Which Treatment for Which Patient: Rectal Cancer Management After PROSPECT Trial.

Determining treatment options for patients with locally advanced rectal cancer after the PROSPECT trial data readout adds an important level to the decision-making process.

Consuming Patients' Days: Time Spent on Ambulatory Appointments by People With Cancer.

BACKGROUND: In qualitative work, patients report that seemingly short trips to clinic (eg, a supposed 10-minute blood draw) often turn into "all-day affairs." We sought to quantify the time patients with cancer spend attending ambulatory appointments. METHODS: We conducted a retrospective study of patients scheduled for oncology-related ambulatory care (eg, labs, imaging, procedures, infusions, and clinician visits) at an academic cancer center over 1 week. The primary exposure was the ambulatory service type(s) (eg, clinician visit only, labs and infusion, etc.). We used Real-Time Location System badge data to calculate clinic times and estimated round-trip travel times and parking times. We calculated and summarized clinic and total (clinic + travel + parking) times for ambulatory service types. RESULTS: We included 435 patients. Across all service day type(s), the median (IQR) clinic time was 119 (78-202) minutes. The estimated median (IQR) round-trip driving distance and travel time was 34 (17-49) miles and 50 (36-68) minutes. The median (IQR) parking time was 14 (12-15) minutes. Overall, the median (IQR) total time was 197 (143-287) minutes. The median total times for specific service type(s) included: 99 minutes for lab-only, 144 minutes for clinician visit only, and 278 minutes for labs, clinician visit, and infusion. CONCLUSION: Patients often spent several hours pursuing ambulatory cancer care on a given day. Accounting for opportunity time costs and the coordination of activities around ambulatory care, these results highlight the substantial time burdens of cancer care, and support the notion that many days with ambulatory health care contact may represent "lost days."

Alliance for clinical trials in Oncology (Alliance) trial A022101/NRG-GI009: a pragmatic randomized phase III trial evaluating total ablative therapy for patients with limited metastatic colorectal cancer: evaluating radiation, ablation, and surgery (ERASur).

BACKGROUND: For patients with liver-confined metastatic colorectal cancer (mCRC), local therapy of isolated metastases has been associated with long-term progression-free and overall survival (OS). However, for patients with more advanced mCRC, including those with extrahepatic disease, the efficacy of local therapy is less clear although increasingly being used in clinical practice. Prospective studies to clarify the role of metastatic-directed therapies in patients with mCRC are needed. METHODS: The Evaluating Radiation, Ablation, and Surgery (ERASur) A022101/NRG-GI009 trial is a randomized, National Cancer Institute-sponsored phase III study evaluating if the addition of metastatic-directed therapy to standard of care systemic therapy improves OS in patients with newly diagnosed limited mCRC. Eligible patients require a pathologic diagnosis of CRC, have BRAF wild-type and microsatellite stable disease, and have 4 or fewer sites of metastatic disease identified on baseline imaging. Liver-only metastatic disease is not permitted. All metastatic lesions must be amenable to total ablative therapy (TAT), which includes surgical resection, microwave ablation, and/or stereotactic ablative body radiotherapy (SABR) with SABR required for at least one lesion. Patients without overt disease progression after 16-26 weeks of first-line systemic therapy will be randomized 1:1 to continuation of systemic therapy with or without TAT. The trial activated through the Cancer Trials Support Unit on January 10, 2023. The primary endpoint is OS. Secondary endpoints include event-free survival, adverse events profile, and time to local recurrence with exploratory biomarker analyses. This study requires a total of 346 evaluable patients to provide 80% power with a one-sided alpha of 0.05 to detect an improvement in OS from a median of 26 months in the control arm to 37 months in the experimental arm with a hazard ratio of 0.7. The trial uses a group sequential design with two interim analyses for futility. DISCUSSION: The ERASur trial employs a pragmatic interventional design to test the efficacy and safety of adding multimodality TAT to standard of care systemic therapy in patients with limited mCRC. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05673148, registered December 21, 2022.

Cutaneous Mycobacterium avium-intracellulare infection masquerading as sarcoidosis.

Mycobacterium avium-intracellulare (MAC) infection may have different skin manifestations, including cutaneous granulomas. Granulomatous skin reactions have distinct morphologic and histopathologic appearances. We present the case of an adolescent male with cutaneous MAC, misdiagnosed as sarcoidosis after initial biopsy results, demonstrated preservation of reticulin fibers and absence of organisms within granulomas. Sarcoidal granulomas often stain positive for reticulin fibers, which could be used to distinguish them from the infectious kind. This case should alert clinicians to the fact that the presence or quantity of intact reticular fibers may not be a reliable tool to differentiate between a sarcoidal and an infectious granuloma. Our case also highlights the diagnostic challenge of cutaneous MAC infection.

