1.45; p = 0.002), buttock pain (RR 1.30; p = 0.050), or increased stool frequency (RR 1.26; p = 0.046) had more clinic visits in the following 6 months than those without these symptoms. Including these three symptoms in one model revealed that only abdominal pain was statistically significantly associated with increased clinic visits (RR 1.36; p = 0.016). Patients with any blood or mucus in stool (RR 2.46; p = 0.009) had significantly more telephone encounters, and those with any abdominal pain (RR 1.65; p = 0.002) had significantly more patient-initiated messages than those without these symptoms. Conclusions: Our findings identify GI symptoms associated with increased use of oncologic specialty care among colon cancer survivors, with abdominal pain as an important predictor of utilization. Implications for cancer survivors: Early identification and anticipatory management of colon cancer survivors experiencing abdominal pain may decrease healthcare utilization. [ABSTRACT FROM AUTHOR]

Background: Herein, we report results from a genome-wide study conducted to identify protein quantitative trait loci (pQTL) for circulating angiogenic and inflammatory protein markers in patients with metastatic colorectal cancer (mCRC). The study was conducted using genotype, protein marker, and baseline clinical and demographic data from CALGB/SWOG 80405 (Alliance), a randomized phase III study designed to assess outcomes of adding VEGF or EGFR inhibitors to systemic chemotherapy in mCRC patients. Germline DNA derived from blood was genotyped on whole-genome array platforms. The abundance of protein markers was quantified using a multiplex enzyme-linked immunosorbent assay from plasma derived from peripheral venous blood collected at baseline. A robust rank-based method was used to assess the statistical significance of each variant and protein pair against a strict genome-wide level. A given pQTL was tested for validation in two external datasets of prostate (CALGB 90401) and pancreatic cancer (CALGB 80303) patients. Bioinformatics analyses were conducted to further establish biological bases for these findings. Results: The final analysis was carried out based on data from 540,021 common typed genetic variants and 23 protein markers from 869 genetically estimated European patients with mCRC. Correcting for multiple testing, the analysis discovered a novel cis-pQTL in LINC02869, a long non-coding RNA gene, for circulating TGF-β2 levels (rs11118119; AAF = 0.11; P-value < 1.4e-14). This finding was validated in a cohort of 538 prostate cancer patients from CALGB 90401 (AAF = 0.10, P-value < 3.3e-25). The analysis also validated a cis-pQTL we had previously reported for VEGF-A in advanced pancreatic cancer, and additionally identified trans-pQTLs for VEGF-R3, and cis-pQTLs for CD73. Conclusions: This study has provided evidence of a novel cis germline genetic variant that regulates circulating TGF-β2 levels in plasma of patients with advanced mCRC and prostate cancer. Moreover, the validation of previously identified pQTLs for VEGF-A, CD73, and VEGF-R3, potentiates the validity of these associations. [ABSTRACT FROM AUTHOR]

Unlocking the full dimensionality of single-cell RNA sequencing data (scRNAseq) is the next frontier to a richer, fuller understanding of cell biology. We introduce q-diffusion, a framework for capturing the coexpression structure of an entire library of genes, improving on state-of-the-art analysis tools. The method is demonstrated via three case studies. In the first, q-diffusion helps gain statistical significance for differential effects on patient outcomes when analyzing the CALGB/SWOG 80405 randomized phase III clinical trial, suggesting precision guidance for the treatment of metastatic colorectal cancer. Secondly, q-diffusion is benchmarked against existing scRNAseq classification methods using an in vitro PBMC dataset, in which the proposed method discriminates IFN-γ stimulation more accurately. The same case study demonstrates improvements in unsupervised cell clustering with the recent Tabula Sapiens human atlas. Finally, a local distributional segmentation approach for spatial scRNAseq, driven by q-diffusion, yields interpretable structures of human cortical tissue. The q-diffusion method uses the full dimensionality of gene coexpression in transcriptomics and benchmarking shows improvment of scRNAseq analyses. [ABSTRACT FROM AUTHOR]

Introduction: Prognosis after resection of hepatocellular carcinoma (HCC) is highly variable. Compared to clinicopathologic factors, the use of molecular markers to predict outcome has not been well studied. We investigated the prognostic importance of thymidylate synthase (TS) gene expression and polymorphisms in patients after resection of HCC. Methods: Patients who underwent complete resection of HCC for whom tissue was available were identified. TS gene expression level and polymorphisms were determined in HCC specimens. Prognostic factors were evaluated using Kaplan-Meier curves and Cox proportional hazard models. Results: The study included 67 patients. In univariate analysis, variables that negatively influenced survival included TNM stage, microvascular invasion, and high TS expression. For the high TS expression group, median survival was 54 months and 5-year actuarial survival was 47%. For the low TS expression group, median survival was not reached and the 5-year actuarial survival was 91%. In multivariate analysis, only high TS expression remained an independent predictor of poor survival (HR = 10.77, 95% CI 1.36–84.91; P = 0.02). TS gene polymorphisms were not associated with TS expression or overall survival. Conclusions: High TS expression predicts poor outcome after resection of HCC. Molecular markers might be robust predictors of patient outcome after resection of HCC. [ABSTRACT FROM AUTHOR]

Background: One in three patients with stage III colon cancer will experience tumor recurrence. It is uncertain whether physical activity during and after postoperative chemotherapy for stage III colon cancer improves overall survival after tumor recurrence. Methods: A prospective cohort study nested within a randomized multicenter trial of patients initially diagnosed with stage III colon cancer who experienced tumor recurrence (N = 399) was conducted. Postoperative physical activity before tumor recurrence was measured. Physical activity energy expenditure was quantified via metabolic equivalent task hours per week (MET‐h/week). The primary end point was overall survival after tumor recurrence. Multivariable flexible parametric survival models estimated relative and absolute effects with two‐sided hypothesis tests. Results: Compared with patients expending <3.0 MET‐h/week of physical activity (comparable to <1.0 h/week of brisk walking), patients with ≥18.0 MET‐h/week of physical activity (comparable to 6 h/week of brisk walking) had a 33% relative improvement in overall survival time after tumor recurrence (hazard ratio, 0.67; 95% CI, 0.42–0.96). The overall survival rate at 3 years after tumor recurrence was 61.3% (95% CI, 51.8%–69.2%) with <3.0 MET‐h/week of physical activity and 72.2% (95% CI, 63.1%–79.6%) with ≥18 MET‐h/week of physical activity (risk difference, 10.9 percentage points; 95% CI, 1.2–20.8 percentage points). Conclusions: Higher postoperative physical activity is associated with improved overall survival after tumor recurrence in patients initially diagnosed with stage III colon cancer. These data may be relevant to patients who, despite optimal postoperative medical therapy, have a high risk of tumor recurrence. Among patients initially diagnosed with stage III colon cancer enrolled in a trial of postoperative treatment, higher postoperative physical activity is associated with improved overall survival after tumor recurrence. Oncologists may wish to include counseling about the potential benefits of physical activity in their postoperative treatment consultations. [ABSTRACT FROM AUTHOR]

