NEO-GAP: A Single-Arm, Phase II Feasibility Trial of Neoadjuvant Gemcitabine, Cisplatin, and Nab-Paclitaxel for Resectable, High-Risk Intrahepatic Cholangiocarcinoma.

PURPOSE: Most patients with intrahepatic cholangiocarcinoma (IHCC) develop recurrence after resection. Adjuvant capecitabine remains the standard of care for resected IHCC. A combination of gemcitabine, cisplatin, and nab-paclitaxel (GAP) was associated with a 45% response rate and 20% conversion rate among patients with unresectable biliary tract cancers. The aim of this study was to evaluate the feasibility of delivering GAP in the neoadjuvant setting for resectable, high-risk IHCC. METHODS: A multi-institutional, single-arm, phase II trial was conducted for patients with resectable, high-risk IHCC, defined as tumor size > 5 cm, multiple tumors, presence of radiographic major vascular invasion, or lymph node involvement. Patients received preoperative GAP (gemcitabine 800 mg/m2, cisplatin 25 mg/m2, and nab-paclitaxel 100 mg/m2 on days 1 and 8 of a 21-day cycle) for a total of 4 cycles prior to an attempt at curative-intent surgical resection. The primary endpoint was completion of both preoperative chemotherapy and surgical resection. Secondary endpoints were adverse events, radiologic response, recurrence-free survival (RFS), and overall survival (OS). RESULTS: Thirty evaluable patients were enrolled. Median age was 60.5 years. Median follow-up for all patients was 17 months. Ten patients (33%) experienced grade ≥ 3 treatment-related adverse events, the most common being neutropenia and diarrhea; 50% required ≥ 1 dose reduction. The disease control rate was 90% (progressive disease: 10%, partial response: 23%, stable disease: 67%). There was zero treatment-related mortality. Twenty-two patients (73%, 90% CI 57-86; p = 0.008) completed all chemotherapy and surgery. Two patients (9%) who successfully underwent resection had minor postoperative complications. Median length of hospital stay was 4 days. Median RFS was 7.1 months. Median OS for the entire cohort was 24 months and was not reached in patients who underwent surgical resection. CONCLUSION: Neoadjuvant treatment with gemcitabine, cisplatin, and nab-paclitaxel is feasible and safe prior to resection of intrahepatic cholangiocarcinoma and does not adversely impact perioperative outcomes.

Sustained Carbohydrate Antigen 19-9 Response to Neoadjuvant Chemotherapy in Borderline Resectable Pancreatic Cancer Predicts Progression and Survival.

BACKGROUND: As neoadjuvant therapy of borderline resectable pancreatic cancer (BRPC) is becoming more widely used, better indicators of progression are needed to help guide therapeutic decisions. MATERIALS AND METHODS: A retrospective review was performed on all patients with BRPC who received 24 weeks of neoadjuvant chemotherapy. Patients with chemotoxicity or medical comorbidities limiting treatment completion and nonexpressors of carbohydrate antigen 19-9 (CA19-9) were excluded. Serum CA19-9 response was analyzed as a predictor of disease progression, recurrence, and survival. RESULTS: One hundred four patients were included; 39 (37%) progressed on treatment (18 local and 21 distant) and 65 (63%) were resected (68% R0). Multivariate logistic regression analysis determined that the percent decrease in CA19-9 from baseline to minimum value (odds ratio [OR] 0.947, p ≤ .0001) and the percent increase from minimum value to final restaging CA19-9 (OR 1.030, p ≤ .0001) were predictive of progression. A receiver operating characteristics curve analysis determined cutoff values predictive of progression, which were used to create four prognostic groups. CA19-9 responses were categorized as follows: (1) always normal (n = 6); (2) poor response (n = 31); (3) unsustained response (n = 19); and (4) sustained response (n = 48). Median overall survival for Groups 1-4 was 58, 16, 20, and 38 months, respectively (p ≤ .0001). CONCLUSION: Patients with initially elevated CA19-9 levels who do not have a decline to a sustained low level are at risk for progression, recurrence, and poor survival. Alternative treatment strategies prior to an attempt at curative resection should be considered in this cohort. IMPLICATIONS FOR PRACTICE: This study identified percent changes in carbohydrate antigen 19-9 blood levels while on chemotherapy that predict tumor growth in patients with advanced pancreas cancer. These changes could be used to better select patients who would benefit from surgical removal of their tumors and improve survival.

