Carboplatin and Paclitaxel Chemoradiation for Localized Anal Cancer in Patients Not Eligible for Mitomycin and 5-Fluorouracil.

BACKGROUND: Although squamous cell carcinoma of the anus (SCCA) is a relatively uncommon malignancy in the United States, it continues to increase in incidence. Treatment for locoregional disease includes mitomycin and 5-fluorouracil with radiation. This combination is associated with significant toxicity, limiting its use in patients who are older or have certain comorbidities. Carboplatin and paclitaxel (C/P) is an accepted treatment regimen for metastatic SCCA. We aim to evaluate the efficacy and toxicity of weekly C/P given with radiation for patients unable to receive standard chemoradiation for SCCA. METHODS: From our cancer registry, adult patients who received weekly intravenous C/P concurrent with standard-dose radiation for localized SCCA were included in this study. Clinical response was determined based on the evidence of disease on imaging and/or anoscopy. Toxicities were graded according to the CTCAE v5. RESULTS: Ten patients were included; eight were female, and the median age was 75.5 years (54-87). Six had T2 disease, and four had T3 tumors. Four had node-positive disease. The majority (70%) of patients were dosed at standard C (AUC 2) and P (50 mg/m2), with a limited subset requiring dose reduction for baseline performance status. Patients completed a mean of 78.3% (40-100%) of the intended treatments. A total of 89% of the patients achieved a complete clinical response. With a median follow-up of 25.8 months (3.4-50.4 months), 67% of the patients are alive and without recurrence. Two patients have had local recurrence, and one patient had metastatic progression. The most common toxicities of any grade included leukopenia (100%), anemia (100%), radiation dermatitis (100%), diarrhea (100%), and fatigue (100%). Grade 3 or higher toxicities included neutropenic fever (20%), neutropenia (30%), and anemia (30%). CONCLUSIONS: This study demonstrates promising tolerability and efficacy for weekly C/P chemoradiation for patients with anal cancer unable to receive mitomycin and 5-fluorouracil. This regimen merits further investigation in prospective clinical trials.

The viscoelasticity of high concentration monoclonal antibodies using particle tracking microrheology.

The viscoelasticity of monoclonal antibodies (mAbs) is important during their production, formulation, and drug delivery. High concentration mAbs can provide higher efficacy therapeutics (e.g., during immunotherapy) and improved efficiency during their production (economy of scale during processing). Two humanized mAbs were studied (mAb-1 and mAb-2) with differing isoelectric points. Using high speed particle tracking microrheology, we demonstrated that the mAb solutions have significant viscoelasticities above concentrations of 40 mg/ml. Power law viscoelasticity was observed over the range of time scales (10-4-1 s) probed for the high concentration mAb suspensions. The terminal viscosity demonstrated an exponential dependence on mAb concentration (a modified Mooney relationship) as expected for charged stabilized Brownian colloids. Gelation of the mAbs was explored by lowering the pH of the buffer and a power law scaling of the gelation transition was observed, i.e., the exponent of the anomalous diffusion of the probe particles scaled inversely with the gelation time.

A modular and multi-functional purification strategy that enables a common framework for manufacturing scale integrated and continuous biomanufacturing.

Biopharmaceutical manufacture is transitioning from batch to integrated and continuous biomanufacturing (ICB). The common framework for most ICB, potentially enables a global biomanufacturing ecosystem utilizing modular and multi-function manufacturing equipment. Integrating unit operation hardware and software from multiple suppliers, complex supply chains enabled by multiple customized single-use flow paths, and large volume buffer production/storage make this ICB vision difficult to achieve with commercially available manufacturing equipment. Thus, we developed SymphonX™, a downstream processing skid with advanced buffer management capabilities, a single disposable generic flow path design that provides plug-and-play flexibility across all downstream unit operations and a single interface to reduce operational risk. Designed for multi-product and multi-process cGMP facilities, SymphonX™ can perform stand-alone batch processing or ICB. This study utilized an Apollo™ X CHO-DG44 mAb-expressing cell line in a steady-state perfusion bioreactor, harvesting product continuously with a cell retention device and connected SymphonX™ purification skids. The downstream process used the same chemistry (resins, buffer composition, membrane composition) as our historical batch processing platform, with SymphonX™ in-line conditioning and buffer concentrates. We used surge vessels between unit operations, single-column chromatography (protein A, cation and anion exchange) and two-tank batch virus inactivation. After the first polishing step (cation exchange), we continuously pooled product for 6 days. These 6 day pools were processed in batch-mode from anion exchange to bulk drug substance. This manufacturing scale proof-of-concept ICB produced 0.54 kg/day of drug substance with consistent product quality attributes and demonstrated successful bioburden control for unit-operations undergoing continuous operation.

