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Syllable period ( SP) selective calling song processing has been demonstrated for the prothoracic, AN2 auditory neurone that correlates very well with SP-selective phonotaxis by female cricket Gryllus bimaculatus De Geer. Both SP-selective processing by the AN2 and the phonotactic behaviour of the female exhibit substantial plasticity. Thus, the question remains as to whether the selective responses of the AN2 neurone and the selective behaviour of the female match in an individual female. The present study is designed to answer that question. The SP-selective phonotactic behaviour of individual females is evaluated, followed immediately by measuring the SP-selective responses of the same female's AN2 neurone. Very significant correlations are found between the selective responses of the AN2 neurone and the same female's selective behaviour. In 208 possible comparisons (26 females, eight behavioural and neuronal tests each), 186 resulted in matches between behaviour and neuronal processing. Dividing the SP-selective females into two groups (one group that responded phonotactically to the shortest SP tested and a second group that did not respond to this SP) resulted in significantly more selective responses to this shortest SP by the AN2 neurone in the females that responded phonotactically to the SP than for the females who did not respond to the shortest SP. The behavioural responses by these two groups to the other SPs tested are shown to be essentially identical. [ABSTRACT FROM AUTHOR]

Background. The number of people surviving cancer for extended periods is increasing. Consequently, due to workload and quality issues, there is considerable interest in alternatives to traditional secondary care-led cancer follow-up.Objective. To explore the views of potential recipients of shared follow-up of cancer. To conduct a modelling exercise for shared follow-up and to explore the opinions and experiences of both the patients and GPs involved.Methods. Semi-structured audio-taped telephone or face-to-face interviews were conducted with 18 patients with a range of cancers currently attending for structured follow-up in secondary care. Six GPs and five patients (four with melanoma and one with stable metastatic colorectal cancer) took part in a shared follow-up modelling exercise. During the modelling exercise, the GPs attended 4 review meetings, which included brief training seminars, and at the conclusion 10 individuals took part in semi-structured audio-taped telephone or face-to-face interviews.Results. Many rural patients, and some urban patients, would appreciate follow-up being available nearer to home with the associated benefits of time saved and easier parking and continuity of care. Patients have concerns related to the level of extra training received by the GP and loss of contact with their consultant. GPs have concerns about gaining and maintaining the clinical skills needed to conduct follow-up, especially if the numbers of patients seen are small. They also have concerns about lack of support from other GPs, and some administrative and organizational issues.Conclusions. Many patients would be willing to have GPs share their cancer follow-up with the caveat that they had received extra training and were appropriately supported by secondary care specialists. Patients attending shared care clinics appreciated a local service and longer appointment times. GPs stress the importance of maintaining their own clinical skills and reliable clinical and administrative support from secondary care. [ABSTRACT FROM PUBLISHER]

This article presents a letter to the editor regarding a case study of a man with an extramedullary plasmacytoma.

Background: Antibiotic-induced gut dysbiosis has been associated with colorectal cancer (CRC) in older adults. This study will investigate whether an association exists between antibiotic usage and early-onset colorectal cancer (CRC), and also evaluate this in later-onset CRC for comparison.Methods: A case-control study was conducted using primary care data from 1999-2011. Analysis were conducted separately in early-onset CRC cases (diagnosed < 50 years) and later-onset cases (diagnosed ≥ 50 years). Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals (CI) for the associations between antibiotic exposure and CRC by tumour location, adjusting for comorbidities.Results: Seven thousands nine hundred and three CRC cases (445 aged <50 years) and 30,418 controls were identified. Antibiotic consumption was associated with colon cancer in both age-groups, particularly in the early-onset CRC cohort (<50 years: adjusted Odds Ratio (ORadj) 1.49 (95% CI 1.07, 2.07), p = 0·018; ≥50 years (ORadj (95% CI) 1.09 (1.01, 1.18), p = 0·029). Antibiotics were not associated with rectal cancer (<50 years: ORadj (95% CI) 1.17 (0.75, 1.84), p = 0.493; ≥50 years: ORadj (95% CI) 1.07 (0.96, 1.19), p = 0.238).Conclusion: Our findings suggest antibiotics may have a role in colon tumour formation across all age-groups. [ABSTRACT FROM AUTHOR]