Impact of initial imaging with gallium-68 dotatate PET/CT on diagnosis and management of patients with neuroendocrine tumors.

BACKGROUND: Somatostatin analog functional imaging with gallium-68 (Ga-68) dotatate positron emission tomography/computed tomography (PET/CT) has demonstrated superiority in lesion detection in patients with neuroendocrine tumors (NETs). The clinical impact of this imaging modality on US surgical and medical oncology practices has not been established. METHODS: Consecutive patients with NET at our institution who received an initial Ga-68 dotatate PET/CT between July 2017 and September 2018 were included. Ga-68 dotatate PET/CT was compared with prior imaging. RESULTS: Among 101 eligible patients, 51 of 50 were female/male, site of origin was gastroenteropancreatic (75%), unknown primary (13%), lung (8%), thymus (2%), and other (2%). All NETs were histologically well/moderately differentiated. Ga-68 dotatate imaging findings altered management in 36 (35.6%) patients: documentation of progression led to the initiation of systemic therapy in 14 patients, obviated the need for biopsy in four patients, and altered surgical plans in 7 of 14 (50%) patients referred for surgery. In 11 patients, decisions regarding peptide receptor radionucleotide therapy and somatostatin analogs were altered. CONCLUSIONS: In this series, Ga-68 dotatate PET/CT altered diagnosis and management in one-third of patients and changed operative plans in half of the patients who were referred for surgical evaluation. These results support the routine use of this imaging in the care of patients with early-stage and advanced NETs.

Gemcitabine and Taxane Adjuvant Therapy with Chemoradiation in Resected Pancreatic Cancer: A Novel Strategy for Improved Survival?

BACKGROUND: Gemcitabine-taxane combination chemotherapy has demonstrated a survival benefit clinically in metastatic pancreatic cancer (PC). The authors present their experience with gemcitabine and docetaxel (gem/tax)-based adjuvant treatment (Rx) after surgery with curative intent. METHODS: Patients with de novo resectable PC from January 2010 to December 2015 were identified from the authors' institutional database and registry. The study included only patients who received gem/tax as their initial Rx administered exclusively at the authors' institution with or without chemoradiation (CRTx). Survival analysis was performed using Kaplan-Meier methods, and prognostic factors were investigated by Cox proportional hazard modeling. RESULTS: Of 102 patients identified, 58 met the study criteria. The median age at diagnosis was 65 years, with 55% of the patients undergoing an R1 resection (margin ≤ 1 mm). Tumor characteristics included a median tumor size of 28 mm, a poor differentiation rate of 54%, and a lymph node positivity of 67%. Most of the patients (90%, 52/58) completed 80% or more of the 24 week Rx. Of these patients, 71% received post-gem/tax CRTx Rx. Grade 3 or 4 toxicity was observed in 52% of the patients. The median follow-up period was 51.2 months, and the observed median overall survival (OS) was 52 months [95% confidence interval (CI) 27.4-not reached]. The actuarial 5-year OS was 49% (95% CI 33.7-63.4%). In the multivariate analysis, an R1 resection and American Joint Committee on Cancer (AJCC) stage 2 versus stage 1 disease were negatively associated with OS, whereas administration of CRTx was positively associated with OS. CONCLUSIONS: Adjuvant gem/tax with or without CRTx is feasible, with a favorable OS. Future prospective studies of gem/taxane-based adjuvant Rx for PC are warranted.

Initiation of adjuvant therapy following surgical resection of pancreatic ductal adenocarcinoma (PDAC): Are patients from rural, remote areas disadvantaged?