NCI Rectal-Anal Task Force consensus recommendations for design of clinical trials in rectal cancer.

The optimal management of locally advanced rectal cancer is rapidly evolving. The National Cancer Institute Rectal-Anal Task Force convened an expert panel to develop consensus on the design of future clinical trials of patients with rectal cancer. A series of 82 questions and subquestions, which addressed radiation and neoadjuvant therapy, patient perceptions, rectal cancer populations of special interest, and unique design elements, were subject to iterative review using a Delphi analytical approach to define areas of consensus and those in which consensus is not established. The task force achieved consensus on several areas, including the following: 1) the use of total neoadjuvant therapy with long-course radiation therapy either before or after chemotherapy, as well as short-course radiation therapy followed by chemotherapy, as the control arm of clinical trials; 2) the need for greater emphasis on patient involvement in treatment choices within the context of trial design; 3) efforts to identify those patients likely, or unlikely, to benefit from nonoperative management or minimally invasive surgery; 4) investigation of the utility of circulating tumor DNA measurements for tailoring treatment and surveillance; and 5) the need for identification of appropriate end points and recognition of challenges of data management for patients who enter nonoperative management trial arms. Substantial agreement was reached on priorities affecting the design of future clinical trials in patients with locally advanced rectal cancer.

Alliance for Clinical Trials in Oncology (Alliance) trial A022101/NRG-GI009: A pragmatic randomized phase III trial evaluating total ablative therapy for patients with limited metastatic colorectal cancer: evaluating radiation, ablation, and surgery (ERASur).

Background: For patients with liver-confined metastatic colorectal cancer (mCRC), local therapy of isolated metastases has been associated with long-term progression-free and overall survival (OS). However, for patients with more advanced mCRC, including those with extrahepatic disease, the efficacy of local therapy is less clear although increasingly being used in clinical practice. Prospective studies to clarify the role of metastatic-directed therapies in patients with mCRC are needed. Methods: The Evaluating Radiation, Ablation, and Surgery (ERASur) A022101/NRG-GI009 trial is a randomized, National Cancer Institute-sponsored phase III study evaluating if the addition of metastatic-directed therapy to standard of care systemic therapy improves OS in patients with newly diagnosed limited mCRC. Eligible patients require a pathologic diagnosis of CRC, have BRAF wild-type and microsatellite stable disease, and have 4 or fewer sites of metastatic disease identified on baseline imaging. Liver-only metastatic disease is not permitted. All metastatic lesions must be amenable to total ablative therapy (TAT), which includes surgical resection, microwave ablation, and/or stereotactic ablative body radiotherapy (SABR) with SABR required for at least one lesion. Patients without overt disease progression after 16-26 weeks of first-line systemic therapy will be randomized 1:1 to continuation of systemic therapy with or without TAT. The trial activated through the Cancer Trials Support Unit on January 10, 2023. The primary endpoint is OS. Secondary endpoints include event-free survival, adverse events profile, and time to local recurrence with exploratory biomarker analyses. This study requires a total of 346 evaluable patients to provide 80% power with a one-sided alpha of 0.05 to detect an improvement in OS from a median of 26 months in the control arm to 37 months in the experimental arm with a hazard ratio of 0.7. The trial uses a group sequential design with two interim analyses for futility. Discussion: The ERASur trial employs a pragmatic interventional design to test the efficacy and safety of adding multimodality TAT to standard of care systemic therapy in patients with limited mCRC.

Reproductive Health Experiences of Females Diagnosed with Young-Onset Colorectal Cancer: A Multi-Method Cross-Sectional Survey.

