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UNLABELLED: Total neoadjuvant therapy (TNT) is the recommended treatment for locally advanced rectal cancer. The optimal sequence of TNT is debated: induction (chemotherapy first) or consolidation (chemoradiation first)? We aim to evaluate the practice patterns and clinical outcomes of total neoadjuvant therapy with either induction or consolidation regiments in the United States for patients with locally advanced rectal cancer. METHODS: This is a retrospective analysis of the National Cancer Database for patients with clinical stage II or stage III rectal cancer, diagnosed between 2006 and 2017, who underwent total neoadjuvant therapy followed by surgery. RESULTS: From 2006 to 2017, we identified 8999 patients and found that the utilization of induction chemotherapy increased from 2.0% to 35.0%. TNT resulted in pathologic downstaging 46.7% of the time and a pathologic complete response 11.6% of the time. Induction chemotherapy lead to higher pathologic downstaging (58% vs. 44.7%, p < 0.001) and pathologic complete responses (16.8% vs. 10.7%, p < 0.001). Similar trends held true in a multivariate analysis and subset analysis of stage II and III disease. CONCLUSIONS: These findings suggest that induction chemotherapy may be preferred over consolidation chemotherapy when downstaging prior to oncologic resection is desired. The optimal treatment plan for total neoadjuvant therapy is multi-factorial and requires further elucidation.

BACKGROUND: Autologous fat grafting (AFG) has shown promise in the treatment of complex wounds, with trials reporting good healing rates and safety profile. We aim to investigate the role of AFG in managing complex anorectal fistulas. METHODS: This was a retrospective review of a prospectively maintained IRB-approved database. We examined the rates of symptom improvement, clinical closure of fistula tracts, recurrence, complications, and worsening fecal incontinence. Perianal disease activity index (PDAI) was obtained for patients undergoing combination of AFG and fistula plug treatment. RESULTS: In total, 52 unique patients underwent 81 procedures, of which Crohns was present in 34 (65.4%) patients. The majority of patients previously underwent more common treatments such as endorectal advancement flap or ligation of intersphincteric fistula tract. Fat-harvesting sites and processing technique were selected by the plastic surgeons based on availability of trunk fat deposits. When analyzing patients by their last procedure, 41 (80.4%) experienced symptom improvement, and 29 (64.4%) experienced clinical closure of all fistula tracts. Recurrence rate was 40.4%, and complication rate was 15.4% (7 postoperative abscesses requiring I&D and 1 bleeding episode ligated at bedside). The abdomen was the most common site of lipoaspirate harvest at 63%, but extremities were occasionally used. There were no statistically significant differences in outcomes when comparing single graft treatment to multiple treatments, Crohns and non-Crohns, different methods of fat preparation, and diversion. CONCLUSION: AFG is a versatile procedure that can be done in conjunction with other therapies and does not interfere with future treatments if recurrence occurs. It is a promising and affordable method to safely address complex fistulas.

Background and purposeClinical outcomes of multiple sclerosis (MS) patients affected by coronavirus disease 2019 (COVID-19) have been thoroughly investigated, but a further analysis on main signs and symptoms and their risk factors still needs attention. The objective of this study was to group together and describe based on similarity the most common signs and symptoms of COVID-19 in MS patients and identify all factors associated with their manifestation.MethodLogistic and linear regression models were run to recognize factors associated with each pooled group of symptoms and their total number.ResultsFrom March 2020 to November 2021, data were collected from 1354 MS patients with confirmed infection of COVID-19. Ageusia and anosmia was less frequent in older people (odds ratio [OR] 0.98; p = 0.005) and more in smoker patients (OR 1.39; p = 0.049). Smoke was also associated with an incremental number of symptoms (OR 1.24; p = 0.031), substance abuse (drugs or alcohol), conjunctivitis and rash (OR 5.20; p = 0.042) and the presence of at least one comorbidity with shortness of breath, tachycardia or chest pain (OR 1.24; p = 0.008). Some disease-modifying therapies were associated with greater frequencies of certain COVID-19 symptoms (association between anti-CD20 therapies and increment in the number of concomitant symptoms: OR 1.29; p = 0.05). Differences in frequencies between the three waves were found for flu-like symptoms (G1, p = 0.024), joint or muscle pain (G2, p = 0.013) and ageusia and anosmia (G5, p