BACKGROUND AND OBJECTIVES: Although race and socioeconomic status have been shown to affect outcomes in pancreatic ductal adenocarcinoma (PDAC), the impact of rural residence on the delivery of adjuvant therapy (AT) has not been studied. METHODS: Patients with resected PDAC were identified using the National Cancer Database (NCDB). Individuals were classified as living in a metro area, urban/rural adjacent to a metro area (URA), and urban/rural remote (URR) area. Multivariate logistic regression was used to assess geographic inhabitance as a predictor of receiving AT. RESULTS: A total of 32 521 individuals who underwent pancreatectomy for PDAC were identified. Univariate analysis demonstrated individuals in URR areas were less likely to receive adjuvant chemotherapy (ACT) than those living in URA or metro areas (55.3% vs 55.6% vs 58.8%, P = 0.011). However on multivariate analysis URR inhabitance was no longer a predictor of ACT (OR = 0.911 P = 0.125) or ART (OR = 0.953 P = 0.462). Cox proportional hazard modeling demonstrated URR inhabitance remained independently associated with poor OS (HR 1.076; 95% CI [1.008, 1.149], P < 0.029). CONCLUSIONS: URR inhabitance does not impact access to AT, however it is independently associated with a decreased OS. Attention must be focused on optimizing oncologic care to patients with disparate access to healthcare.

Implementation of an electronic genomic and family health history tool in primary prenatal care.

"The Pregnancy and Health Profile," (PHP) is a free genetic risk assessment software tool for primary prenatal providers that collects patient-entered family (FHH), personal, and obstetrical health history, performs risk assessment, and presents the provider with clinical decision support during the prenatal encounter. The tool is freely available for download at www.hughesriskapps.net. We evaluated the implementation of PHP in four geographically diverse clinical sites. Retrospective chart reviews were conducted for patients seen prior to the study period and for patients who used the PHP to collect data on documentation of FHH, discussion of cystic fibrosis (CF) and hemoglobinopathy (HB) carrier screening, and CF and HB interventions (tests, referrals). Five hundred pre-implementation phase and 618 implementation phase charts were reviewed. Documentation of a 3-generation FHH or pedigree improved at three sites; patient race/ethnicity at three sites, father of the baby (FOB) race/ethnicity at all sites, and ancestry for the patient and FOB at three sites (P < 0.001-0001). CF counseling improved for implementation phase patients at one site (8% vs. 48%, P < 0.0001) and CF screening/referrals at two (2% vs. 14%, P < 0.0001; 6% vs. 14%; P = 0.05). Counseling and intervention rates did not increase for HB. This preliminary study suggests that the PHP can improve documentation of FHH, race, and ancestry, as well as the compliance with current CF counseling and intervention guidelines in some prenatal clinics. Future evaluation of the PHP should include testing in a larger number of clinical environments, assessment of additional performance measures, and evaluation of the system's overall clinical utility.

Extended neoadjuvant chemotherapy for borderline resectable pancreatic cancer demonstrates promising postoperative outcomes and survival.

BACKGROUND: The optimum approach to neoadjuvant therapy for patients with borderline resectable pancreatic cancer is undefined. Herein we report the outcomes of an extended neoadjuvant chemotherapy regimen in patients presenting with borderline resectable adenocarcinoma of the pancreatic head. METHODS: Patients identified as having borderline resectable pancreatic head cancer by American Hepato-Pancreato-Biliary Association/Society of Surgical Oncology consensus criteria from 2008 to 2012 were tracked in a prospectively maintained registry. Included patients were initiated on a 24-week course of neoadjuvant chemotherapy. Medically fit patients who completed neoadjuvant treatment without radiographic progression were offered resection with curative intent. Clinicopathologic variables and surgical outcomes were collected retrospectively and analyzed. RESULTS: Sixty-four patients with borderline resectable pancreatic cancer started neoadjuvant therapy. Thirty-nine (61 %) met resection criteria and underwent operative exploration with curative intent, and 31 (48 %) were resected. Of the resected patients, 18 (58 %) had positive lymph nodes, 15 (48 %) required en-bloc venous resection, 27 (87 %) had a R0 resection, and 3 (10 %) had a complete pathologic response. There were no postoperative deaths at 90 days, 16 % of patients had a severe complication, and the 30-day readmission rate was 10 %. The median overall survival of all 64 patients was 23.6 months, whereas that of unresectable patients was 15.4 months. Twenty-five of the resected patients (81 %) are still alive at a median follow-up of 21.6 months. CONCLUSIONS: Extended neoadjuvant chemotherapy is well tolerated by patients with borderline resectable pancreatic head adenocarcinoma, selects a subset of patients for curative surgery with low perioperative morbidity, and is associated with favorable survival.