Simple Summary: The trillions of microorganisms found in the human gut have broad impacts on health and disease including altering the risk of colorectal cancer. Given the emerging evidence that both the microbiome and colorectal cancer differ between racial and ethnic groups, we sought to explore the relationship between the gut microbiome and cancer health disparities. We performed a pilot and feasibility study in which 30 colorectal cancer patients from different racial and ethnic backgrounds were recruited to provide a stool sample and to complete a dietary survey. The majority (18/30) of participants were successfully sampled, providing preliminary support for associations between their gut microbes according to racial and ethnic background. Overall, this study supports the feasibility of analyzing the links between gut microbes and colorectal cancer disparities, laying the groundwork for large follow-up studies. Background: Colorectal cancer (CRC) is more prevalent among some racial and ethnic minority and low socioeconomic status populations. Although the gut microbiota is a risk factor for CRC and varies with race and ethnicity, its role in CRC disparities remains poorly understood. Methods: We examined the feasibility of recruiting sociodemographically diverse CRC patients for a microbiome study involving a home stool collection. We also explored whether race and ethnicity were associated with gut microbiome composition. We recruited Black/African American, Hispanic/Latino, and non-Hispanic White patients who were receiving care for active CRC to complete a comprehensive dietary and lifestyle survey, self-collect a stool sample, and complete an exit interview. Gut microbial diversity and composition were analyzed using 16S rRNA gene sequencing. Results: 30 individuals consented (of 35 who were eligible and contacted) with 5 (17%) Black/African American, 11 (37%) Hispanic/Latino, and 14 (46%) non-Hispanic White. A total of 22 (73%) completed the dietary and lifestyle survey; 18 (63%) returned a stool sample. Even after controlling for socioeconomic, dietary, or treatment-related covariates, microbiome composition was associated with race and ethnicity. Fusobacteriota (a phylum associated with the development and progression of CRC) was significantly higher in the Black/African American group compared to others, and microbial diversity was higher in samples from non-Hispanic White individuals compared to Hispanic/Latino individuals. Conclusion: Our study shows that it is feasible to recruit and collect stool samples from diverse individuals with CRC and found significant associations in gut microbial structure with race and ethnicity. [ABSTRACT FROM AUTHOR]

Simple Summary: In colon cancer clinical trials, treatment response is determined from the overall tumor measurement by summing up the individual lesion measurements. However, varied inter-tumor or individual tumor responses are commonly observed in clinical practice. Varied responses are well characterized in clinical trials when measuring one's response to treatment but its impact on clinical outcomes is unknown. To examine this question, we looked at patients that were enrolled in first-line clinical trials in metastatic colorectal cancer and measured individual lesion changes from their baseline measurements to 12 weeks. Varied responses were very common and occurred in more than 50% of patients. Associations between individual lesion response and patient outcomes were observed where overall survival varied (better or worse) based on the most commonly observed lesion response. A lesion-based criterion demonstrates some of the limitations in the way we currently measure treatment response in clinical trials and could be helpful for treatment decision-making and understanding the prognosis of patients. Metastatic colorectal cancer (mCRC) is a heterogeneous disease that can evoke discordant responses to therapy among different lesions in individual patients. The Response Evaluation Criteria in Solid Tumors (RECIST) criteria do not take into consideration response heterogeneity. We explored and developed lesion-based measurement response criteria to evaluate their prognostic effect on overall survival (OS). Patients and Methods: Patients enrolled in 17 first-line clinical trials, who had mCRC with ≥ 2 lesions at baseline, and a restaging scan by 12 weeks were included. For each patient, lesions were categorized as a progressing lesion (PL: > 20% increase in the longest diameter (LD)), responding lesion (RL: > 30% decrease in LD), or stable lesion (SL: neither PL nor RL) based on the 12-week scan. Lesion-based response criteria were defined for each patient as follows: PL only, SL only, RL only, and varied responses (mixture of RL, SL, and PL). Lesion-based response criteria and OS were correlated using stratified multivariable Cox models. The concordance between OS and classifications was measured using the C statistic. Results: Among 10,551 patients with mCRC from 17 first-line studies, varied responses were noted in 51.6% of patients, among whom, 3.3% had RL/PL at 12 weeks. Among patients with RL/SL, 52% had stable disease (SD) by RECIST 1.1, and they had a longer OS (median OS (mOS) = 19.9 months) than those with SL only (mOS = 16.8 months, HR (95% CI) = 0.81 (0.76, 0.85), p < 0.001), although a shorter OS than those with RL only (mOS = 25.8 months, HR (95% CI) = 1.42 (1.32, 1.53), p < 0.001). Among patients with SL/PL, 74% had SD by RECIST 1.1, and they had a longer OS (mOS = 9.0 months) than those with PL only (mOS = 8.0 months, HR (95% CI) = 0.75 (0.57, 0.98), p = 0.040), yet a shorter OS than those with SL only (mOS = 16.8 months, HR (95% CI) = 1.98 (1.80, 2.18), p < 0.001). These associations were consistent across treatment regimen subgroups. The lesion-based response criteria showed slightly higher concordance than RECIST 1.1, although it was not statistically significant. Conclusion: Varied responses at first restaging are common among patients receiving first-line therapy for mCRC. Our lesion-based measurement criteria allowed for better mortality discrimination, which could potentially be informative for treatment decision-making and influence patient outcomes. [ABSTRACT FROM AUTHOR]