OBJECTIVE: Given the increasing risk of young-onset colorectal cancer (yCRC) among adults under 50 years, it is important to understand impacts on reproductive health. Our objective was to assess experiences with reproductive health after yCRC diagnosis among females. METHODS: We conducted a cross-sectional study among females, 18 years or older, who have been diagnosed yCRC and are able to communicate in English. Data were gathered using an online survey involving both quantitative (e.g., multiple choice) and qualitative (e.g., open-ended text) questions on pregnancy history, influence of yCRC on reproductive decisions, and experiences with reproductive healthcare. RESULTS: Altogether, 101 females with yCRC participated, including 23 who had never been pregnant and 78 who had been pregnant. yCRC influenced family planning goals for one-third of participants. Furthermore, compared to participants who completed treatment, those currently undergoing treatment had higher odds of indicating their yCRC diagnosis influenced family planning goals (adjusted odds ratio 4.93; 95% confidence interval 1.29 to 18.78). Although 53 (52.5%) participants indicated having discussions regarding reproductive health with healthcare provider(s), 44 (43.6%) did not. Content analysis of open-ended survey questions identified themes on the emotional impacts, experiences with reproductive healthcare, reproductive and family planning considerations, and the related issue of sexual health impacts of yCRC. CONCLUSIONS: Gaps in care, related to limited reproductive health discussions, influence of yCRC on family planning, and experiencing lasting reproductive health impacts highlight the need for improving reproductive healthcare, particularly for females diagnosed with yCRC.

Impact of Immunoscore on the Management of Stage II Colon Cancer Patients: A Physician Survey.

BACKGROUND: Adjuvant chemotherapy use in stage II colon cancer is controversial. Current prognostic risk factors do not take the tumor immune microenvironment into account. Consideration of the Immunoscore, which measures the host immune response at the tumor site, may assist clinicians in reducing adjuvant chemotherapy use in patients who are unlikely to benefit from it. This study sought to determine the potential clinical utility of the Immunoscore, via its effect on medical oncologists' recommendations for management of patients with stage II colon cancer. METHODS: De-identified vignettes of 10 patients with stage II colon cancer were presented to 25 practicing medical oncologists. Each participant completed surveys indicating recommendations for adjuvant chemotherapy and surveillance strategies. An educational session was subsequently conducted, and the same patient profiles were re-presented but included immunoscore results. Participants were again asked to provide their recommendations. A participant was counted as influenced if their responses were altered after immunoscore test results were provided. RESULTS: All but one participant (96%) altered a management recommendation for ≥1 case. For individual cases, a mean of 55% (range, 40-80%) of participants altered their recommendations for adjuvant chemotherapy and/or surveillance. For the immunoscore-high cases (low-risk of recurrence), recommendations for adjuvant chemotherapy use decreased from 60% to 31%. CONCLUSIONS: These results indicate a willingness by oncologists to integrate immunoscore information into clinical practice recommendations. Incorporation of immunoscore data resulted in the reduction of nonvalue care in the simulated population. Confirmation in prospective studies is planned.

A pilot study on right ventricular longitudinal strain as a predictor of outcome in COVID-19 patients with evidence of cardiac involvement.

AIMS: The aim of this investigation was to evaluate echocardiographic parameters of cardiac function and in particular right ventricular (RV) function as a predictor of mortality in patients with coronavirus disease-2019 (COVID-19) pneumonia. METHODS AND RESULTS: This prospective observational study included 35 patients admitted to a UK district general hospital with COVID-19 and evidence of cardiac involvement, that is, raised Troponin I levels or clinical evidence of heart failure during the first wave of the COVID-19 pandemic (March-May 2020). All patients underwent echocardiography including speckle tracking for right ventricular longitudinal strain (RVLS) providing image quality was sufficient (30 out of 35 patients). Upon comparison of patients who survived COVID-19 with non-survivors, survivors had significantly smaller RVs (basal RV diameter 38.2 vs 43.5 mm P = .0295) with significantly better RV function (Tricuspid annular plane systolic excursion (TAPSE): 17.5 vs 15.3 mm P = .049; average RVLS: 24.3% vs 15.6%; P = .0018). Tricuspid regurgitation (TR) maximal velocity was higher in survivors (2.75 m/s vs 2.11 m/s; P = .0045) indicating that pressure overload was not the predominant driver of this effect and there was no significant difference in left ventricular (LV) ejection fraction. Kaplan-Meier and log-rank analysis of patients split into groups according to average RVLS above or below 20% revealed significantly increased 30-day mortality in patients with average RVLS under 20% (HR: 3.189; 95% CI: 1.297-12.91; P = .0195). CONCLUSION: This study confirms that RVLS is a potent and independent predictor of outcome in COVID-19 patients with evidence of cardiac involvement.

Correlation of cognitive functions with emotional dysregulation in alcohol dependence: A preliminary study.

