Is an uncomplicated postoperative recovery following total pelvic exenteration a more important prognostic factor than achieving R0 in the first 2 years?

AIM: Total pelvic exenteration (TPE) can achieve an R0 resection in locally advanced and recurrent rectal cancer (LARC and RRC) and remains the only curative option. The resultant high morbidity creates prolonged complex recoveries, rendering patients unfit for adjuvant chemotherapy. This study aims to evaluate the impact of this on overall survival (OS) and disease-free survival (DFS) as it has not been studied previously. METHOD: This is a retrospective single-centre study from 2017 to 2021 evaluating patients with LARC or RRC who underwent a curative TPE. Demographics, oncological history, perioperative data [using Clavien-Dindo (CD) scoring], disease recurrence and mortality were analysed using multivariate Cox regression to assess the impact of variables on DFS and OS. RESULTS: A total of 120 patients were included with a median follow-up of 3 years. 28% of patients received adjuvant chemotherapy, 27.5% had surgical follow-up and 44% missed systemic treatment. Missed treatment was predominantly due to prolonged recovery or poor performance status (59%). Patients who missed adjuvant chemotherapy experienced significantly higher CD scores (p = 0.0031), reintervention rates (p=0.0056) and further related surgeriesp (p = 0.0314). Missing adjuvant chemotherpy is a significant factor for poorer survival, with almost a three times higher mortality (p=0.0096, hazard ratio 2.7). R status was not a significant factor for OS following multivariate analysis (p = 0.336), indicating that another factor has an impact on survival within the first 2 years. CONCLUSIONS: In the initial 2 years after exenteration, an uncomplicated postoperative recovery allows for the delivery of adjuvant chemotherapy, prolonging survival. R0/R1 status was not the main prognostic factor. Longer follow-up and further multivariate analysis may influence decisions about aggressive R0 resection balanced against the patient being fit for chemotherapy postoperatively.

Functional implications of assigned, assumed and assembled PKC structures.

The empirical derivation of PKC (protein kinase C) domain structures and those modelled by homology or imputed from protein behaviour have been extraordinarily valuable both in the elucidation of PKC pathway mechanisms and in the general lessons that extrapolate to other signalling pathways. For PKC family members, there are many domain/subdomain structures and models, covering all of the known domains, variably present in this family of protein serine/threonine kinases (C1, C2, PB1, HR1, kinase domains). In addition to these structures, there are a limited number of complexes defined, including the structure of the PKCε V3-14-3-3 complex. In the context of structure-driven insights into PKC pathways, there are several broadly applicable principles and mechanisms relevant to the operation of and intervention in signalling pathways. These principles have an impact in unexpected ways, from the regulation of membrane targeting, through strategies for pharmacological intervention, to biomarkers.

Challenges in management of gastrointestinal cancers in pregnancies: A report of three cases.

Gastrointestinal cancer occurs in approximately 1 in 13,000 pregnancies, making up 4% of malignancies detected in pregnancy. It is a complex and challenging condition to diagnose and manage and is often only detected in its more advanced stages. This is partly due to symptoms of gastrointestinal cancer being incorrectly attributed to physiological symptoms of pregnancy, as well as concerns about the safety of diagnostic investigations in pregnancy, both of which may delay diagnosis and lead to disease progression. Challenges in management also arise from under-treatment in pregnancy due to concerns about the impact of surgery or chemotherapy on the pregnancy. We present here three cases of gastrointestinal cancer diagnosed in pregnancy in our centre and discuss the challenges and pitfalls one may encounter in the diagnosis and management of gastrointestinal malignancies in pregnancy.

Acute Immune Signatures and Their Legacies in Severe Acute Respiratory Syndrome Coronavirus-2 Infected Cancer Patients.

Given the immune system's importance for cancer surveillance and treatment, we have investigated how it may be affected by SARS-CoV-2 infection of cancer patients. Across some heterogeneity in tumor type, stage, and treatment, virus-exposed solid cancer patients display a dominant impact of SARS-CoV-2, apparent from the resemblance of their immune signatures to those for COVID-19+ non-cancer patients. This is not the case for hematological malignancies, with virus-exposed patients collectively displaying heterogeneous humoral responses, an exhausted T cell phenotype and a high prevalence of prolonged virus shedding. Furthermore, while recovered solid cancer patients' immunophenotypes resemble those of non-virus-exposed cancer patients, recovered hematological cancer patients display distinct, lingering immunological legacies. Thus, while solid cancer patients, including those with advanced disease, seem no more at risk of SARS-CoV-2-associated immune dysregulation than the general population, hematological cancer patients show complex immunological consequences of SARS-CoV-2 exposure that might usefully inform their care.

High-throughput time-resolved FRET reveals Akt/PKB activation as a poor prognostic marker in breast cancer.

Dysregulation of the Akt/PKB pathway has been associated with poor prognosis in several human carcinomas. Current approaches to assess Akt activation rely on intensity-based methods, which are limited by the subjectivity of manual scoring and poor specificity. Here, we report the development of a novel assay using amplified, time-resolved Förster resonance energy transfer (FRET), which is highly specific and sensitive and can be adapted to any protein. Using this approach to analyze primary breast tissue microarrays, we quantified levels of activated pAkt at a spatial resolution that revealed molecular heterogeneity within tumors. High pAkt status assessed by amplified FRET correlated with worse disease-free survival. Our findings support the use of amplified FRET to determine pAkt status in cancer tissues as candidate biomarker for the identification of high-risk patients.