Purpose: Exercise and healthy diet are key components of cancer survivorship. We sought to explore perceived barriers to engaging in healthy diet and exercise, and whether these barriers change throughout remote-based behavioral interventions. Methods: Smart Pace (SP) and Prostate 8 (P8) were two 12-week pilot randomized controlled trials (RCTs) among 42 colorectal cancer (CRC) survivors and 76 prostate cancer (PC) survivors, respectively, that encouraged participants to implement exercise (both) and healthy diet (P8 only) through text messaging and wearable fitness monitors; P8 also included web materials. Participants completed surveys on perceived barriers and confidence in their ability to implement healthy behaviors at enrollment and 12 weeks; P8 also included a 52-week assessment. Results: At enrollment, CRC survivors commonly reported a lack of discipline/willpower (36%), time (33%), and energy (31%); PC survivors often reported a lack of knowledge about healthy dietary behaviors (26%). Not having anyone with whom to exercise with was a common barrier among both groups (21% in CRC, 20% in PC). Among the intervention groups in both studies, various enrollment barriers (overall, functional/psychological disability, aversiveness, excuses, and inconveniences) were associated with change in behavior over time. Conclusions: Among CRC and PC survivors, there are multiple potential barriers related to motivation, time, social support, and lack of knowledge, that can be addressed and overcome to improve healthy behaviors. Tailoring lifestyle interventions to participants’ individual barriers and confidence is needed to promote and sustain behavior change long-term. [ABSTRACT FROM AUTHOR]

BACKGROUND Pelvic radiation plus sensitizing chemotherapy with a fluoropyrimidine (chemoradiotherapy) before surgery is standard care for locally advanced rectal cancer in North America. Whether neoadjuvant chemotherapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) can be used in lieu of chemoradiotherapy is uncertain. METHODS We conducted a multicenter, unblinded, noninferiority, randomized trial of neoadjuvant FOLFOX (with chemoradiotherapy given only if the primary tumor decreased in size by <20% or if FOLFOX was discontinued because of side effects) as compared with chemoradiotherapy. Adults with rectal cancer that had been clinically staged as T2 node-positive, T3 node-negative, or T3 node-positive who were candidates for sphincter-sparing surgery were eligible to participate. The primary end point was disease-free survival. Noninferiority would be claimed if the upper limit of the two-sided 90.2% confidence interval of the hazard ratio for disease recurrence or death did not exceed 1.29. Secondary end points included overall survival, local recurrence (in a time-to-event analysis), complete pathological resection, complete response, and toxic effects. RESULTS From June 2012 through December 2018, a total of 1194 patients underwent randomization and 1128 started treatment; among those who started treatment, 585 were in the FOLFOX group and 543 in the chemoradiotherapy group. At a median follow-up of 58 months, FOLFOX was noninferior to chemoradiotherapy for disease-free survival (hazard ratio for disease recurrence or death, 0.92; 90.2% confidence interval [CI], 0.74 to 1.14; P=0.005 for noninferiority). Five-year disease-free survival was 80.8% (95% CI, 77.9 to 83.7) in the FOLFOX group and 78.6% (95% CI, 75.4 to 81.8) in the chemoradiotherapy group. The groups were similar with respect to overall survival (hazard ratio for death, 1.04; 95% CI, 0.74 to 1.44) and local recurrence (hazard ratio, 1.18; 95% CI, 0.44 to 3.16). In the FOLFOX group, 53 patients (9.1%) received preoperative chemoradiotherapy and 8 (1.4%) received postoperative chemoradiotherapy. CONCLUSIONS In patients with locally advanced rectal cancer who were eligible for sphinctersparing surgery, preoperative FOLFOX was noninferior to preoperative chemoradiotherapy with respect to disease-free survival. (Funded by the National Cancer Institute; PROSPECT ClinicalTrials.gov number, NCT01515787.). [ABSTRACT FROM AUTHOR]

Summary: The recommendation of sorafenib as standard of care in advanced hepatocellular carcinoma has lent support to the increased use of antiangiogenic therapies. However, in three phase 3 randomised trials that compared other antiangiogenics with sorafenib, results did not show superiority or non-inferiority of the new therapies. The 10-month median overall survival shown in these studies for patients given sorafenib might be a ceiling for single-agent antiangiogenic therapy. Strategies to increase survival time include combination therapies that pair antiangiogenic treatment with biological therapy or chemotherapy. The combination of sorafenib and erlotinib was not superior to sorafenib alone, which suggests no positive interaction between antiangiogenics and tyrosine kinase inhibitors in the treatment of advanced hepatocellular carcinoma. A combination of sorafenib and doxorubicin is being assessed in a randomised phase 3 trial. Differences in patient outcome with sorafenib because of disease cause and the ethnic origin of patients suggest that sorafenib's multitarget capacity, including RAF kinase inhibition, might be important. MET inhibitors cabozantinib and tivantinib are drugs that might also bypass the so-called antiangiogenic ceiling and have led to selective treatment of patients that overexpress MET with these drugs. Although this intense period of research activity has not yet resulted in significant improvements in survival for patients with advanced hepatocellular carcinoma, we are certainly closer to a customised treatment, which should increase the antiangiogenic survival ceiling. [ABSTRACT FROM AUTHOR]

Background Women diagnosed with colorectal cancer (CRC) or anal squamous cell carcinoma (ASCC) are at high risk of sexual dysfunction after treatment, yet little is known about recovery and risk factors for chronic dysfunction. Aim We aimed to describe sexual function and sexual activity among women who underwent definitive treatment for CRC or ASCC, examine relationships between time since treatment completion and sexual function, and explore factors associated with desire and changes in sexual desire over time. Methods As part of a prospective cohort study of patients with gastrointestinal cancer at the University of California San Francisco, female-identifying participants who finished definitive treatment for CRC or ASCC completed the Female Sexual Function Index (FSFI) at 6- to 12-month intervals. We used multivariable linear mixed models to explore factors associated with the FSFI desire subscale. Outcomes Outcomes were rates of sexual activity, proportion at risk for sexual dysfunction (FSFI score <26.55), total FSFI score, and FSFI desire subscale. Results Among the 97 cancer survivors who completed at least 1 FSFI, the median age was 59 years, the median time since treatment end was 14 months, and 87% were menopausal. Fifty-five women (57%) had a history of colon cancer; 21 (22%), rectal cancer; and 21 (22%), ASCC. An additional 13 (13%) had a current ostomy. Approximately half the women were sexually active (n = 48, 49%). Among these 48 sexually active women, 34 (71%) had FSFI scores indicating risk for sexual dysfunction. Among the 10 sexually active women who completed a FSFI ≥2 years since end of treatment, the median total score was 22.6 (IQR, 15.6-27.3). None of the evaluated characteristics were associated with desire (age, tumor site, treatment, menopause status, or ostomy status). Clinical Implications Consistent with prior studies, we found low desire scores after treatment for CRC or ASCC, with little recovery over time, suggesting that patients should not expect an eventual rebound of sexual function. Strengths and Limitations Strengths of our study include longitudinal data and use of the validated FSFI. Women with ASCC composed 22% of our cohort, allowing for insight into this rare disease group. Limitations of this study include the small sample size, particularly for longitudinal analyses, and the enrollment of patients at variable times since treatment end. Conclusion We observed a high prevalence of sexual health concerns, including low desire, after the treatment of CRC and ASCC that persisted for years after treatment was completed. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer," by N. Kemeny, Y. Huang, and A.M. Cohen, published in the December 30 issue.

