PTEN mutations are common in sporadic microsatellite stable colorectal cancer

The tumour suppressor gene PTEN, located at chromosome sub-band 10q23.3, encodes a dual-specificity phosphatase that negatively regulates the phosphatidylinositol 3′-kinase (PI3 K)/Akt-dependent cellular survival pathway. PTEN is frequently inactivated in many tumour types including glioblastoma, prostate and endometrial cancers. While initial studies reported that PTEN gene mutations were rare in colorectal cancer, more recent reports have shown an approximate 18% incidence of somatic PTEN mutations in colorectal tumours exhibiting microsatellite instability (MSI+). To verify the role of this gene in colorectal tumorigenesis, we analysed paired normal and tumour DNA from 41 unselected primary sporadic colorectal cancers for PTEN inactivation by mutation and/or allelic loss. We now report PTEN gene mutations in 19.5% (8/41) of tumours and allele loss, including all or part of the PTEN gene, in a further 17% (7/41) of the cases. Both PTEN alleles were affected in over half (9/15) of these cases showing PTEN genetic abnormalities. Using immunohistochemistry, we have further shown that all tumours harbouring PTEN alterations have either reduced or absent PTEN expression and this correlated strongly with later clinical stage of tumour at presentation (P = 0.02). In contrast to previous reports, all but one of the tumours with PTEN gene mutations were microsatellite stable (MSI-), suggesting that PTEN is involved in a distinct pathway of colorectal tumorigenesis that is separate from the pathway of mismatch repair deficiency. This work therefore establishes the importance of PTEN in primary sporadic colorectal cancer

Tetranucleotide and Low Microsatellite Instability Are Inversely Associated with the CpG Island Methylator Phenotype in Colorectal Cancer

MSH3 gene or protein deficiency or loss-of-function in colorectal cancer can cause a DNA mismatch repair defect known as “elevated microsatellite alterations at selected tetranucleotide repeats” (EMAST). A high percentage of MSI-H tumors exhibit EMAST, while MSI-L is also linked with EMAST. However, the distribution of CpG island methylator phenotype (CIMP) within the EMAST spectrum is not known. Five tetranucleotide repeat and five MSI markers were used to classify 100 sporadic colorectal tumours for EMAST, MSI-H and MSI-L according to the number of unstable markers detected. Promoter methylation was determined using methylation-specific PCR for MSH3, MCC, CDKN2A (p16) and five CIMP marker genes. EMAST was found in 55% of sporadic colorectal carcinomas. Carcinomas with only one positive marker (EMAST-1/5, 26%) were associated with advanced tumour stage, increased lymph node metastasis, MSI-L and lack of CIMP-H. EMAST-2/5 (16%) carcinomas displayed some methylation but MSI was rare. Carcinomas with ≥3 positive EMAST markers (13%) were more likely to have a proximal colon location and be MSI-H and CIMP-H. Our study suggests that EMAST/MSI-L is a valuable prognostic and predictive marker for colorectal carcinomas that do not display the high methylation phenotype CIMP-H

Blood pressure surveillance in cancer patients treated with immune checkpoint inhibitors

Published online: 19 April 2023. OnlinePublImmune checkpoint inhibitors (ICI) are cancer therapies that have been associated with increased risk of atherosclerotic cardiovascular disease (ASCVD). Blood pressure (BP) measurements are routinely performed during day oncology center visits for administration of ICI therapy but are often not assessed temporally to screen and monitor hypertension, which could independently increase the risk of ASCVD in cancer survivorship. This study reports the feasibility of using serial BP measurements from routine visits to day oncology center to diagnose and monitor hypertension control in cancer patients receiving ICIs.Sean Tan, Ella Spear, Nikhita Sane, Adam J. Nelson, Nitesh Nerlekar, Eva Segelov and Stephen J. Nicholl

Physical activity and fitness in women with metastatic breast cancer.

PURPOSE: This study aimed to explore differences in physical activity and fitness between women with metastatic breast cancer compared to healthy controls and factors associated with their physical activity levels. METHODS: Seventy-one women with metastatic breast cancer, aged (mean (SD)) 57.7 (9.5) and 2.9 (3.1) years after the onset of metastatic disease, and 71 healthy controls aged 55.0 (9.4) years participated. Of those with metastatic disease, 27% had bone-only metastases, 35% visceral-only metastases and 38% bone and visceral metastases. Patient-reported outcomes and physical measures of muscle strength and aerobic fitness assessments were obtained. Participants wore a SenseWear® physical activity monitor over 7 days, and the average steps/day and the time spent in moderate-to-vigorous intensity physical activity were determined. RESULTS: Women with metastases were significantly (i) less aerobically fit than the control group (25.3 (5.4) vs. 31.9 (6.1) mL • kg(-1) • min(-1); P < 0.001); (ii) weaker (e.g. lower limb strength for the metastatic and control groups was 53.5 (23.7) vs. 76.0 (27.4) kg, respectively; P < 0.001); (iii) less active, with the metastatic group attaining only 56% of the mean daily step counts of the healthy women; and (iv) more symptomatic, reporting higher levels of fatigue and dyspnoea (P < 0.001). CONCLUSION: Women living in the community with metastatic breast cancer possessed lower aerobic fitness, reduced muscular strength and less daily physical activity compared to healthy counterparts. They also experienced poorer functioning and higher symptom burden. IMPLICATIONS FOR CANCER SURVIVORS: Women living with metastatic breast cancer may benefit from a physical activity programme to address their physical impairments