Evaluation of a novel electronic genetic screening and clinical decision support tool in prenatal clinical settings.

"The Pregnancy and Health Profile" (PHP) is a free prenatal genetic screening and clinical decision support (CDS) software tool for prenatal providers. PHP collects family health history (FHH) during intake and provides point-of-care risk assessment for providers and education for patients. This pilot study evaluated patient and provider responses to PHP and effects of using PHP in practice. PHP was implemented in four clinics. Surveys assessed provider confidence and knowledge and patient and provider satisfaction with PHP. Data on the implementation process were obtained through semi-structured interviews with administrators. Quantitative survey data were analyzed using Chi square test, Fisher's exact test, paired t tests, and multivariate logistic regression. Open-ended survey questions and interviews were analyzed using qualitative thematic analysis. Of the 83% (513/618) of patients that provided feedback, 97% felt PHP was easy to use and 98% easy to understand. Thirty percent (21/71) of participating physicians completed both pre- and post-implementation feedback surveys [13 obstetricians (OBs) and 8 family medicine physicians (FPs)]. Confidence in managing genetic risks significantly improved for OBs on 2/6 measures (p values ≤0.001) but not for FPs. Physician knowledge did not significantly change. Providers reported value in added patient engagement and reported mixed feedback about the CDS report. We identified key steps, resources, and staff support required to implement PHP in a clinical setting. To our knowledge, this study is the first to report on the integration of patient-completed, electronically captured and CDS-enabled FHH software into primary prenatal practice. PHP is acceptable to patients and providers. Key to successful implementation in the future will be customization options and interoperability with electronic health records.

Spatiotemporal signaling underlies progressive vascular rarefaction in myocardial infarction.

Therapeutic angiogenesis represents a promising avenue to revascularize the ischemic heart. Its limited success is partly due to our poor understanding of the cardiac stroma, specifically mural cells, and their response to ischemic injury. Here, we combine single-cell and positional transcriptomics to assess the behavior of mural cells within the healing heart. In response to myocardial infarction, mural cells adopt an altered state closely associated with the infarct and retain a distinct lineage from fibroblasts. This response is concurrent with vascular rarefaction and reduced vascular coverage by mural cells. Positional transcriptomics reveals that the infarcted heart is governed by regional-dependent and temporally regulated programs. While the remote zone acts as an important source of pro-angiogenic signals, the infarct zone is accentuated by chronic activation of anti-angiogenic, pro-fibrotic, and inflammatory cues. Together, our work unveils the spatiotemporal programs underlying cardiac repair and establishes an association between vascular deterioration and mural cell dysfunction.

Sex biased human thymic architecture guides T cell development through spatially defined niches.

Within the thymus, regulation of the cellular cross-talk directing T cell development is dependent on spatial interactions within specialized niches. To create a holistic, spatially defined map of tissue niches guiding postnatal T cell development we employed the multidimensional imaging platform CO-detection by indEXing (CODEX), as well as CITE-seq and ATAC-seq. We generated age-matched 4-5-month-old postnatal thymus datasets for male and female donors, and identify significant sex differences in both T cell and thymus biology. We demonstrate a crucial role for JAG ligands in directing thymic-like dendritic cell development, reveal important functions of a novel population of ECM- fibroblasts, and characterize the medullary niches surrounding Hassall's corpuscles. Together, these data represent a unique age-matched spatial multiomic resource to investigate how sex-based differences in thymus regulation and T cell development arise, and provide an essential resource to understand the mechanisms underlying immune function and dysfunction in males and females.