Purpose: We aimed to estimate the effect of a 12-week web-based dietary intervention with text messages on quality of life (QoL) among colorectal cancer (CRC) survivors. Methods: Between 2017 and 2018, 50 CRC survivors were randomized (1:1) to receive a 12-week web-based dietary intervention with daily text messages or wait-list control. Health-related QoL was assessed using the European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire–Core 30 (QLQ-C30) and colorectal quality of life module (QLQ-CR29) at baseline, 12, and 24 weeks. Within- and between-group mean changes in health-related QoL with 95% confidence intervals (CI) were calculated for both arms. Results: Compared to the controls, participants receiving the intervention had an improvement in emotional functioning (mean change: 14.3; 95% CI: 3.0, 25.6) at 12 weeks and social functioning (mean change: 13.8; 95% CI: 2.1, 25.5) at 24 weeks. A decrease of fatigue from baseline was also observed in the intervention arm (mean change: − 9.1; 95% CI: − 17.1, − 1.1) at 24 weeks. No other changes in QoL scores were associated with the intervention. Conclusion: CRC survivors randomized to receive a web-based dietary intervention with text messages experienced higher emotional and social functioning. Further study with a larger population may be warranted. Trial registration: clinicaltrials.gov, NCT02965521. Registered 16 November 2016, [ABSTRACT FROM AUTHOR]

Background & Aims GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib) is a prospective, observational registry study evaluating the safety of sorafenib and treatment practices in hepatocellular carcinoma patients. This large global database allowed for assessment of the use and tolerability of sorafenib in patients with liver dysfunction. Methods Baseline characteristics and medical/treatment history were collected in patients for whom a decision to treat with sorafenib had been made. Adverse event, dosing, and outcomes data were collected during follow-up. Results In the overall safety population (n = 3202), 1968 patients (61%) had Child-Pugh A status and 666 (21%) had Child-Pugh B. The majority of Child-Pugh A (72%) and Child-Pugh B (70%) patients received an initial sorafenib dose of 800 mg, consistent with the label, and dose reduction rates were 40% and 29%, respectively. The type and incidence of adverse events were generally consistent across Child-Pugh subgroups. The incidence of drug-related adverse events leading to discontinuation was similar between Child-Pugh A and Child-Pugh B patients (17% and 21%). In the intent-to-treat population (n = 3213), median overall survival (months [95% confidence interval]) was longer in Child-Pugh A patients (13.6 [12.8–14.7]) compared with Child-Pugh B patients (5.2 [4.6–6.3]). Conclusions In clinical practice, the safety profile of sorafenib appeared to be consistent across Child-Pugh A and Child-Pugh B patients. Findings suggest sorafenib may be safely used in some Child-Pugh B patients and indicate the importance of careful patient evaluation when making treatment decisions. Lay summary The GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib) study is a large prospective registry of patients with liver cancer who were treated with sorafenib. The aims were to evaluate the safety and tolerability of sorafenib among those in which the liver was not functioning properly. The study showed that the safety profile of sorafenib was consistent across patients with preserved liver function and those in which the liver was not functioning properly, and therefore, suggesting that sorafenib may be a valid treatment for some patients with liver impairment. [ABSTRACT FROM AUTHOR]

Background: Extrahepatic disease progression limits clinical efficacy of Yttrium-90 (90Y) radioembolization (TARE) for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC). Trifluridine and tipiracil (TAS-102) has overall survival benefit for patients with refractory mCRC and may be a radiosensitizer. Methods: Sequential lobar TARE using 90Y resin microspheres in combination with TAS-102 in 28-day cycles were used to treat adult patients with bilobar liver-dominant chemo-refractory mCRC according to 3 + 3 dose escalation design with a 12-patient dose expansion cohort. Study objectives were to establish safety and determine maximum tolerated dose (MTD) of TAS-102 in combination with TARE. Results: A total of 21 patients (14 women, 7 men) with median age of 60 years were enrolled. No dose limiting toxicities were observed. Treatment related severe adverse events included cytopenias (10 patients, 48%) and radioembolization-induced liver disease (2 patients, 10%). Disease control rate in the liver lobes treated with TARE was 100%. Best observed radiographic responses were partial response for 4 patients (19%) and stable disease for 12 patients (57%). Conclusions: The combination of TAS-102 and TARE for patients with liver-dominant mCRC is safe and consistently achieves disease control within the liver. Trial registration: ClinicalTrials.gov identifier NCT02602327 (first posted 11/11/2015). [ABSTRACT FROM AUTHOR]

Peritoneal dialysis (PD) patients are at high risk for peritonitis, an infection of the peritoneum that affects 13% of PD users annually. Relying on subjective peritonitis symptoms results in delayed treatment, leading to high hospitalisation costs, peritoneal scarring, and premature transition to haemodialysis. We have developed and tested a low-cost, easy-to-use technology that uses microscopy and image analysis to screen for peritonitis across the effluent drain tube. Compared to other technologies, our prototype is made from off-the-shelf, low-cost materials. It can be set up quickly and key stakeholders believe it can improve the overall PD experience. We demonstrate that our prototype classifies infection-indicating and healthy white blood cell levels in clinically collected patient effluent with 94% accuracy. Integration of our technology into PD setups as a screening tool for peritonitis would enable earlier physician notification, allowing for prompt diagnosis and treatment to prevent hospitalisations, reduce scarring, and increase PD longevity. Our findings demonstrate the versatility of microscopy and image analysis for infection screening and are a proof of principle for their future applications in health care. [ABSTRACT FROM AUTHOR]