Does the chemotherapy backbone impact on the efficacy of targeted agents in metastatic colorectal cancer? A systematic review and meta-analysis of the literature

IMPORTANCE The EGFR inhibitors (EGFR-I) cetuximab and panitumumab and the angiogenesis inhibitors (AIs) bevacizumab and aflibercept have demonstrated varying efficacy in mCRC. OBJECTIVE To document the overall impact of specific chemotherapy regimens on the efficacy of targeted agents in treating patients with mCRC. Data sources: MEDLINE, EMBASE and Cochrane databases were searched to 2014, supplemented by hand-searching ASCO/ESMO conference abstracts. STUDY SELECTION Published RCTs of patients with histologically confirmed mCRC were included if they investigated either 1) chemotherapy with or without a biological agent or 2) different chemotherapy regimens with the same biological agent. EGFR-I trials were restricted to KRAS exon 2 wild-type (WT) populations. DATA EXTRACTION AND SYNTHESIS Data were independently abstracted by two authors and trial quality assessed according to Cochrane criteria. The primary outcome was overall survival with secondary endpoints progression free survival (PFS), overall response rate (ORR) and toxicity. RESULTS EGFR-I added to irinotecan-based chemotherapy modestly improved OS with HR 0.90 (95% CI 0.81–1.00, p = 0.04), but more so PFS with HR 0.77 (95% CI 0.69–0.86, p<0.00001). No benefit was evident for EGFR-I added to oxaliplatin-based chemotherapy (OS HR 0.97 (95% CI 0.87–1.09) and PFS HR 0.92 (95% CI 0.83–1.02)). Significant oxaliplatin-irinotecan subgroup interactions were present for PFS with I2 = 82%, p = 0.02. Further analyses of oxaliplatin+EGFR-I trials showed greater efficacy with infusional 5FU regimens (PFS HR 0.82, 95% CI 0.72–0.94) compared to capecitabine (HR 1.09; 95% CI 0.91–1.30) and bolus 5FU (HR 1.07; 95% CI 0.79–1.45); subgroup interaction was present with I2 = 72%, p = 0.03. The oxaliplatin-irinotecan interaction was not evident for infusional 5FU regimens. For AIs, OS benefit was observed with both oxaliplatin-based (HR 0.83) and irinotecan-based (HR 0.77) regimens without significant subgroup interactions. Oxaliplatin+AI trials showed no subgroup interactions by type of FP, whilst an interaction was present for irinotecan+AI trials although aflibercept was only used with infusional FP (I2 = 89.7%, p = 0.002). CONCLUSION AND RELEVANCE The addition of EGFR-I to irinotecan-based chemotherapy has consistent efficacy, regardless of FP regimen, whereas EGFR-I and oxaliplatin-based regimens were most active with infusional 5FU. No such differential activity was observed with the varying chemotherapy schedules when combined with AIs.David L. Chan, Nick Pavlakis, Jeremy Shapiro, Timothy J. Price, Christos S. Karapetis, Niall C. Tebbutt, Eva Segelo

Human germ cell tumours: expression of γ-glutamyl transpeptidase and sensitivity to cisplatin

Previous studies have shown that the enzyme γ-glutamyl transpeptidase (GGT) is essential for the nephrotoxicity of cisplatin. This study was designed to determine whether GGT activity is necessary for the therapeutic effect of the drug. The relationship between GGT expression and clinical response to platinum-based chemotherapy was examined in 41 human germ cell tumours. Sections of formalin-fixed, paraffin-embedded tumours were immunohistochemically stained with an antibody directed against human GGT. There was no expression of GGT in any of the 17 seminomas or four dysgerminomas; whereas, 12/12 ovarian yolk sac tumours and 4/4 embryonal carcinomas of the testis were GGT-positive. In stage I tumours fewer tumour cells expressed GGT than in later stage tumours. In four germ cell tumours of mixed histology, the seminomatous and dysgerminoma areas were GGT-negative while the areas of the tumour with yolk sac or embryonal histology contained GGT-positive tumour cells. The patients with seminomas or dysgerminomas who were treated with cisplatin-based chemotherapy, all had a complete response despite the absence of GGT expression in these tumours. Fifteen of the 16 patients with yolk sac or embryonal carcinomas received cisplatin-based chemotherapy following surgery. Twelve had a complete response, while three failed to respond to platinum-based therapy. There was no correlation between the level of GGT-expression and response to therapy in this group. Three of the four patients with tumours of mixed histology were treated with cisplatin-based therapy, and had a complete response. Therefore, expression of GGT is not necessary for the therapeutic effect of cisplatin in germ cell tumours. The results from this study suggest that systemic inhibition of GGT would inhibit the nephrotoxic side-effect of cisplatin without interfering with its activity towards germ cell tumours. © 1999 Cancer Research Campaig

