Does complete pathological response increase perioperative morbidity risk in rectal cancer?

AIM: The optimal management of patients with clinical complete response after neoadjuvant treatment for rectal cancer is controversial. The aim of this study is to compare the morbidity between patients with locally advanced rectal cancer who have had a pathological complete response (pCR) or not after neoadjuvant chemoradiotherapy (NCRT) and total mesorectal excision (TME). The study hypothesis was that pCR may impact the surgical complication rate. METHOD: A retrospective cohort study was conducted of a prospectively maintained database in Australia and New Zealand, the Binational Colorectal Cancer Audit, that identified patients with locally advanced rectal cancer (<15 cm from anal verge) from 1 January 2007 to 31 December 2019. Patients were included if they had locally advanced rectal cancer and had undergone NCRT and proceeded to surgical resection. RESULTS: There were 4584 patients who satisfied the inclusion criteria, 65% being male. The mean age was 63 years and 11% had a pCR (ypT0N0). TME with anastomosis was performed in 67.8% of patients, and the majority of the cohort received long-course radiotherapy (81.7%). Both major and minor complications were higher in the TME without anastomosis group (17.3% vs. 14.7% and 30.6% vs. 20.8%, respectively), and the 30-day mortality was 1.31%. In the TME with anastomosis group, pCR did not contribute to higher rates of surgical complications, but male gender (p < 0.0012), age (p < 0.0001), preoperative N stage (p = 0.0092) and American Society of Anesthesologists (ASA) score ≥3 (p < 0.0002) did. In addition, pCR had no significant effect (p = 0.44) but male gender (p = 0.0047) and interval to surgery (p = 0.015) contributed to higher rates of anastomotic leak. In the TME without anastomosis cohort, the only variable that contributed to higher rates of complications was ASA score ≥3 (p = 0.033). CONCLUSION: Patients undergoing TME dissection for rectal cancer following NCRT showed no difference in complications whether they had achieved pCR or not.

Prophylactic negative pressure wound therapy to improve wound healing rates following ileostomy closure: a randomized controlled trial.

BACKGROUND: Reversal of ileostomy is associated with morbidity including wound infection and prolonged wound healing. Negative pressure wound therapy (NPWT) has been shown to reduce time to wound healing by secondary intention. The aim of this study was to determine whether NPWT improved wound healing rates, compared with simple wound dressings, in patients undergoing reversal of ileostomy where the skin wound is closed with a purse-string suture. METHODS: This was a dual-centre, open-label, randomized controlled trial with two parallel intervention arms. Patients undergoing elective loop ileostomy reversal were randomized 1:1 to receive NPWT or simple wound dressings. The primary endpoint of the study was assessment of complete wound healing at day 42 post reversal of ileostomy and the secondary endpoints were patient-reported wound cosmesis using a visual analogue scale and rates of surgical site infection (SSI). RESULTS: The study was conducted from June 2018 to December 2021. The trial was approved by the local ethics committee. We enrolled 40 patients, 20 in each arm. One patient in each arm was lost to follow up. Nine patients (9/19, 47.36%) in the simple dressing group had wound healing vs. 13 patients (13/19, 68.42%) in the NPWT group (P = 0.188). There was no significant difference in patient- reported wound cosmesis or SSI. CONCLUSION: There was no difference in wound healing rates when comparing NPWT to simple wound dressings at early and late time points post reversal of ileostomy, where the skin wound was closed with a purse-string suture.

The impact of COVID-19 on general surgical trainees' surgical exposure in Australia.

BACKGROUND: The COVID-19 pandemic disrupted the provision of surgical services in Australia. To prepare for a surge of COVID-19 patients, elective surgery was mandatorily reduced or ceased at multiple timepoints in Australian states between 2020 and 2022. Operative exposure is a critical component of surgical training in general surgery, and readiness for practice is an ongoing priority. However, the impact of COVID-19 on operative exposure in Australian General Surgical Trainees (AGST) has not been quantified. METHODS: This study was a retrospective longitudinal cohort study using de-identified operative logbook data for Australian General surgical Trainees (AGST) from the Royal Australasian College of Surgeons (RACS) Morbidity and Audit Logbook Tool (MALT) system between February 2019 and July 2021. Bivariate analysis was used to determine the impact of COVID-19 on general surgical trainees' exposure to operative surgery and trainees' operative autonomy. RESULTS: Data from 1896 unique 6-month training terms and 543 285 surgical cases was included over the data collection period. There was no statistically significant impact of the COVID-19 pandemic on AGST operative exposure to major, minor operations, endoscopies, or operative autonomy. CONCLUSIONS: The impact of COVID-19 on surgical trainees globally has been significant. Although this study does not assess all aspects of surgical training, this data demonstrates that there has not been a significant impact of the pandemic on operative exposure or autonomy of AGST.