Surgical Site Infection Prevention Using "Strike Teams": The Experience of an Academic Colorectal Surgical Department.

ABSTRACT: Surgical site infections (SSIs) are healthcare-acquired infections with substantial morbidity. Surgical site infection persist because of low adherence to prevention bundles comprising multiple infection control elements. We propose the "Strike Team" as an implementation strategy to improve adherence and reduce SSI in colorectal surgery. At an academic medical center, a multidisciplinary Strike Team met monthly to review colorectal SSI cases, audit and discuss barriers to adherence to SSI prevention bundle, and propose actionable feedback. The latter was shared with frontline clinicians by the Strike Team's surgical leaders in everyday practice. Colorectal SSI rates and bundle adherence data were disseminated quarterly via the hospital intranet and reviewed with surgeons at departmental meetings. Trends in adherence and SSI rates were analyzed by regression analysis using a time series model. While the Strike Team was active, adherence to antibiotic prophylaxis, maintenance of normoglycemia, and standardized intraoperative skin preparation significantly increased (p < .05). There was a trend toward statistically significant reduction in SSI (p = .07), although it was not maintained once the Strike Team activity was disrupted by the COVID-19 pandemic. Colorectal SSI prevention requires a resource-intensive, multidisciplinary approach with numerous strategies to improve adherence to infection control bundles, as illustrated by our SSI Strike Team experience.

Treating acute diverticulitis in pre- and post-solid-organ transplant patients: a single-institution cohort study.

AIM: Immunosuppressed patients are more likely to fail nonoperative management of acute diverticulitis and have more postoperative complications than the immunocompetent. Transplant recipients form a subcategory among the immunosuppressed with unique challenges. The aim of this work is to report 30-day postoperative complications after colectomy for acute diverticulitis and success rates of nonoperative management in pre- and post-transplant patients. METHOD: This is a retrospective cohort study at a single-institution tertiary referral centre. Patients with a history of acute diverticulitis were extracted from a database of 6152 recipients of solid-organ abdominal transplant between 2000 and 2015 and stratified by the index episode of diverticulitis: before or after solid-organ transplant surgery. Outcomes included 30-day postoperative complications and failure of nonoperative management. RESULTS: Acute diverticulitis occurred in 93 patients, 69 (74%) posttransplant. Postcolectomy complications were higher posttransplant than pretransplant (43% vs. 13%, p = 0.04). Posttransplant status was not an independent risk factor for complications (odds ratio 3.59, 95% CI 0.79-16.31) when adjusting for sex and surgical acuity. Immediate urgent colectomy (29% vs. 31%, p = 0.84) and failure of nonoperative management (7% vs. 9%, p = 0.82) were similar. Complications occurred equally in those requiring urgent colectomy after nonoperative management and those undergoing immediate urgent colectomy. CONCLUSION: Urgent colectomy rates are similar in solid-organ abdominal transplant recipients pre- and posttransplant. Posttransplant complication rates appear to be increased but transplant status as an independent factor is not significantly associated with an increased risk in this study cohort. These findings should be considered when counselling patients on the relative risks and benefits of surgical intervention for diverticulitis before versus after solid-organ transplantation.

Surgeons' mental models of surgical site infection: Insights into adherence with complex prevention bundles.

Of 10 surgeons interviewed in a descriptive qualitative study, 6 believed that surgical site infections are inevitable. Bundle adherence was felt to be more likely with strong evidence-based measures developed by surgical leaders. The intrinsic desire to excel was viewed as the main adherence motivator, rather than "pay-for-performance" models.

Prevalence of High-Grade Anal Dysplasia and Anal Cancer in Veterans Living With HIV and CD4/CD8 Ratio as a Marker For Increased Risk: A Regional Retrospective Cohort Study.