Abstract SAR439459 (SAR'459), a “second‐generation” human anti‐transforming growth factor beta (TGFβ) monoclonal antibody, enhances the activity of immune checkpoint inhibitors. In this phase I/Ib study, we evaluated the safety, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of SAR'459 ± cemiplimab (intravenous) in patients with advanced solid tumors. Increasing doses of SAR'459 were administered every 2 or 3 weeks (Q2W, Q3W) alone (Part 1A) or with 3 mg/kg cemiplimab Q2W or 350 mg Q3W (Part 1B). In Part 2A (dose expansion), melanoma patients were randomly (1:1) administered 22.5 or 7.5 mg/kg SAR'459. In Part 2B (dose expansion), 22.5 mg/kg SAR'459 and 350 mg cemiplimab Q3W were administered. The primary end points were maximum tolerated dose (MTD) or maximum administered dose (MAD; Part 1), preliminary antitumor activity (Part 2B), and optimal monotherapy dose (Part 2A). Twenty‐eight and 24 patients were treated in Parts 1A and 1B, respectively; MTD was not reached, MAD was 15 (Q2W) and 22.5 mg/kg (Q3W) alone and in combination, respectively. Fourteen and 95 patients, including 14 hepatocellular carcinoma (HCC) patients, were treated in Parts 2A and 2B, respectively. The population PK model yielded satisfactory goodness‐of‐fit plots and adequately described the observed data by a two‐compartment PK model with linear elimination. Objective responses were not observed in Parts 1 and 2A. In Part 2B, objective response rate was 8.4% and 7.1% across tumor types and the HCC cohort, respectively. The most frequent treatment‐emergent adverse effects were hemorrhagic events (43.5%), keratoacanthoma (6.8%), and skin neoplasms (6.2%). Fatal bleeding occurred in 21.4% HCC patients despite the implementation of mitigation measures. SAR'459 monotherapy and combination with cemiplimab appeared relatively safe and tolerable in limited number of patients in dose escalation. However, the study was discontinued due to the unclear efficacy of SAR'459 and bleeding risk, particularly in HCC patients.

The intricate parallels in structure and function between the human retina and the central nervous system designate the retina as a prospective avenue for understanding brain-related processes. This review extensively explores the shared physiopathological mechanisms connecting age-related macular degeneration (AMD) and proteinopathies, with a specific focus on tauopathies. The pivotal involvement of oxidative stress and cellular senescence emerges as key drivers of pathogenesis in both conditions. Uncovering these shared elements not only has the potential to enhance our understanding of intricate neurodegenerative diseases but also sets the stage for pioneering therapeutic approaches in AMD.

BackgroundAlthough there is extensive literature on robotic total intracorporeal anastomosis (TICA) for right colon resection, left total ICA using the da Vinci Xi robotic platform has only been described in short case series previously. In this study, we report on the largest cohort of robotic left total ICA, provide a description of our institution's techniques, and compare outcomes to robotic left partial extracorporeal anastomosis (PECA).MethodsPatients who underwent robotic left colectomy for any underlying pathology from July 1, 2016 through April 30, 2020 were identified by procedure code. A technical description is provided for two unique techniques performed at our institution. Outcomes included operative time, length of stay, supply cost, post-operative ileus, post-operative morbidity and mortality and need for complete mobilization of the splenic flexure.ResultsFrom a review of our institution's data, 83 robotic TICA cases were identified and 76 robotic PECA cases were identified. Common procedures included low anterior resection, sigmoidectomy, left hemicolectomy, and rectopexy with resection. TICA was associated with significantly shorter intraoperative time compared to PECA.ConclusionsOur series shows that TICA is a safe and feasible technique that does not increase the risk of adverse outcomes. Using either the anvil-forward or anvil-backward technique, we were able to reliably reproduce this method in a total of 83 patients undergoing left colon resection for either benign or malignant diseases.

Abstract SAR439459, a ‘second‐generation’ human anti‐transforming growth factor‐beta (TGFβ) monoclonal antibody, inhibits all TGFβ isoforms and improves the antitumor activity of anti‐programmed cell death protein‐1 therapeutics. This study reports the pharmacodynamics (PD) and biomarker results from phase I/Ib first‐in‐human study of SAR439459 ± cemiplimab in patients with advanced solid tumors (NCT03192345). In dose‐escalation phase (Part 1), SAR439459 was administered intravenously at increasing doses either every 2 weeks (Q2W) or every 3 weeks (Q3W) with cemiplimab IV at 3 mg/kg Q2W or 350 mg Q3W, respectively, in patients with advanced solid tumors. In dose‐expansion phase (Part 2), patients with melanoma received SAR439459 IV Q3W at preliminary recommended phase II dose (pRP2D) of 22.5/7.5 mg/kg or at 22.5 mg/kg with cemiplimab 350 mg IV Q3W. Tumor biopsy and peripheral blood samples were collected for exploratory biomarker analyses to assess target engagement and PD, and results were correlated with patients' clinical parameters. SAR439459 ± cemiplimab showed decreased plasma and tissue TGFβ, downregulation of TGFβ‐pathway activation signature, modulation of peripheral natural killer (NK) and T cell expansion, proliferation, and increased secretion of CXCL10. Conversion of tumor tissue samples from ‘immune‐excluded’ to ‘immune‐infiltrated’ phenotype in a representative patient with melanoma SAR439459 22.5 mg/kg with cemiplimab was observed. In paired tumor and plasma, active and total TGFβ1 was more consistently elevated followed by TGFβ2, whereas TGFβ3 was only measurable (lower limit of quantitation ≥2.68 pg/mg) in tumors. SAR439459 ± cemiplimab showed expected peripheral PD effects and TGFβ alteration. However, further studies are needed to identify biomarkers of response.