Have changing practices in salvage medical options affected colectomy rates in acute severe ulcerative colitis?

BACKGROUND: In 2014, infliximab (IFX) was listed on the Australian Pharmaceutical Benefits Scheme for acute severe ulcerative colitis (ASUC) and is now the preferred option for medical salvage, superseding cyclosporin A (CsA). Optimal dosing schedules for IFX remain unknown. AIM: The authors aim to evaluate the effect of changing from predominantly CsA to almost exclusively IFX for the treatment of steroid-refractory ASUC on colectomy rates. METHODS: A retrospective review was performed of patients admitted with ASUC between 2012 and 2020. Patients were categorised into two groups according to year of presentation - either 'historical treatment' cohort (2012-2014), when CsA was primarily used, or 'contemporary treatment' cohort (2014-2020), when IFX was mostly prescribed, in either standard or intensive doses. RESULTS: One hundred thirty-nine patients were included; 37 in the historical treatment cohort and 102 in the contemporary treatment cohort. In the historical treatment cohort, 12 of 37 received salvage therapy and eight (67%) received CsA. In the contemporary treatment cohort, 49 of 102 patients received salvage therapy, 40 (82%) with IFX, of whom 22 (53%) received intensified doses. Colectomy rates were similar at 30 days, 6 months and 12 months between historical and contemporary treatment cohorts (14% vs 12% [P = 0.77], 19% vs 18% [P > 0.99],and 22% vs 18% [P = 0.63], respectively). Difference in 12-month colectomy rates between standard versus intensive IFX did not meet statistical significance (three of 21 [14%] vs nine of 22 [41%]. respectively; P = 0.09). CONCLUSION: There was no difference in 30-day, 6-month or 12-month colectomy rates between the historical treatment and contemporary treatment cohorts. The use of IFX, rather than CsA, even at intensified dosing, does not appear to reduce the colectomy rate observed in our patients.

Autologous fat graft injections for the treatment of perianal fistulas in Crohn's disease: a systematic review and single-arm meta-analysis.

BACKGROUND: Crohn's perianal fistulas are often refractory to standard management. Fat graft injections are hypothesised to improve fistula healing rates. We evaluated the treatment efficacy of fat graft injections for Crohn's perianal fistulas in a systematic review (PRISMA). METHODS: We completed database searches of MEDLINE (Ovid), Embase, and PubMed. All studies published in English in full text or abstract, from January 2001 to August 2021, evaluating fat graft injections for Crohn's perianal fistulas were selected. Included randomized controlled trials, single-arm intervention trials, cohort studies, and case series; excluded single case reports. Primary outcome was pooled clinical healing, defined as non-draining treated fistulas, or closure, defined as closure of treated fistulas. Secondary outcomes were clinical healing, clinical closure, radiologic response, and adverse events. RESULTS: Of 1258 publications identified, 891 articles were assessed for eligibility, and 107 relevant for manuscript review. Forty-nine patients received fat graft injections for Crohn's perianal fistulas across four single-arm intervention trials. Clinical healing or closure was achieved in 74% in a pooled single-arm meta-analysis (95% confidence interval: 57%, 85%), with moderate heterogeneity between studies. Clinical healing was achieved in 20% and 60% at 3 and 12 months, respectively. Clinical closure was achieved in 83% at 6 months. Variable parameters were used to define radiologic response, with success rates from 20% to 67%. Minimal adverse events were reported. CONCLUSION: Fat graft injections show promise as a novel treatment for Crohn's perianal fistulas in this systematic review and meta-analysis. Assessment in controlled matched studies is warranted.

Lung-resident memory B cells established after pulmonary influenza infection display distinct transcriptional and phenotypic profiles.

Recent studies have established that memory B cells, largely thought to be circulatory in the blood, can take up long-term residency in inflamed tissues, analogous to widely described tissue-resident T cells. The dynamics of recruitment and retention of memory B cells to tissues and their immunological purpose remains unclear. Here, we characterized tissue-resident memory B cells (BRM) that are stably maintained in the lungs of mice after pulmonary influenza infection. Influenza-specific BRM were localized within inducible bronchus-associated lymphoid tissues (iBALTs) and displayed transcriptional signatures distinct from classical memory B cells in the blood or spleen while showing partial overlap with memory B cells in lung-draining lymph nodes. We identified lung-resident markers, including elevated expression of CXCR3, CCR6, and CD69, on hemagglutinin (HA)- and nucleoprotein (NP)-specific lung BRM. We found that CCR6 facilitates increased recruitment and/or retention of BRM in lungs and differentiation into antibody-secreting cells upon recall. Although expression of CXCR3 and CCR6 was comparable in total and influenza-specific memory B cells isolated across tissues of human donors, CD69 expression was higher in memory B cells from lung and draining lymph nodes of human organ donors relative to splenic and PBMC-derived populations, indicating that mechanisms underpinning BRM localization may be evolutionarily conserved. Last, we demonstrate that human memory B cells in lungs are transcriptionally distinct to populations in lung-draining lymph nodes or PBMCs. These data suggest that BRM may constitute a discrete component of B cell immunity, positioned at the lung mucosa for rapid humoral response against respiratory viral infections.