BACKGROUND: The Department of Veterans Affairs cares for the largest population of patients with HIV of any healthcare system in the United States. Screening for anal dysplasia/cancer is recommended for all veterans with HIV. Exams are invasive, burdensome, and resource intensive. We currently lack markers of disease to tailor screening. OBJECTIVE: The purpose of this study was to establish the prevalence of advanced anal disease (high-grade dysplasia and anal cancer) and to determine whether CD4/CD8 ratio correlates with risk. DESIGN: This was a retrospective regional cohort study of veterans with HIV. SETTINGS: The study was conducted at eight medical centers between 2001 and 2019. PATIENTS: Patients with advanced disease were compared with patients with nonadvanced anal pathology. MAIN OUTCOME MEASURES: Logistic regression modeling was used to estimate adjusted odds of disease as a function of CD4/CD8. Lowest (nadir) CD4/CD8 and nearest CD4/CD8 ratio in each cohort were evaluated. RESULTS: A total of 2267 veterans were included. Fifteen percent had anal pathology (112 with advanced disease (37 cancer and 75 high-grade), 222 with nonadvanced disease). Nadir and nearest ratio were lower in patients with advanced disease versus nonadvanced (0.24 vs 0.45 (p < 0.001) and 0.50 vs 0.88 (p < 0.001)). In adjusted models, a 1-unit increase in nadir or nearest ratio conferred decreased risk of advanced disease (OR = 0.19 (95% CI, 0.07-0.53); p < 0.001; OR = 0.22 (95% CI, 0.12-0.43); p < 0.001). Using a minimum sensitivity analysis, a cutoff nadir ratio of 0.42 or nearest ratio of 0.76 could be used to risk stratify. LIMITATIONS: This was a retrospective analysis with a low screening rate. CONCLUSIONS: In a regional cohort of veterans with HIV, 15% were formally assessed for anal dysplasia. Advanced anal disease was present in 33% of those screened, 5% of the HIV-positive population. A strong predictor of advanced disease in this cohort is the CD4/CD8 ratio, which is a promising marker to stratify screening practices. Risk stratification using CD4/CD8 has the potential to decrease burdensome invasive examinations for low-risk patients and to intensify examinations for those at high risk. See Video Abstract at http://links.lww.com/DCR/B528. PREVALENCIA DE DISPLASIA ANAL DE ALTO GRADO Y CNCER ANAL EN VETERANOS QUE VIVEN CON EL VIH Y LA RELACIN CD / CD COMO MARCADOR DE MAYOR RIESGO UN ESTUDIO DE COHORTE REGIONAL RETROSPECTIVE: ANTECEDENTES:El Departamento de Asuntos de Veteranos atiende a la población más grande de pacientes con el virus de inmunodeficiencia humana (VIH) de cualquier sistema de salud en los Estados Unidos. Se recomienda la detección de displasia / cáncer anal para todos los veteranos con VIH. Los exámenes son invasivos, onerosos y requieren muchos recursos. Actualmente carecemos de marcadores de enfermedad para adaptar la detección.OBJETIVO:Establecer la prevalencia de enfermedad anal avanzada (displasia de alto grado y cáncer anal) y determinar si la relación CD4 / CD8 se correlaciona con el riesgo.DISEÑO:Estudio de cohorte regional retrospectivo de veteranos con VIH.AJUSTE:Ocho centros médicos entre 2001-2019.PACIENTES:Se comparó a pacientes con enfermedad avanzada con pacientes con patología anal no avanzada.PRINCIPALES MEDIDAS DE RESULTADO:Se utilizó un modelo de regresión logística para estimar las probabilidades ajustadas de enfermedad en función de CD4 / CD8. Se evaluó la relación CD4 / CD8 más baja (nadir) y la relación CD4 / CD8 más cercana en cada cohorte.RESULTADOS:Se incluyeron un total de 2267 veteranos. El 15% tenía patología anal (112 enfermedad avanzada (37 cáncer, 75 de alto grado), 222 enfermedad no avanzada). El nadir y el cociente más cercano fueron menores en los pacientes con enfermedad avanzada frente a los no avanzados (0,24 frente a 0,45 (p <0,001) y 0,50 frente a 0,88 (p <0,001)), respectivamente. En modelos ajustados, el aumento de una unidad en el nadir o el cociente más cercano confirió una disminución del riesgo de enfermedad avanzada (OR 0,19 (IC del 95%: 0,07, 0,53, p <0,001)) y (OR 0,22 (IC del 95%: 0,12, 0,43, p <0,001))), respectivamente. Utilizando un análisis de sensibilidad mínima, se podría utilizar un cociente del nadir de corte de 0,42 o el cociente más cercano de 0,76 para estratificar el riesgo.LIMITACIONES:Análisis retrospectivo con una tasa de detección baja.CONCLUSIONES:En una cohorte regional de veteranos con VIH, el 15% fueron evaluados formalmente por displasia anal. La enfermedad anal avanzada estuvo presente en el 33% de los examinados, el 5% de la población VIH +. Un fuerte predictor de enfermedad avanzada en esta cohorte es la relación CD4 / CD8, que es un marcador prometedor para estratificar las prácticas de detección. La estratificación del riesgo usando CD4 / CD8 tiene el potencial de disminuir los exámenes invasivos onerosos para los pacientes de bajo riesgo e intensificar los exámenes para los de alto riesgo. Consulte Video Resumen en http://links.lww.com/DCR/B528.