CONTEXT AND AIMS: Dysfunction of cognition and emotion is known in alcohol dependence; however, their relationship in alcohol dependence is unknown. Thus, this study aimed to know the level of emotional dysregulation and cognitive functions and their correlation in patients with alcohol dependence. MATERIALS AND METHODS: In this hospital-based cross-sectional study, 120 patients with alcohol dependence were consecutively recruited and assessed with sociodemographic and clinical pro forma, Montreal Cognitive Assessment (MoCA), and Difficulty in Emotional Regulation Scale-Short Form (DERS-SF). STATISTICAL ANALYSIS: Descriptive statistical, Kruskal-Wallis H, and regression analysis. RESULTS: Results revealed a mild level of cognitive impairment (mean MoCA score = 0 23.76) and high levels of emotional dysregulation (mean DERS-SF score = 0 26.90). On linear regression analysis (R 2 = 0.266, df = 0 1, F = 0 42.782, P =0.000), the score on MoCA had statistically significant negative association with score on DERS-SF (P = 0.001). CONCLUSIONS: Cognitive impairment and emotional dysregulation are inversely related in patients with alcohol dependence. Improving the dysfunction may improve the outcome of alcohol dependence.

Psychosocial interventions for sexual dysfunction in addictive disorders.

Substance abuse and addictive disorders are very common in the community. Patients with addictive disorders frequently experience sexual dysfunctions and chronic use of substances tends to adversely affect all stages of sexual response, in both male and female abusers. An important aspect in the management of sexual dysfunction is psychosocial intervention. In addictive disorders, sexual dysfunction is of high clinical relevance, as it often leads to treatment non adherence and sexual or marital disharmony. Instead of a disease-centred approach, a couple and relationship centred approach of management is desirable. A detailed history about the sexual dysfunction, the addictive disorder and enquiry into various psychosocial aspects is mandatory for adequate management of the same. Sexual therapy, behavioural techniques, systematic sensitization and desensitization are some of the techniques used in the management of sexual dysfunction in addictive disorders. The assessment and treatment need to be tailored depending upon the various psychosocial aspects of the individual.

Psychosocial intervention for sexual addiction.

Addiction is the term employed not only for excess consumption of substances, but also for problem behaviours like eating disorders, pathological gambling, computer addiction and pathological preoccupation with video games and sexual acts. No clear diagnostic criterion has been established with validity for behavioral addictions. Sexual addiction, including addiction to pornography is not included as a separate entity because of a lack of strong empirical evidence in this area. Different scales can be used for assessment of sexual addiction. Since there is an absence of established diagnostic criteria, the significance of validity of these scales is doubted. Several of the questions in these scales do not yield information about whether the diagnostic criteria are met or not. Pharmacotherapy, together with psychotherapy proves to have a better outcome in such patients as it helps to synthesize the role of developmental antecedents, reduce current anxiety, depression, guilt and to improve social adjustment.

Understanding the schizophrenia prodrome.

Schizophrenia is a neurodevelopmental disorder and its course is said to have an onset much before the presentation with psychotic symptoms. Even though the concept of prodrome in schizophrenia has been accepted, there is still an existence of a diagnostic dilemma. Various imaging studies and biomarkers have also been studied for confirmation of this diagnosis. The critical period of intervention when identified clarifies the doubts about faster and better outcomes.

Endocytic recycling protein EHD1 regulates primary cilia morphogenesis and SHH signaling during neural tube development.

Members of the four-member C-terminal EPS15-Homology Domain-containing (EHD) protein family play crucial roles in endocytic recycling of cell surface receptors from endosomes to the plasma membrane. In this study, we show that Ehd1 gene knockout in mice on a predominantly B6 background is embryonic lethal. Ehd1-null embryos die at mid-gestation with a failure to complete key developmental processes including neural tube closure, axial turning and patterning of the neural tube. We found that Ehd1-null embryos display short and stubby cilia on the developing neuroepithelium at embryonic day 9.5 (E9.5). Loss of EHD1 also deregulates the ciliary SHH signaling with Ehd1-null embryos displaying features indicative of increased SHH signaling, including a significant downregulation in the formation of the GLI3 repressor and increase in the ventral neuronal markers specified by SHH. Using Ehd1-null MEFS we found that EHD1 protein co-localizes with the SHH receptor Smoothened in the primary cilia upon ligand stimulation. Under the same conditions, EHD1 was shown to co-traffic with Smoothened into the developing primary cilia and we identify EHD1 as a direct binding partner of Smoothened. Overall, our studies identify the endocytic recycling regulator EHD1 as a novel regulator of the primary cilium-associated trafficking of Smoothened and Hedgehog signaling.

The endocytic recycling regulatory protein EHD1 Is required for ocular lens development.