The liver is the most frequent site of metastases in colorectal cancer (CRC). This study aimed to assess the response rate and survival outcomes in metastatic CRC patients with non-liver metastases (NLM) compared to those with liver metastases (LM) across different lines of treatment. A total of 17,924 mCRC patients included in 26 trials from the ARCAD CRC database were analyzed. The analysis was conducted based on the presence or absence of LM across different treatment groups: chemotherapy (CT) alone, CT + anti-VEGF, CT + anti-EGFR in KRAS wild-type tumors, within the first-line (1 L) and second-line (2 L), and patients enrolled in third-line (≥3 L) trials treated with trifluridine/tipiracil or regorafenib or placebo. The endpoints were overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). Out of the 17,924 patients, 14,066 had LM (30.6 % with only liver involvement and 69.4 % with liver and other metastatic sites), while 3858 patients had NLM. In the CT alone and CT + anti-VEGF subgroups, NLM patients showed better OS and PFS in the 1 L and 2 L settings. However, in the CT + anti-EGFR 1 L and 2 L subgroups, there was no significant difference in OS and PFS between NLM and LM patients. In the ≥ 3 L subgroups, better OS and PFS were observed in NLM patients. ORRs were higher in LM patients than in NLM patients across all cohorts treated in the 1 L and only in the anti-EGFR cohort in the 2 L. LM is a poor prognostic factor for mCRC increasing from 1 L to ≥ 3 L except for patients in 1 L and 2 L receiving CT+anti-EGFR. These data justify using LM as a stratification factor in future trials for patients with unresectable mCRC. • LM in CRC are associated with poorer OS and PFS versus NLM across treatment lines. • Prognostic impact of LM increases from first-line to third-line therapy settings. • The presence of LM is a poor prognostic factor particularly in third-line therapy. • Using LM as a stratification factor in future trials for mCRC is recommended. [ABSTRACT FROM AUTHOR]

Treatment with the MTOR inhibitor everolimus improves progression-free survival (PFS) in pancreatic neuroendocrine tumors (pNETs), but it is not known if the addition of a VEGF pathway inhibitor to an MTOR inhibitor enhances antitumor activity. We performed a randomized phase II study evaluating everolimus with or without bevacizumab in patients with advanced pNETs. One hundred and fifty patients were randomized to receive everolimus 10 mg daily with or without bevacizumab 10 mg/kg i.v. every 2 weeks. Patients also received standard dose of octreotide in both arms. The pri mary endpoint was PFS, based on local investigator review. Treatment with the combination of everolimus and bevacizumab resulted in improved progression-free survival compared to everolimus (16.7 months compared to 14.0 months; one-sided stratified log-rank P = 0.1028; hazard ratio (HR) 0.80 (95% CI 0.56-1.13)), meeting the predefined primary endpoint. Confirmed tumor responses were observed in 31% (95% CI 20%, 41%) of patients receiving combination therapy, as compared to only 12% (95% CI 5%, 19%) of patients receiving treatment with everolimus (P = 0.0053). Median overall survival duration was similar in the everolimus and combination arm (42.5 and 42.1 mo nths, respectively). Treatment-related toxicities were more common in the combination arm. In summary, treatment with everolimus and bevacizumab led to superior PFS and higher response rates compared to everolimus in patients with advanced pNETs. Although the higher rate of treatment-related adverse events may limit the use of this c ombination, our results support the continued evaluation of VEGF pathway inhibitors in pNETs. [ABSTRACT FROM AUTHOR]

Purpose: There are over 1.3 million colorectal cancer (CRC) survivors in the USA, many of whom report lower health-related quality of life (HRQoL) years after treatment. This study aimed to explore the effect of digital health tools on HRQoL in CRC survivors. Methods: We conducted a two-arm, randomized controlled trial of 42 subjects who had completed treatment for CRC. Participants in the intervention arm received a Fitbit Flex™ and daily text messages for 12 weeks. HRQoL was assessed as a secondary endpoint in both arms at enrollment and 12 weeks using the Medical Outcomes Study Short Form Survey (SF-36) and the Functional Assessment of Cancer Therapy–Colorectal (FACT-C). Survey score changes from enrollment to 12 weeks were compared between the two arms using independent t tests, and scores at enrollment and 12 weeks were compared using paired t tests. Results: An increase in the FACT-C functional well-being subscale was observed in individuals in the intervention arm pre- to post-intervention (median difference, 2; interquartile range (IQR), 1, 4; P =.02). Although the between-group comparison was not statistically significant, no change in the functional well-being subscale was observed in the control arm (median difference, 0; IQR, 1, 1; P =.71). No other measures of HRQoL appeared to differ within arm across time points or between arms. Conclusion: A 12-week digital physical activity intervention may improve functional well-being among CRC survivors. Larger randomized studies are needed to determine if digital health tools improve functional well-being among CRC survivors and if this improvement can be sustained over time. Trial registration: NCT02966054; registration date, November 17, 2016 [ABSTRACT FROM AUTHOR]

Purpose: The optimal strategy for treating locally advanced pancreatic cancer remains controversial, including the respective roles and timing of chemotherapy and radiation. We conducted a Phase II nonrandomized trial to evaluate sequential chemotherapy followed by chemoradiation in this patient population. Methods and Materials: Chemotherapy naive patients with locally advanced pancreatic adenocarcinoma were treated with fixed-dose rate gemcitabine (1,000 mg/m2 at 10 mg/m2/min) plus cisplatin 20 mg/m2 on Days 1 and 15 of a 28-day cycle. Those without evidence of extrapancreatic metastases after six cycles of chemotherapy received radiation (5,040 cGy over 28 fractions) with concurrent capecitabine (800 mg/m2 orally twice daily on the day of radiation) as a radiosensitizer. Results: A total of 25 patients were enrolled with a median follow-up time of 656 days. Twelve patients (48%) successfully received all six cycles of chemotherapy plus chemoradiation. Eight patients (32%) progressed during chemotherapy, including 7 with extrapancreatic metastases. Grade 3/4 hematologic toxicities were uncommon. Two patients sustained myocardial infarctions during chemotherapy, and 4 were hospitalized for infectious complications, although none in the setting of neutropenia. Median time to progression was 10.5 months and median survival was 13.5 months, with an estimated 1-year survival rate of 62%. Patients receiving all components of therapy had a median survival of 17.0 months. Conclusions: A strategy of initial fixed-dose rate gemcitabine-based chemotherapy, followed by chemoradiation, shows promising efficacy for treatment of locally advanced disease. A substantial proportion of patients will be identified early on as having extrapancreatic disease and spared the potential toxicities associated with radiation. [Copyright &y& Elsevier]