Background and purposeSome studies have shown that air pollution, often assessed by thin particulate matter with diameter below 2.5 µg/m3 (PM2.5), may contribute to severe COVID-19 courses, as well as play a role in the onset and evolution of multiple sclerosis (MS). However, the impact of air pollution on COVID-19 has never been explored specifically amongst patients with MS (PwMS). This retrospective observational study aims to explore associations between PM2.5 and COVID-19 severity amongst PwMS.MethodsData were retrieved from an Italian web-based platform (MuSC-19) which includes PwMS with COVID-19. PM2.5 2016-2018 average concentrations were provided by the Copernicus Atmospheric Monitoring Service. Italian patients inserted in the platform from 15 January 2020 to 9 April 2021 with a COVID-19 positive test were included. Ordered logistic regression models were used to study associations between PM2.5 and COVID-19 severity.ResultsIn all, 1087 patients, of whom 13% required hospitalization and 2% were admitted to an intensive care unit or died, were included. Based on the multivariate analysis, higher concentrations of PM2.5 increased the risk of worse COVID-19 course (odds ratio 1.90; p = 0.009).ConclusionsEven if several other factors explain the unfavourable course of COVID-19 in PwMS, the role of air pollutants must be considered and further investigated.

BackgroundRectal neuroendocrine tumors comprise 20% of neuroendocrine tumors in the alimentary tract, but there is controversy surrounding the optimal management of this disease. The purpose of this study is to better define treatment for patients with rectal neuroendocrine tumors.MethodsUsing the National Cancer Database, we analyzed patients with rectal neuroendocrine tumors between 2004 and 2015. Patients with metastatic disease and missing treatment data were excluded. We examined overall survival stratified by tumor size, treatment type, and presence of positive lymph nodes using Kaplan-Meier analysis with log-rank test. Cox proportional hazard regression model was performed to identify factors associated with overall survival.ResultsIn total, 17,448 patients with rectal neuroendocrine tumors were identified; 16,531 of these patients met inclusion criteria. The majority of patients had tumors ≤ 10 mm (9216 patients, 79.8%), and approximately 90% underwent local excision. The probability of 5-year overall survival was significantly higher for patients with smaller tumors (≤ 10 mm: 94.1% 11-20 mm: 85.7%, > 20 mm: 71.8%; p

BackgroundCommon colorectal procedures that require access to all quadrants of the abdomen are subtotal colectomy (STC) and total proctocolectomy (TPC). These are frequently performed with a surgical robot, but multiquadrant operations have unique challenges during robot-assisted surgery.MethodsPatients who underwent robotic STC or TPC with the da Vinci Xi surgical robot at our institution from July 1, 2016 through June 30, 2019 were identified by diagnosis and procedure codes. A technical description is provided for the techniques utilized at our institution. Outcomes included operative times (OT), supply cost and length of stay. Associated morbidity and mortality was also analyzed.ResultsFrom a review of our institution's robotic surgery data, 37 cases were identified that utilized the described technique. Of these cases, 21 were robotic STC and 16 were TPC. Total mean OT was 276.86 min (SD ± 119.49). Mean OT was further analyzed by year, which demonstrated an overall decrease in OT from 350.91 min (SD ± 46.38) in 2016 to 221.43 min (SD ± 16.46) in 2018 (p = 0.008). A total of 21 cases were performed prior to 2018. Overall OT for STC was 222.81 min (SD ± 14.54) compared to overall TPC OT 347.81 min (SD ± 34.35). Median length of stay was 5 days [25th and 75th percentiles 4, 6, respectively]. There was no 30-day mortality and only one return to operating room for mesenteric bleeding. There was a low risk of mortality associated with this technique.ConclusionsThe current study provides the largest cohort of patients assessed who have undergone multiquadrant robotic STC or TPC. The study provides a detailed description of the technique utilized at our institution. There was no associated 30-day mortality and a low risk of morbidity. The data suggest that the learning curve for improved operative time is between 15 and 20 cases.