The C-terminal Eps15 homology domain-containing (EHD) proteins play a key role in endocytic recycling, a fundamental cellular process that ensures the return of endocytosed membrane components and receptors back to the cell surface. To define the in vivo biological functions of EHD1, we have generated Ehd1 knockout mice and previously reported a requirement of EHD1 for spermatogenesis. Here, we show that approximately 56% of the Ehd1-null mice displayed gross ocular abnormalities, including anophthalmia, aphakia, microphthalmia and congenital cataracts. Histological characterization of ocular abnormalities showed pleiotropic defects that include a smaller or absent lens, persistence of lens stalk and hyaloid vasculature, and deformed optic cups. To test whether these profound ocular defects resulted from the loss of EHD1 in the lens or in non-lenticular tissues, we deleted the Ehd1 gene selectively in the presumptive lens ectoderm using Le-Cre. Conditional Ehd1 deletion in the lens resulted in developmental defects that included thin epithelial layers, small lenses and absence of corneal endothelium. Ehd1 deletion in the lens also resulted in reduced lens epithelial proliferation, survival and expression of junctional proteins E-cadherin and ZO-1. Finally, Le-Cre-mediated deletion of Ehd1 in the lens led to defects in corneal endothelial differentiation. Taken together, these data reveal a unique role for EHD1 in early lens development and suggest a previously unknown link between the endocytic recycling pathway and regulation of key developmental processes including proliferation, differentiation and morphogenesis.

A kinase inhibitor screen reveals protein kinase C-dependent endocytic recycling of ErbB2 in breast cancer cells.

ErbB2 overexpression drives oncogenesis in 20-30% cases of breast cancer. Oncogenic potential of ErbB2 is linked to inefficient endocytic traffic into lysosomes and preferential recycling. However, regulation of ErbB2 recycling is incompletely understood. We used a high-content immunofluorescence imaging-based kinase inhibitor screen on SKBR-3 breast cancer cells to identify kinases whose inhibition alters the clearance of cell surface ErbB2 induced by Hsp90 inhibitor 17-AAG. Less ErbB2 clearance was observed with broad-spectrum PKC inhibitor Ro 31-8220. A similar effect was observed with Go 6976, a selective inhibitor of classical Ca(2+)-dependent PKCs (α, ß1, ßII, and γ). PKC activation by PMA promoted surface ErbB2 clearance but without degradation, and ErbB2 was observed to move into a juxtanuclear compartment where it colocalized with PKC-α and PKC-δ together with the endocytic recycling regulator Arf6. PKC-α knockdown impaired the juxtanuclear localization of ErbB2. ErbB2 transit to the recycling compartment was also impaired upon PKC-δ knockdown. PMA-induced Erk phosphorylation was reduced by ErbB2 inhibitor lapatinib, as well as by knockdown of PKC-δ but not that of PKC-α. Our results suggest that activation of PKC-α and -δ mediates a novel positive feedback loop by promoting ErbB2 entry into the endocytic recycling compartment, consistent with reported positive roles for these PKCs in ErbB2-mediated tumorigenesis. As the endocytic recycling compartment/pericentrion has emerged as a PKC-dependent signaling hub for G-protein-coupled receptors, our findings raise the possibility that oncogenesis by ErbB2 involves previously unexplored PKC-dependent endosomal signaling.

A function for EHD family proteins in unidirectional retrograde dendritic transport of BACE1 and Alzheimer's disease Aß production.

Abnormal accumulation of ß-secretase (BACE1) in dystrophic neurites and presynaptic ß-amyloid (Aß) production contribute to Alzheimer's disease pathogenesis. Little, however, is known about BACE1 sorting and dynamic transport in neurons. We investigated BACE1 trafficking in hippocampal neurons using live-cell imaging and selective labeling. We report that transport vesicles containing internalized BACE1 in dendrites undergo exclusive retrograde transport toward the soma, whereas they undergo bidirectional transport in axons. Unidirectional dendritic transport requires Eps15-homology-domain-containing (EHD) 1 and 3 protein function. Furthermore, loss of EHD function compromises dynamic axonal transport and overall BACE1 levels in axons. EHD1/3 colocalize with BACE1 and APP ß-C-terminal fragments in hippocampal mossy fiber terminals, and their depletion in neurons significantly attenuates Aß levels. These results demonstrate unidirectional endocytic transport of a dendritic cargo and reveal a role for EHD proteins in neuronal BACE1 transcytosis and Aß production, processes that are highly relevant for Alzheimer's disease.