Natural killer (NK) cells express activating and inhibitory receptors that, in concert, survey cells for proper expression of cell surface major histocompatibility complex (MHC) class I molecules. The mouse cytomegalovirus encodes an MHC-like protein, m157, which is the only known viral antigen to date capable of engaging both activating (Ly49H) and inhibitory (Ly491) NK cell receptors. We have determined the 3D structure of m157 and studied its biochemical and cellular interactions with the Ly49H and Ly491 receptors, m157 has a characteristic MHC-fold, yet possesses several unique structural features not found in other MHC class I-like molecules, m157 does not bind peptides or other small ligands, nor does it associate with β2-microglobulin. Instead, m157 engages in extensive intra- and intermolecular interactions within and between its domains to generate a compact minimal MHC-like molecule, m157's binding affinity for Ly49I (Kd ≈ 0.2 μM) is significantly higher than that of classical inhibitory Ly49-MHC interactions. Analysis of viral escape mutations on m157 that render it resistant to NK killing reveals that it is likely to be recognized by Ly49H in a binding mode that differs from Ly49/MHC-I. In addition, Ly49H+ NK cells can efficiently lyse RMA cells expressing m157, despite the presence of native MHC class I. Collectively, our results show that m157 represents a structurally divergent form of MHC class I-like proteins that directly engage Ly49 receptors with appreciable affinity in a noncanonical fashion. [ABSTRACT FROM AUTHOR]

The use of serial serum measurements of the carbohydrate antigen 19-9 (CA19-9) to guide treatment decisions and serve as a surrogate end point in clinical trial design requires further validation. We investigated whether CA19-9 decline represents an accurate surrogate for survival and time to treatment failure (TTF) in a cohort of 76 patients with advanced pancreatic cancer receiving fixed-dose rate gemcitabine in three separate studies. Statistically significant correlations between percentage CA19-9 decline and both overall survival and TTF were found, with median survival ranging from 12.0 months for patients with the greatest degree of biomarker decline (>75%) compared with 4.3 months in those whose CA19-9 did not decline during therapy (P<0.001). Using specific thresholds, patients with 25% decline in CA19-9 during treatment had significantly better outcomes than those who did not (median survival and TTF of 9.6 and 4.6 months vs 4.4 and 1.5 months; P<0.001). Similar results were seen using both 50 and 75% as cutoff points. We conclude that serial CA19-9 measurements correlate well with clinical outcomes in this patient population, and that decline in this biomarker should be entertained for possible use as a surrogate end point in clinical trials for the selection of new treatments in this disease.British Journal of Cancer (2005) 93, 195–199. doi:10.1038/sj.bjc.6602687 www.bjcancer.com Published online 5 July 2005 [ABSTRACT FROM AUTHOR]

Background: The incidence of young-onset colorectal cancer (yoCRC) is increasing. It is unknown if there are survival differences between young and older patients with metastatic colorectal cancer (mCRC).Methods: We studied the association of age with survival in 2326 mCRC patients enrolled in the Cancer and Leukemia Group B and SWOG 80405 trial, a multicenter, randomized trial of first-line chemotherapy plus biologics. The primary and secondary outcomes of this study were overall survival (OS) and progression-free survival (PFS), respectively, which were assessed by Kaplan-Meier method and compared among younger vs older patients with the log-rank test. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated based on Cox proportional hazards modeling, adjusting for known prognostic variables. All statistical tests were 2-sided.Results: Of 2326 eligible subjects, 514 (22.1%) were younger than age 50 years at study entry (yoCRC cohort). The median age of yoCRC patients was 44.3 vs 62.5 years in patients aged 50 years and older. There was no statistically significant difference in OS between yoCRC vs older-onset patients (median = 27.07 vs 26.12 months; adjusted HR = 0.98, 95% CI = 0.88 to 1.10; P = .78). The median PFS was also similar in yoCRC vs older patients (10.87 vs 10.55 months) with an adjusted hazard ratio of 1.02 (95% CI = 0.92 to 1.13; P = .67). Patients younger than age 35 years had the shortest OS with median OS of 21.95 vs 26.12 months in older-onset patients with an adjusted hazard ratio of 1.08 (95% CI = 0.81 to 1.44; Ptrend = .93).Conclusion: In this large study of mCRC patients, there were no statistically significant differences in survival between patients with yoCRC and CRC patients aged 50 years and older. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) affects many older adults. We investigated the efficacy and safety of adding anti-epidermal growth factor receptor (EGFR) agents to doublet chemotherapy (DC) in older patients. Patients with RAS wild-type (WT) metastatic CRC (mCRC) receiving first-line DC + anti-EGFR (n = 1191) or DC alone (n = 729) from seven trials in the Aide de Recherche en Cancerologie Digestive database were included. The prognostic and predictive effects of age were investigated. Progression-free and overall survival (OS) were evaluated between age groups (≥70 vs <70) for DC + anti-EGFR. In addition, outcomes were compared between DC+/-anti-EGFR within age groups in three trials with a DC alone arm. Subsequently, the same analysis was conducted for left-sided tumours. Adverse events grade ≥3 (G3+) were compared between age groups. Older (vs younger) patients receiving DC + anti-EGFR had similar progression-free survival (PFS) (8.7 vs 10.3 months; hazard ratio (HR) = 1.20 [0.96–1.49];p = 0.107) but inferior OS (21.3 vs 26.3; HR = 1.36 [1.08–1.72];p = 0.011). DC + anti-EGFR (vs DC alone) improved OS (23.9 vs 20.3; HR = 0.82 [0.70–0.95];p = 0.008) and PFS (11.2 vs 8.9; HR = 0.70 [0.60–0.82];p < 0.001) in younger but not older patients: OS (24.7 vs 17.6; HR [95% confidence interval {CI}] = 0.77 [0.58–1.04];p = 0.092) and PFS (9.1 vs 8.7; HR [95% CI] = 0.85[0.63–1.15];p = 0.287). In left-sided 'only' tumours, the following outcomes for older (vs younger) patients were observed. For DC + anti-EGFR, PFS 9 versus 11.2 months; HR1.10 (95% CI 0.83–1.46); p = 0.52, OS 25.6 vs 30.3 HR 1.32 (95% CI 0.97–1.79), p = 0.086. For DC + anti-EGFR (vs DC alone), PFS and OS for younger patients were 11.9 vs 9.2 months HR 0.60 (95% CI 0.47–0.78) p < 0.001 and 24.1 versus 23.3 months HR 0.84 (95% CI 0.67–1.04), respectively. For older patients, PFS and OS were 13.1 versus 8.5 months, HR 0.51 (95% CI, 0.28–0.93), P = 0.027 and 26.3 versus 16.5 months HR 0.49 (95% CI, 0.28–0.85), respectively. There was no significant difference in toxicity among different age groups. Older (vs younger) patients with mCRC RAS WT patients had comparable toxicity and efficacy with the addition of anti-EGFR agents to chemotherapy. • Older patients with colorectal cancer are under-represented in clinical trials. • Investigated effect of age in patients treated with chemotherapy and anti-EGFR agents. • No significant difference in the risk for G3+ toxicity between over and under 70s. • Comparable efficacy outcomes for younger and older patients receiving anti-EGFR agents. [ABSTRACT FROM AUTHOR]