Role of obesity in a randomized placebo-controlled trial of difluoromethylornithine (DFMO) + sulindac for the prevention of sporadic colorectal adenomas.

BACKGROUND: Chemoprevention with the polyamine-inhibitory regimen difluoromethylornithine (DFMO) + sulindac markedly reduces risk of recurrent adenoma in colorectal adenoma patients. Obesity is associated with risk of colorectal adenoma and colorectal cancer. This study investigates how obesity influences risk of recurrent adenoma after prolonged treatment with DFMO + sulindac versus placebo. METHODS: Our analysis included subjects enrolled in the phase III colorectal adenoma prevention clinical trial investigating DFMO + sulindac versus placebo. Patients were classified by obesity (body mass index, BMI ≥ 30 kg/m(2)) status at baseline. Pearson χ(2) statistic and Mann-Whitney U test were used to compare baseline characteristics, including rectal tissue polyamine levels. Log-binomial regression analysis was used to determine the risk ratio (RR) of recurrent adenomas, adjusted for covariates and an interaction term for obesity and treatment. RESULTS: The final analytic cohort was comprised of 267 patients. In separate regression models, the risk of adenoma recurrence after treatment compared to placebo was similar for obese (RR = 0.32, 95 % CI 15-71) and non-obese patients (RR = 0.27, 95 % CI 15-49). No significant interaction was detected between obesity, treatment, and risk of colorectal adenoma in the full regression model (p (interaction) = 0.91). CONCLUSIONS: Obesity does not substantially modify the colorectal adenoma risk reduction ascribed to DFMO + sulindac versus placebo.

Meat consumption, ornithine decarboxylase gene polymorphism, and outcomes after colorectal cancer diagnosis.

BACKGROUND: Dietary arginine and meat consumption are implicated in colorectal cancer (CRC) progression via polyamine-dependent processes. Polymorphism in the polyamine-regulatory gene, ornithine decarboxylase 1 (Odc1, rs2302615) is prognostic for CRC-specific mortality. Here, we examined joint effects of meat consumption and Odc1 polymorphism on CRC-specific mortality. MATERIALS AND METHODS: The analytic cohort was comprised of 329 incident stage I-III CRC cases diagnosed 1994-1996 with follow- up through March 2008. Odc1 genotyping was conducted using primers that amplify a 172-bp fragment containing the polymorphic base at +316. Dietary questionnaires were administered at cohort entry. Multivariate Cox proportional hazards regression analysis for CRC-specific mortality was stratified by tumor, node, metastasis (TNM) stage, and adjusted for clinically relevant variables, plus meat consumption (as a continuous variable, i.e., the number of medium-sized servings/week), Odc1 genotype, and a term representing the meat consumption and Odc1 genotype interaction. The primary outcome was the interaction of Odc1 and meat intake on CRC-specific mortality, as assessed by departures from multiplicative joint effects. RESULTS: Odc1 genotype distribution was 51% GG, 49% GA/AA. In the multivariate model, there was a significant interaction between meat consumption and Odc1 genotype, P-int = 0.01. Among Odc1 GA/AA CRC cases in meat consumption Quartiles 1-3, increased mortality risk was observed when compared to GG cases (adjusted hazards ratio (HR) = 7.06 [95% CI 2.34-21.28]) - a difference not found among cases in the highest dietary meat consumption Quartile 4. CONCLUSIONS: Effects of meat consumption on CRC-specific mortality risk differ based on genetic polymorphism at Odc1. These results provide further evidence that polyamine metabolism and its modulation by dietary factors such as meat may have relevance to CRC outcomes.