Adaptive immunity to human coronaviruses is widespread but low in magnitude.

OBJECTIVES: Endemic human coronaviruses (hCoVs) circulate worldwide but cause minimal mortality. Although seroconversion to hCoV is near ubiquitous during childhood, little is known about hCoV-specific T-cell memory in adults. METHODS: We quantified CD4 T-cell and antibody responses to hCoV spike antigens in 42 SARS-CoV-2-uninfected individuals. Antigen-specific memory T cells and circulating T follicular helper (cTFH) cells were identified using an activation-induced marker assay and characterised for memory phenotype and chemokine receptor expression. RESULTS: T-cell responses were widespread within conventional memory and cTFH compartments but did not correlate with IgG titres. SARS-CoV-2 cross-reactive T cells were observed in 48% of participants and correlated with HKU1 memory. hCoV-specific T cells exhibited a CCR6+ central memory phenotype in the blood, but were enriched for frequency and CXCR3 expression in human lung-draining lymph nodes. CONCLUSION: Overall, hCoV-specific humoral and cellular memory are independently maintained, with a shared phenotype existing among coronavirus-specific CD4 T cells. This understanding of endemic coronavirus immunity provides insight into the homeostatic maintenance of immune responses that are likely to be critical components of protection against SARS-CoV-2.

Analysis of the MTHFR C677T variant with migraine phenotypes.

BACKGROUND: The methylenetetrahydrofolate reductase (MTHFR) gene variant C677T has been implicated as a genetic risk factor in migraine susceptibility, particularly in Migraine with Aura. Migraine, with and without aura (MA and MO) have many diagnostic characteristics in common. It is postulated that migraine symptomatic characteristics might themselves be influenced by MTHFR. Here we analysed the clinical profile, migraine symptoms, triggers and treatments of 267 migraineurs previously genotyped for the MTHFR C677T variant. The chi-square test was used to analyse all potential relationships between genotype and migraine clinical variables. Regression analyses were performed to assess the association of C677T with all migraine clinical variables after adjusting for gender. FINDINGS: The homozygous TT genotype was significantly associated with MA (P < 0.0001) and unilateral head pain (P = 0.002). While the CT genotype was significantly associated with physical activity discomfort (P < 0.001) and stress as a migraine trigger (P = 0.002). Females with the TT genotype were significantly associated with unilateral head pain (P < 0.001) and females with the CT genotype were significantly associated with nausea (P < 0.001), osmophobia (P = 0.002), and the use of natural remedy for migraine treatment (P = 0.003). Conversely, male migraineurs with the TT genotype experienced higher incidences of bilateral head pain (63% vs 34%) and were less likely to use a natural remedy as a migraine treatment compared to female migraineurs (5% vs 20%). CONCLUSIONS: MTHFR genotype is associated with specific clinical variables of migraine including unilateral head pain, physical activity discomfort and stress.

Gene expression profiling of esophageal cancer: comparative analysis of Barrett's esophagus, adenocarcinoma, and squamous cell carcinoma.

Esophageal cancer is a particularly aggressive tumor with poor prognosis, however, our current knowledge of the genes and pathways involved in tumorigenesis of the esophagus are limited. To obtain insight into the molecular processes underlying tumorigenesis of the esophagus, we have used cDNA microarrays to compare the gene expression profiles of 128 tissue samples representing the major histological subtypes of esophageal cancer (squamous cell carcinoma and adenocarcinoma (ADC)) as well as Barrett's esophagus (BE), the precursor lesion to ADC, and normal esophageal epithelium. Linear discriminant analysis and unsupervised hierarchical clustering show the separation of samples into 4 distinct groups consistent with their histological subtype. Differentially expressed genes were identified between each of the tissue types. Comparison of gene ontologies and gene expression profiles identified gene profiles specific to esophageal cancer, as well as BE. "Esophageal cancer clusters," representing proliferation, immune response, and extracellular matrix genes were identified, as well as digestion, hydrolase, and transcription factor clusters specific to the columnar phenotype observed during BE and esophageal ADC. These clusters provide valuable insight into the molecular and functional differences between normal esophageal epithelium, BE, and the 2 histologically distinct forms of esophageal cancers. Our thorough, unbiased analysis provides a rich source of data for further studies into the molecular basis of tumorigenesis of the esophagus, as well as identification of potential biomarkers for early detection of progression.