Novel therapies are needed for locally advanced pancreatic carcinoma. ONYX-015 (dl1520) is an E1B-55 kDa regiondeleted adenovirus that selectively replicates in and lyses tumor cells with abnormalities in p53 function (eg gene mutation). We carried out a phase I dose escalation study of ONYX-015 in patients with unresectable pancreatic cancer. ONYX-015 was administered via CT-guided injection (n = 22 patients) or intraoperative injection (n = 1) into pancreatic primary tumors every 4 weeks until tumor progression. Interpatient dose escalation was carried out with at least three patients per dose level from 10[sup 8] p.f.u. up to the 10[sup 11] p.f.u. dose level (two patients treated at this dose). The majority of patients had abnormally low cellular immunity (CD4 counts and hypersensitivity skin testing). Injection of ONYX-015 into pancreatic carcinomas was well-tolerated. Mild, transient pancreatitis was noted in only one patient. Dose-escalation proceeded to the highest dose level. Neutralizing antibodies rose post-treatment in all patients. After injection, ONYX-015 was detectable in the blood 15 min later, but not between 1 and 15 days later. Viral replication was not documented, however, in contrast to trials in other tumor types. No objective responses were demonstrated. Intratumoral injection of an E1B-55 kDa region-deleted adenovirus into primary pancreatic tumors was feasible and well-tolerated at doses up to 10[sup 11] p.f.u. (2 × 10[sup 12] particles), but viral replication was not detectable. [ABSTRACT FROM AUTHOR]

Background: Unplanned subgroup analyses from several studies have suggested primary tumor sidedness (PTS) as a potential prognostic and predictive parameter in metastatic colorectal cancer (mCRC). We aimed to investigate the impact of PTS on outcomes of mCRC patients.Methods: PTS data of 9277 mCRC patients from 12 first-line randomized trials in the ARCAD database were pooled. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier and Cox models adjusting for age, sex, performance status, prior radiation/chemotherapy, and stratified by treatment arm. Predictive value was tested by interaction term between PTS and treatment (cetuximab plus chemotherapy vs chemotherapy alone). All statistical tests were 2-sided.Results: Compared with right-sided metastatic colorectal cancer patients (n = 2421, 26.1%), left-sided metastatic colorectal cancer patients (n = 6856, 73.9%) had better OS (median = 21.6 vs 15.9 months; adjusted hazard ratio [HRadj] = 0.71, 95% confidence interval [CI] = 0.67 to 0.76; P < .001) and PFS (median = 8.6 vs 7.5 months; HRadj = 0.80, 95% CI = 0.75 to 0.84; P < .001). Interaction between PTS and KRAS mutation was statistically significant (Pinteraction < .001); left-sidedness was associated with better prognosis among KRAS wild-type (WT) (OS HRadj = 0.59, 95% CI = 0.53 to 0.66; PFS HRadj =0.68, 95% CI = 0.61 to 0.75) but not among KRAS mutated tumors. Among KRAS-WT tumors, survival benefit from anti-EGFR was confirmed for left-sidedness (OS HRadj = 0.85, 95% CI = 0.75 to 0.97; P = .01; PFS HRadj = 0.77, 95% CI = 0.67 to 0.88; P < .001) but not for right-sidedness.Conclusions: The prognostic value of PTS is restricted to the KRAS-WT population. PTS is predictive of anti-EGFR efficacy, with a statistically significant improvement of survival for left-sidedness mCRC patients. These results suggest treatment choice in mCRC should be based on both PTS and KRAS status. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to evaluate the association between self‐identified race and overall survival (OS), progression‐free survival (PFS), and response to therapy among patients enrolled in the randomized Cancer and Leukemia Group B (CALGB)/SWOG 80405 trial. Methods: Patients with advanced or metastatic colorectal cancer who were enrolled in the CALGB/SWOG 80405 trial were identified by race. On the basis of covariates (treatment arm, KRAS status, sex, age, and body mass index), each Black patient was exact matched with a White patient. The association between race and OS and PFS was examined using a marginal Cox proportional hazard model for matched pairs. The interaction between KRAS status and race was tested in the model. The association between race and response to therapy and adverse events were examined using a marginal logistic regression model. Results: In total, 392 patients were matched and included in the final data set. No difference in OS (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.73‐1.16), PFS (HR, 0.97; 95% CI, 0.78‐1.20), or response to therapy (odds ratio [OR], 1.00; 95% CI, 0.65‐1.52) was observed between Black and White patients. Patients with KRAS mutant status (HR, 1.31; 95% CI, 1.02‐1.67), a performance statusscore of 1 (reference, a performance status of 0; HR, 1.49; 95% CI, 1.18‐1.88), or ≥3 metastatic sites (reference, 1 metastatic site; HR, 1.67; 95% CI, 1.22‐2.28) experienced worse OS. Black patients experienced lower rates and risk of grade ≥3 fatigue (6.6% vs 13.3%; OR, 0.46; 95% CI, 0.24‐0.91) but were equally likely to be treated with a dose reduction (OR, 1.09; 95% CI, 0.72‐1.65). Conclusions: No difference in OS, PFS, or response to therapy was observed between Black patients and White patients in an equal treatment setting of the CALGB/SWOG 80405 randomized controlled trial. Lay Summary: Despite improvements in screening and treatment, studies have demonstrated worse outcomes in Black patients with colorectal cancer.The purpose of this study was to determine whether there was a difference in cancer‐specific outcomes among Black and White patients receiving equivalent treatment on the CALGB/SWOG 80405 randomized clinical trial.In this study, there was no difference in overall survival, progression‐free survival, or response to therapy between Black and White patients treated on a clinical trial.These findings suggest that access to care and differences in treatment may be responsible for racial disparities in colorectal cancer. In a secondary analysis of the CALGB/SWOG 80405 randomized clinical trial, there was no difference in overall survival, progression‐free survival, or response to therapy between matched Black patients and White patients with advanced or metastatic colorectal cancer. Because racial disparities in metastatic colorectal cancer survival were not seen in an equal treatment setting, differences in access to care and treatment delivery may be responsible for the racial disparities observed in epidemiological studies. [ABSTRACT FROM AUTHOR]