A Machine-Learning-Based Bibliometric Analysis of the Scientific Literature on Anal Cancer

Squamous-cell carcinoma of the anus (ASCC) is a rare disease. Barriers have been encountered to conduct clinical and translational research in this setting. Despite this, ASCC has been a prime example of collaboration amongst researchers. We performed a bibliometric analysis of ASCC-related literature of the last 20 years, exploring common patterns in research, tracking collaboration and identifying gaps. The electronic Scopus database was searched using the keywords “anal cancer”, to include manuscripts published in English, between 2000 and 2020. Data analysis was performed using R-Studio 0.98.1091 software. A machine-learning bibliometric method was applied. The bibliometrix R package was used. A total of 2322 scientific documents was found. The average annual growth rate in publication was around 40% during 2000–2020. The five most productive countries were United States of America (USA), United Kingdom (UK), France, Italy and Australia. The USA and UK had the greatest link strength of international collaboration (22.6% and 19.0%). Two main clusters of keywords for published research were identified: (a) prevention and screening and (b) overall management. Emerging topics included imaging, biomarkers and patient-reported outcomes. Further efforts are required to increase collaboration and funding to sustain future research in the setting of ASCC

Management of Asymptomatic Sporadic Nonfunctioning Pancreatic Neuroendocrine Neoplasms (ASPEN) ≤2 cm: Study Protocol for a Prospective Observational Study

Introduction: The optimal treatment for small, asymptomatic, nonfunctioning pancreatic neuroendocrine neoplasms (NF-PanNEN) is still controversial. European Neuroendocrine Tumor Society (ENETS) guidelines recommend a watchful strategy for asymptomatic NF-PanNEN 18 years, the presence of asymptomatic sporadic NF-PanNEN ≤2 cm proven by a positive fine-needle aspiration (FNA) or by the presence of a measurable nodule on high-quality imaging techniques that is positive at 68Gallium DOTATOC-PET scan. Conclusion: The ASPEN study is designed to investigate if an active surveillance of asymptomatic NF-PanNEN ≤2 cm is safe as compared to surgical approach.info:eu-repo/semantics/publishedVersio

Management of Asymptomatic Sporadic Non-Functioning Pancreatic Neuroendocrine Neoplasms No Larger Than 2 Cm: Interim Analysis of Prospective ASPEN Trial

info:eu-repo/semantics/publishedVersio

Management of Asymptomatic Sporadic Nonfunctioning Pancreatic Neuroendocrine Neoplasms (ASPEN) <= 2 cm: Study Protocol for a Prospective Observational Study

Introduction: The optimal treatment for small, asymptomatic, nonfunctioning pancreatic neuroendocrine neoplasms (NF-PanNEN) is still controversial. European Neuroendocrine Tumor Society (ENETS) guidelines recommend a watchful strategy for asymptomatic NF-PanNEN <2 cm of diameter. Several retrospective series demonstrated that a non-operative management is safe and feasible, but no prospective studies are available. Aim of the ASPEN study is to evaluate the optimal management of asymptomatic NF-PanNEN ≤2 cm comparing active surveillance and surgery. Methods: ASPEN is a prospective international observational multicentric cohort study supported by ENETS. The study is registered in ClinicalTrials.gov with the identification code NCT03084770. Based on the incidence of NF-PanNEN the number of expected patients to be enrolled in the ASPEN study is 1,000 during the study period (2017–2022). Primary endpoint is disease/progression-free survival, defined as the time from study enrolment to the first evidence of progression (active surveillance group) or recurrence of disease (surgery group) or death from disease. Inclusion criteria are: age >18 years, the presence of asymptomatic sporadic NF-PanNEN ≤2 cm proven by a positive fine-needle aspiration (FNA) or by the presence of a measurable nodule on high-quality imaging techniques that is positive at 68Gallium DOTATOC-PET scan. Conclusion: The ASPEN study is designed to investigate if an active surveillance of asymptomatic NF-PanNEN ≤2 cm is safe as compared to surgical approach