Population-based evaluation of adenosquamous carcinoma of the colon and rectum.

BACKGROUND: Information about adenosquamous carcinoma of the colon and rectum is scarce because of its extremely low incidence. OBJECTIVE: The aim of this study was to examine the prognostic significance of a histological diagnosis of adenosquamous carcinoma in comparison with adenocarcinoma of the colon and rectum. DESIGN: This study was retrospective in design. SETTING: California Cancer Registry data from 1994 through 2004 with follow-up through 2008 were analyzed. PATIENTS: Patients were included whose cancer of the colon and rectum, excluding the anus with a tumor histology of adenocarcinoma and adenosquamous carcinoma, was surgically treated. MAIN OUTCOME MEASURES: The primary outcomes measured were histology-specific survival analyses (with the use of the Kaplan-Meier method), and overall and colorectal-specific mortality (with the use of multivariable Cox proportional hazards regression analyses). RESULTS: A total of 111,263 adenocarcinoma and adenosquamous carcinoma of colon and rectal cancer cases were identified (adenocarcinoma, 99.91%; adenosquamous carcinoma, 0.09%). There was no significant difference in sex, age, race, and socioeconomic status between the 2 groups. The most common location of adenocarcinoma and adenosquamous carcinoma was the right and transverse colon. The adenosquamous carcinoma group was significantly associated with a higher rate of metastasis at the time of operation (adenosquamous carcinoma, 36.56% vs adenocarcinoma, 13.92%) and with poorly differentiated tumor grade (adenosquamous carcinoma, 65.96% vs adenocarcinoma, 19.74%) in comparison with the adenocarcinoma group. The median overall survival time was significantly greater in the adenocarcinoma group (82.4 months) in comparison with the adenosquamous carcinoma group (35.3 months). With the use of multivariable hazard regression analyses, adenosquamous carcinoma histology was independently associated with increased overall mortality (hazard ratio, 1.67) and colorectal-specific mortality (hazard ratio, 1.69) in comparison with adenocarcinoma. CONCLUSIONS: This is one of the largest studies of adenosquamous carcinoma of the colon and rectum to date. This uncommon colorectal cancer subtype was associated with higher overall and colorectal-specific mortality in comparison with adenocarcinoma. Among colorectal cancer cases, adenosquamous carcinoma histology should be considered a poor prognostic feature.

A case report of the rarest anal cancer: Basal cell carcinoma.

A 69-year-old male truck driver with history of chronic anal fissures and facial basal cell carcinoma developed rectal bleeding and pain, and was diagnosed with a 5cm basal cell cancer of the anus with sphincter invasion. His workup entailed physical exam, CT and MRI which confirmed external and internal sphincter invasion without evidence of distant metastatic disease. After review of chemoradiation and surgical options, the patient elected to proceed with robotic-assisted abdominoperineal resection with end colostomy with complex local-tissue reconstruction. He is now two years out and disease free. While radiation and surgery have both been described in the literature as viable treatments, surgical resection may be the best option for patients with large lesions with sphincter invasion, who travel from afar and have occupational restrictions. This case highlights the importance of a multidisciplinary approach in assessing the patient with a rare disease process, presenting all viable options for treatment, and electing the optimal treatment through shared decision making.

Severe Thrombocytopenia in Patients With Advanced Neuroendocrine Tumor Treated With Peptide Receptor Radioligand Therapy.