Background: First-line therapeutic strategies for patients with BRAFV600E-mutated (BRAFmt) metastatic colorectal cancer (mCRC) mainly rely on subgroup analyses from randomized controlled trials (RCTs). We aimed to assess the prognostic and predictive impact of BRAFmt on the efficacy of targeted therapies with first-line chemotherapy.Methods: Individual patient data from first-line RCTs with BRAF and KRAS status data in the ARCAD database were pooled. Progression-free survival and overall survival (OS) were assessed using Kaplan-Meier and Cox models. Outcomes were compared between treatment groups that were concurrently randomly assigned whenever possible.Results: A total of 6391 patients from 10 RCTs were included: 573 BRAFmt (9.0%), 2059 KRASmt (32.2%), and 3759 double wild type (58.8%). BRAFmt mCRC patients experienced statistically significantly poorer OS than those with KRASmt (adjusted hazard ratio [HRadj] = 1.46, 95% confidence interval [CI] = 1.30 to 1.64) and patients with double wild-type tumors (HRadj = 2.14, 95% CI = 1.94 to 2.36). Anti-EGFR agents did not improve progression-free survival or OS of BRAFmt mCRC patients, based on 4 RCTs testing chemotherapy with or without anti-epidermal growth factor receptor (anti-EGFR) (HRadj = 0.96, 95% CI = 0.71 to 1.30; and HRadj = 0.85, 95% CI = 0.66 to 1.14, respectively).Conclusions: Our data suggest that the addition of anti-EGFR agents to chemotherapy is ineffective as first-line treatment for BRAFmt mCRC patients. [ABSTRACT FROM AUTHOR]

Objective  Umbilical central lines deliver life-saving medications and nutrition for neonates; however, complications associated with umbilical catheters (UCs) occur more frequently than in adults with central lines (i.e., line migration, systemic infection). We have developed a device for neonatal UC protection and stabilization to reduce catheter exposure to bacteria compared with the standard of care: "goal post" tape configuration. This study analyzes the effect of device venting and material on bacterial load of human umbilical cords in vitro. Study Design  Catheters were inserted into human umbilical cord segments in vitro , secured with plastic or silicone vented prototype versus tape, and levels of bacterial colonization were compared between groups after 7 days of incubation. Results  Nonvented plastic prototype showed increased bacterial load compared with goal post (p  = 0.04). Colonization was comparable between the goal post and all vented plastic prototypes (p  ≥ 0.30) and when compared with the vented silicone device (p  = 1). Conclusion  A novel silicone device does not increase external bacterial colonization compared with the current standard of care for line securement, and may provide a safe, convenient alternative to standard adhesive tape for UC stabilization. Future studies are anticipated to establish safety in vivo , alongside benefits such as migration and infection reduction. [ABSTRACT FROM AUTHOR]

Importance: Aspirin and cyclooxygenase 2 (COX-2) inhibitors have been associated with a reduced risk of colorectal polyps and cancer in observational and randomized studies. The effect of celecoxib, a COX-2 inhibitor, as treatment for nonmetastatic colon cancer is unknown.Objective: To determine if the addition of celecoxib to adjuvant chemotherapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) improves disease-free survival in patients with stage III colon cancer.Design, Setting, and Participants: Cancer and Leukemia Group B (Alliance)/Southwest Oncology Group 80702 was a 2 × 2 factorial design, phase 3 trial conducted at 654 community and academic centers throughout the United States and Canada. A total of 2526 patients with stage III colon cancer were enrolled between June 2010 and November 2015 and were followed up through August 10, 2020.Interventions: Patients were randomized to receive adjuvant FOLFOX (every 2 weeks) for 3 vs 6 months with or without 3 years of celecoxib (400 mg orally daily; n = 1263) vs placebo (n = 1261). This report focuses on the results of the celecoxib randomization.Main Outcomes and Measures: The primary end point was disease-free survival, measured from the time of randomization until documented recurrence or death from any cause. Secondary end points included overall survival, adverse events, and cardiovascular-specific events.Results: Of the 2526 patients who were randomized (mean [SD] age, 61.0 years [11 years]; 1134 women [44.9%]), 2524 were included in the primary analysis. Adherence with protocol treatment, defined as receiving celecoxib or placebo for more than 2.75 years or continuing treatment until recurrence, death, or unacceptable adverse events, was 70.8% for patients treated with celecoxib and 69.9% for patients treated with placebo. A total of 337 patients randomized to celecoxib and 363 to placebo experienced disease recurrence or died, and with 6 years' median follow-up, the 3-year disease-free survival was 76.3% for celecoxib-treated patients vs 73.4% for placebo-treated patients (hazard ratio [HR] for disease recurrence or death, 0.89; 95% CI, 0.76-1.03; P = .12). The effect of celecoxib treatment on disease-free survival did not vary significantly according to assigned duration of adjuvant chemotherapy (P for interaction = .61). Five-year overall survival was 84.3% for celecoxib vs 81.6% for placebo (HR for death, 0.86; 95% CI, 0.72-1.04; P = .13). Hypertension (any grade) occurred while treated with FOLFOX in 14.6% of patients in the celecoxib group vs 10.9% of patients in the placebo group, and a grade 2 or higher increase in creatinine levels occurred after completion of FOLFOX in 1.7% vs 0.5% of patients, respectively.Conclusions and Relevance: Among patients with stage III colon cancer, the addition of celecoxib for 3 years, compared with placebo, to standard adjuvant chemotherapy did not significantly improve disease-free survival.Trial Registration: ClinicalTrials.gov Identifier: NCT01150045. [ABSTRACT FROM AUTHOR]