Sleep is a fundamental human need; sleep disruption, in fact, causes an increase in the activity of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis, metabolic effects, changes in circadian rhythms, and pro-inflammatory responses. The scientific literature is finally starting to pay attention to the central role of sleep alterations in patients health. Oxaliplatin is extensively used for the treatment of gastrointestinal cancer and other malignancies, with an increased frequency of use in recent years. This study aims to understand the effects of sleep complaints on health and quality of life in cancer patients treated with oxaliplatin. A study has been conducted through the creation and distribution of questionnaires to patients to investigate their complaints about sleep quality. We observed significant differences between males and females in evaluating sleep hygiene scores, the Pittsburgh Sleep Quality Index, and previous difficulty sleeping. Moreover, in females, stress, worries, and anxiety seem to play a negative role in the sleep hygiene score. The obtained results could improve the interest of healthcare personnel and caregivers in sleep quality in patients undergoing chemotherapy.

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Total neoadjuvant therapy (TNT) is the recommended treatment for locally advanced rectal cancer. The optimal sequence of TNT is debated: induction (chemotherapy first) or consolidation (chemoradiation first)? We aim to evaluate the practice patterns and clinical outcomes of total neoadjuvant therapy with either induction or consolidation regiments in the United States for patients with locally advanced rectal cancer. Methods: This is a retrospective analysis of the National Cancer Database for patients with clinical stage II or stage III rectal cancer, diagnosed between 2006 and 2017, who underwent total neoadjuvant therapy followed by surgery. Results: From 2006 to 2017, we identified 8999 patients and found that the utilization of induction chemotherapy increased from 2.0% to 35.0%. TNT resulted in pathologic downstaging 46.7% of the time and a pathologic complete response 11.6% of the time. Induction chemotherapy lead to higher pathologic downstaging (58% vs. 44.7%, p < 0.001) and pathologic complete responses (16.8% vs. 10.7%, p < 0.001). Similar trends held true in a multivariate analysis and subset analysis of stage II and III disease. Conclusions: These findings suggest that induction chemotherapy may be preferred over consolidation chemotherapy when downstaging prior to oncologic resection is desired. The optimal treatment plan for total neoadjuvant therapy is multi-factorial and requires further elucidation.

BackgroundThe use of the surgical robot has increased annually since its introduction, especially in general surgery. Despite the tremendous increase in utilization, there are currently no validated curricula to train residents in robotic surgery, and the effects of robotic surgery on general surgery residency training are not well defined. In this study, we aim to explore the perceptions of resident and attending surgeons toward robotic surgery education in general surgery residency training.MethodsWe performed a qualitative thematic analysis of in-person, one-on-one, semi-structured interviews with general surgery residents and attending surgeons at a large academic health system. Convenient and purposeful sampling was performed in order to ensure diverse demographics, experiences, and opinions were represented. Data were analyzed continuously, and interviews were conducted until thematic saturation was reached, which occurred after 20 residents and seven attendings.ResultsAll interviewees agreed that dual consoles are necessary to maximize the teaching potential of the robotic platform, and the importance of simulation and simulators in robotic surgery education is paramount. However, further work to ensure proper access to simulation resources for residents is necessary. While most recognize that bedside-assist skills are essential, most think its educational value plateaus quickly. Lastly, residents believe that earlier exposure to robotic surgery is necessary and that almost every case has a portion that is level-appropriate for residents to perform on the robot.ConclusionsAs robotic surgery transitions from novelty to ubiquity, the importance of effective general surgery robotic surgery training during residency is paramount. Through in-depth interviews, this study provides examples of effective educational tools and techniques, highlights the importance of simulation, and explores opinions regarding the role of the resident in robotic surgery education. We hope the insights gained from this study can be used to develop and/or refine robotic surgery curricula.