BACKGROUND: Peptide receptor radioligand therapy (PRRT) was Food and Drug Administration approved in 2018 for the treatment of unresectable somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (NETs) and provides an important option for patients with advanced disease. A known adverse effect of this treatment is hematologic toxicity, although usually transient. We present 3 patients with metastatic gastroenteropancreatic NETs treated with PRRT who were evaluated for severe persistent thrombocytopenia. METHODS: Three patients who commenced therapy with PRRT were known to proceed to a bone marrow (BM) biopsy for persistent severe thrombocytopenia and were included in this study. These patients were identified retrospectively and evaluated for their tumor properties, including immunohistochemical markers, treatment modalities, and clinical outcomes. RESULTS: All 3 patients had metastatic NETs that progressed on prior lines of therapy and were treated with 1 to 4 doses of 177Lu-DOTATATE 7.4 GBq (200 mCi) before developing grade 3 (25,000 to 50,000/µL) refractory thrombocytopenia. All patients had concurrent bone metastases, and 2 of the 3 had baseline grade 1 thrombocytopenia. In all 3 cases, BM biopsy documented widespread tumor infiltration. CONCLUSIONS: Severe refractory thrombocytopenia after PRRT is rare and may result from numerous known causes, including radiation-induced myelotoxicity, myelodysplastic syndrome, and tumor BM infiltration. We present 3 cases of thrombocytopenia related to persistent or progressive BM metastasis. Although known bone metastasis is not a contraindication to PRRT, thrombocytopenia may be a manifestation of tumor progression and should be considered when making decisions about continuation of therapy.

Contemporary, national patterns of surgery after preoperative therapy for stage II/III rectal adenocarcinoma.

BACKGROUND: Contemporary treatment of stage II/III rectal cancer combines chemotherapy, chemoradiation, and surgery, though the sequence of surgery with neoadjuvant treatments and benefits of minimally-invasive surgery (MIS) is debated. AIM: To describe patterns of surgical approach for stage II/III rectal cancer in relation to neoadjuvant therapies. METHODS: A retrospective cohort was created using the National Cancer Database. Primary outcome was rate of sphincter-sparing surgery after neoadjuvant therapy. Secondary outcomes were surgical approach (open, laparoscopic, or robotic), surgical quality (R0 resection and 12+ lymph nodes), and overall survival. RESULTS: A total of 38927 patients with clinical stage II or III rectal adenocarcinoma underwent surgical resection from 2010-2016. Clinical stage II patients had neoadjuvant chemoradiation less frequently compared to stage III (75.8% vs 84.7%, P < 0.001), but had similar rates of total neoadjuvant therapy (TNT) (27.0% vs 27.2%, P = 0.697). Overall rates of total mesorectal excision without sphincter preservation were similar between clinical stage II and III (30.0% vs 30.3%) and similar if preoperative treatment was chemoradiation (31.3%) or TNT (30.2%). Over the study period, proportion of cases approached laparoscopically increased from 24.9% to 32.5% and robotically 5.6% to 30.7% (P < 0.001). This cohort showed improved survival for MIS approaches compared to open surgery (laparoscopy HR 0.85, 95%CI 0.78-0.93, and robotic HR 0.82, 95%CI 0.73-0.92). CONCLUSION: Sphincter preservation rates are similar across stage II and III rectal cancer, regardless of delivery of preoperative chemotherapy, chemoradiation, or both. At a national level, there is a shift to predominantly MIS approaches for rectal cancer, regardless of whether sphincter sparing procedure is performed.

Patterns of Practice and Improvements in Survival Among Patients With Stage 2/3 Rectal Cancer Treated With Trimodality Therapy.