The Optimal Ileal Pouch: Physiologic Parameters Significantly Correlate with Overall Pouch Function.

BACKGROUND: Ileal pouch function is affected by several patient factors and pouch physiology. The significance of pouch physiology on optimal pouch function has not been well characterized. The purpose of this study was to examine specific post-ileal pouch anal anastomosis (IPAA) physiologic parameters to determine impact on pouch function and quality of life. METHODS: Patients undergoing proctocolectomy with IPAA for ulcerative colitis were examined. Post-IPAA compliance, pouch anal pressure gradient (PAPG), and function were assessed 6-8 months postoperatively. Compliance was calculated as change in volume divided by change in pressure. PAPG was calculated as the difference between anal pressure and intra-pouch pressure at a fixed volume. Pouch function evaluation included stool frequency and episodes of incontinence. Quality of life was evaluated using the Rockwood Fecal Incontinence Quality of Life Scale. RESULTS: A total of 125 patients were investigated. Post-IPAA resting anal pressure averaged 58.1 ± 15 mmHg. Mean volume and intra-pouch pressure at evacuation were 245 mL and 33.9 mmHg, respectively. Compliance averaged 11.2 mmHg/mL with a mean PAPG of - 29.3 mmHg. Compliance and PAPG correlated with 24-h (p = 0.003, p = 0.004) and nighttime stool frequency (p = 0.04, p = 0.03). Daytime continence was impacted by compliance (p = 0.04), PAPG (p = 0.02), and resting anal pressure (p = 0.02). CONCLUSION: This unique evaluation reveals a significant correlation between IPAA physiologic properties and function. Optimal function and quality of life depend in part on maintaining optimal pouch compliance and pressure differentials between the pouch and anal canal, defined by the pouch anal pressure gradient.

Gaining momentum in colorectal surgical site infection reduction through a human factors engineering approach.

Surgical site infection (SSI) prevention requires multiple interventions packaged into "bundles." The implementation of all bundle elements is key to the bundle's efficacy. A human-factors engineering approach can be used to identify key barriers and facilitators to implementing elements and develop recommendations for bundle implementation within the clinical work system.

Colorectal bundles for surgical site infection prevention: A systematic review and meta-analysis.

OBJECTIVE: In colorectal surgery, the composition of the most effective bundle for prevention of surgical site infections (SSI) remains uncertain. We performed a meta-analysis to identify bundle interventions most associated with SSI reduction. METHODS: We systematically reviewed 4 databases for studies that assessed bundles with ≥3 elements recommended by clinical practice guidelines for adult colorectal surgery. The main outcome was 30-day postoperative SSI rate (overall, superficial, deep, and/or organ-space). RESULTS: We included 40 studies in the qualitative review, and 35 studies (54,221 patients) in the quantitative review. Only 3 studies were randomized controlled trials. On meta-analyses, bundles were associated with overall SSI reductions of 44% (RR, 0.57; 95% CI, 0.48-0.65); superficial SSI reductions of 44% (RR, 0.56; 95% CI, 0.42-0.75); deep SSI reductions of 33% (RR, 0.67; 95% CI, 0.46-0.98); and organ-space SSI reductions of 37% (RR, 0.63; 95% CI, 0.50-0.81). Bundle composition was heterogeneous. In our meta-regression analysis, bundles containing ≥11 elements, consisting of both standard of care and new interventions, demonstrated the greatest SSI reduction. Separate instrument trays, gloves with and without gown change for wound closure, and standardized postoperative dressing change at 48 hours correlated with the highest reductions in superficial SSIs. Mechanical bowel preparation combined with oral antibiotics, and preoperative chlorhexidine showers correlated with highest organ-space SSI reductions. CONCLUSIONS: Preventive bundles emphasizing guideline-recommended elements from both standard of care as well as new interventions were most effective for SSI reduction following colorectal surgery. High clinical-bundle heterogeneity and low quality for most observational studies significantly limit our conclusion.