ObjectiveTo determine barriers associated with the transition from bedside assistant to console surgeon for general surgery residents in the era of robotic surgery in general surgery training.DesignQualitative thematic analysis using one-on-one interviews of general surgery residents and attendings conducted between June 2018 and February 2019.SettingAn urban, academic, multihospital general surgery residency program with a robust robotic surgery program.ParticipantsConvenient and purposeful sampling was performed to ensure a variety of resident graduate-years and attending subspecialties were represented. Sample size was determined by data saturation, which occurred after 20 resident and 7 attending interviews.ResultsResidents identified the low volume of general surgery robotic cases, the infrequency of exposure to robotic surgery, and attending comfort with robotic surgery (and with teaching on the robot) as potential barriers in the transition from bedside assistant to console surgeon. Residents had to find a replacement bedside assistant in order to be the console surgeon, which was challenging. In addition, residents felt that the current culture surrounding robotic surgery is very hierarchal, limiting their exposure. Attendings' trust in the residents' console skills was a major determining factor in allowing residents on the console.ConclusionsMost robotic surgery education curricula are sequential, requiring the resident to progress from bedside assistant to console surgeon. Unfortunately, there are many potential barriers for residents in the transition from bedside assistant to console surgeon. Some barriers apply to general surgery training overall, but are amplified in robotic surgery, while others are unique to robotic surgery education. Recognition of, and rectifying, these barriers may increase resident participation as the console surgeon.

The NCCN Guidelines for Colorectal Cancer (CRC) Screening describe various colorectal screening modalities as well as recommended screening schedules for patients at average or increased risk of developing sporadic CRC. They are intended to aid physicians with clinical decision-making regarding CRC screening for patients without defined genetic syndromes. These NCCN Guidelines Insights focus on select recent updates to the NCCN Guidelines, including a section on primary and secondary CRC prevention, and provide context for the panel's recommendations regarding the age to initiate screening in average risk individuals and follow-up for low-risk adenomas.

Glaucoma is a chronic neurodegenerative disorder affecting the visual system which can result in vision loss and blindness. The pathogenetic mechanisms underlying glaucomatous optic neuropathy are ultimately enigmatic, prompting ongoing investigations into its potential shared pathogenesis with other neurodegenerative neurological disorders. Tauopathies represent a subclass of neurodegenerative diseases characterized by the abnormal deposition of tau protein within the brain and consequent microtubule destabilization. The extended spectrum of tauopathies includes conditions such as frontotemporal dementias, progressive supranuclear palsy, chronic traumatic encephalopathy, and Alzheimer’s disease. Notably, recent decades have witnessed emerging documentation of tau inclusion among glaucoma patients, providing substantiation that this ocular disease may similarly manifest features of tauopathies. These studies found that: (i) aggregated tau inclusions are present in the somatodendritic compartment of RGCs in glaucoma patients; (ii) the etiology of the disease may affect tau splicing, phosphorylation, oligomerization, and subcellular localization; and (iii) short interfering RNA against tau, administered intraocularly, significantly decreased retinal tau accumulation and enhanced RGC somas and axon survival, demonstrating a crucial role for tau modifications in ocular hypertension-induced neuronal injury. Here, we examine the most recent evidence surrounding the interplay between tau protein dysregulation and glaucomatous neurodegeneration. We explore the novel perspective of glaucoma as a tau-associated disorder and open avenues for cross-disciplinary collaboration and new treatment strategies.

Background and Objectives: Sexual violence (SV) is a major global public health concern. While socioeconomic factors and familial relationships have been widely reported to contribute to SV, the role of alcohol consumption should not be ignored. Indeed, alcohol can impair cognition, distort reality, increase aggression, and ease drug-facilitated sexual assault. This retrospective study aims to explore the relationship between alcohol consumption and SV by examining the prevalence, characteristics, and consequences of violence episodes. Materials and Methods: A total of 1481 women accessed the Rape Centre “Centro Soccorso Violenza Sessuale” in Turin, Italy between 2008 and 2019, with 223 reporting alcohol consumption before the assault. Results: The alcohol group had a younger age profile, predominantly within the 18–25-year-old category. SV incidents involving alcohol consumers were more likely to occur in public places or in someone else’s home, while the non-alcohol-consuming group experienced more violence in their own homes. Acquaintances and unknown individuals were primarily responsible, whereas partners were the most common perpetrators of violence against non-alcohol-consuming women. Alcohol consumers sought medical attention sooner after the assault and exhibited more symptoms and injuries, particularly of neurological origin. Concurrent use of recreational drugs was higher among alcohol consumers. The logistic regression analysis revealed higher odds of injury for Italian women and those in the 18–35 age groups after consuming alcohol. Conclusions: This study contributes to the understanding of the relationship between alcohol consumption and SV. The prevalence of alcohol-related sexual aggression is lower compared to that shown in previous studies. Nationality, age, and assailant identity influence SV dynamics. These findings can guide well-targeted interventions and prevention strategies to address SV and inform communities facing similar challenges.