Importance: This study quantifies the trends in trimodality therapy use and its association with pathologic stage and overall survival of patients with rectal cancer at the population level. Objective: To describe changes between 2006 and 2016 in the sequence and use of chemotherapy/radiation therapy (C/RT), multiagent (MA) chemotherapy, and total neoadjuvant therapy (TNT) for patients with stage 2/3 rectal cancer and identify associations with pathologic stage and survival over time. Design, Setting, and Participants: This retrospective cohort analysis included patient records from the National Cancer Database between 2006 and 2016. Of 110 372 patient records, 77 905 were excluded owing to not receiving trimodality therapy and other predefined exclusion criteria. The final analytic cohort comprised 32 467 patients records treated with trimodality therapy, with 24 297 considered in the survival analysis. Data analysis was performed between June 2020 and December 2021. Exposures: Trimodality therapy was defined as including all of the following: definitive surgery; radiation therapy (RT), alone or in combination with chemotherapy; and neoadjuvant/adjuvant single-agent (SA) or multiagent (MA) chemotherapy independent of RT. Main Outcomes and Measures: Using Cox multivariable survival analyses across demographics, surgery type, stage, year of diagnosis, and facility type, treatment groups were allocated as the following: group A: TNT (n = 8883 [27%]); group B: preoperative C/RT plus postoperative SA chemotherapy (n = 5967 [18%]); group C: preoperative C/RT plus postoperative MA chemotherapy (n = 12 926 [40%]); and group D: postoperative C/RT plus MA chemotherapy (n = 4689 [14%]). Results: The final analytic cohort comprised 32 467 patients (mean [SD] age at diagnosis, 57.6 [11.6] years; 12 549 [38.7%] women and 19 918 [61.3%] men). Comparing 2016 with 2006, treatment shifted to fewer patients receiving postoperative C/RT (group D) (28% vs 8%; P < .001), and more preoperative C/RT and postoperative MA chemotherapy (group C) (24% vs 45%; P < .001) being used. While clinical stage 2 and 3 distribution remained unchanged, pathologic downstaging was observed to stages 0, 1, 2, and 3: 0.60%, 10%, 31%, and 57% vs 2.8%, 22%, 29%, and 45%, from 2006 to 2015, respectively (P < .001). More recent year of diagnosis was associated with an adjusted hazard ratio of 0.77 (95% CI, 0.67-0.87) for mortality within 36 months after diagnosis (2015 vs 2006). Conclusions and Relevance: In this cohort study, the shift toward preoperative C/RT and lower pathologic stage was associated with improved overall survival in stage 2/3 rectal cancers.

Systematic comparison of activity and mechanism of antimicrobial peptides against nosocomial pathogens.

The World Health Organisation has deemed several multi-drug resistant (MDR) nosocomial bacterial pathogens to be of significant threat to human health. A stark increase in morbidity, mortality and the burden to healthcare systems around the world can be attributed to the development of resistance in these bacteria. Accordingly, alternative antimicrobial agents have been sought as an attractive means to combat MDR pathogens, with one such example being antimicrobial peptides (AMPs). Given the reported activity of AMPs, including Pardaxin, MSI-78, dermaseptin-PC (DMPC) and Cecropin B, it is important to understand their activities and modes of action against bacteria for further AMP design. In this study, we compared these AMPs against a panel of nosocomial bacterial pathogens, followed by detailed mechanistic studies. It was found that Pardaxin (1-22) and MSI-78 (4-20) displayed the most pronounced antimicrobial activity against the tested bacteria. The mechanistic studies by membrane permeability and molecular dynamics simulation further confirmed the strong membrane interaction and structure of Pardaxin (1-22) and MSI-78 (4-20), which contributed to their potent activity. This study demonstrated a structure and activity guidance for further design of Pardaxin (1-22) and MSI-78 (4-20) as therapeutics against MDR pathogens. The different effects of DMPC (1-19) and Cecropin B (1-21) on membrane integrity and phospholipid membrane interactions provided critical information for the rational design of next-generation analogues with specificity against either Gram-negative or Gram-positive bacteria.

Cationic Antimicrobial Peptides Are Leading the Way to Combat Oropathogenic Infections.

Oral dental infections are one of the most common diseases affecting humans, with caries and periodontal disease having the highest incidence. Caries and periodontal disease arise from infections caused by oral bacterial pathogens. Current misuse and overuse of antibiotic treatments have led to the development of antimicrobial resistance. However, recent studies have shown that cationic antimicrobial peptides are a promising family of antibacterial agents that are active against oral pathogenic bacteria and also possess less propensity for development of antimicrobial resistance. This timely Review has a focus on two primary subjects: (i) the oral bacterial pathogens associated with dental infections and (ii) the current development of antimicrobial peptides targeting oral pathogens.