Background: Advances in multi-modality treatment of locally advanced rectal cancer (LARC) have resulted in low local recurrence rates, but around 30% of patients will still die from distant metastatic disease. In parallel, there is increasing recognition that with radiotherapy and systemic treatment, some patients achieve a complete response and may avoid surgical resection, including in many cases, the need for a permanent stoma. Extended neoadjuvant regimes have emerged to address these concerns. The inclusion of immunotherapy in the neoadjuvant setting has the potential to further enhance this strategy by priming the local immune microenvironment and engaging the systemic immune response. Methods: PRIME-RT is a multi-centre, open label, phase II, randomised trial for patients with newly diagnosed LARC. Eligible patients will be randomised to receive either: short course radiotherapy (25 Gray in 5 fractions over one week) with concomitant durvalumab (1500 mg administered intravenously every 4 weeks), followed by FOLFOX (85 mg/m2 oxaliplatin, 350 mg folinic acid and 400 mg/m2 bolus 5-fluorouracil (5-FU) given on day 1 followed by 2400 mg/m2 5-FU infusion over 46–48 h, all administered intravenously every 2 weeks), and durvalumab, or long course chemoradiotherapy (50 Gray to primary tumour in 25 fractions over 5 weeks with concomitant oral capecitabine 825 mg/m2 twice per day on days of radiotherapy) with durvalumab followed by FOLFOX and durvalumab. The primary endpoint is complete response rate in each arm. Secondary endpoints include treatment compliance, toxicity, safety, overall recurrence, proportion of patients with a permanent stoma, and survival. The study is translationally rich with collection of bio-specimens prior to, during, and following treatment in order to understand the molecular and immunological factors underpinning treatment response. The trial opened and the first patient was recruited in January 2021. The main trial will recruit up to 42 patients with LARC and commence after completion of a safety run-in that will recruit at least six patients with LARC or metastatic disease. Discussion: PRIME-RT will explore if adding immunotherapy to neoadjuvant radiotherapy and chemotherapy for patients with LARC can prime the tumour microenvironment to improve complete response rates and stoma free survival. Sequential biopsies are a key component within the trial design that will provide new knowledge on how the tumour microenvironment changes at different time-points in response to multi-modality treatment. This expectation is that the trial will provide information to test this treatment within a large phase clinical trial. Trial registration Clinicaltrials.gov NCT04621370 (Registered 9th Nov 2020) EudraCT number 2019-001471-36 (Registered 6th Nov 2020) [ABSTRACT FROM AUTHOR]

Background: Advances in multi-modality treatment of locally advanced rectal cancer (LARC) have resulted in low local recurrence rates, but around 30% of patients will still die from distant metastatic disease. In parallel, there is increasing recognition that with radiotherapy and systemic treatment, some patients achieve a complete response and may avoid surgical resection, including in many cases, the need for a permanent stoma. Extended neoadjuvant regimes have emerged to address these concerns. The inclusion of immunotherapy in the neoadjuvant setting has the potential to further enhance this strategy by priming the local immune microenvironment and engaging the systemic immune response. Methods: PRIME-RT is a multi-centre, open label, phase II, randomised trial for patients with newly diagnosed LARC. Eligible patients will be randomised to receive either: short course radiotherapy (25 Gray in 5 fractions over one week) with concomitant durvalumab (1500 mg administered intravenously every 4 weeks), followed by FOLFOX (85 mg/m2 oxaliplatin, 350 mg folinic acid and 400 mg/m2 bolus 5-fluorouracil (5-FU) given on day 1 followed by 2400 mg/m2 5-FU infusion over 46–48 h, all administered intravenously every 2 weeks), and durvalumab, or long course chemoradiotherapy (50 Gray to primary tumour in 25 fractions over 5 weeks with concomitant oral capecitabine 825 mg/m2 twice per day on days of radiotherapy) with durvalumab followed by FOLFOX and durvalumab. The primary endpoint is complete response rate in each arm. Secondary endpoints include treatment compliance, toxicity, safety, overall recurrence, proportion of patients with a permanent stoma, and survival. The study is translationally rich with collection of bio-specimens prior to, during, and following treatment in order to understand the molecular and immunological factors underpinning treatment response. The trial opened and the first patient was recruited in January 2021. The main trial will recruit up to 42 patients with LARC and commence after completion of a safety run-in that will recruit at least six patients with LARC or metastatic disease. Discussion: PRIME-RT will explore if adding immunotherapy to neoadjuvant radiotherapy and chemotherapy for patients with LARC can prime the tumour microenvironment to improve complete response rates and stoma free survival. Sequential biopsies are a key component within the trial design that will provide new knowledge on how the tumour microenvironment changes at different time-points in response to multi-modality treatment. This expectation is that the trial will provide information to test this treatment within a large phase clinical trial. Trial registration Clinicaltrials.gov NCT04621370 (Registered 9th Nov 2020) EudraCT number 2019-001471-36 (Registered 6th Nov 2020) [ABSTRACT FROM AUTHOR]

Diflomotecan, a homocamptothecin, targets DNA topoisomerase I. Previous clinical trials have demonstrated a variable degree of dose limiting toxicity. The purpose of this study was to further evaluate the safety and pharmacokinetic profile of a range of diflomotecan doses administered intravenously. Patients with advanced solid malignant tumours, refractory to standard therapies, with adequate haematologic, renal and hepatic function, received diflomotecan administered as a 20 min intravenous infusion every 21 days. Cohorts of six patients were recruited sequentially to one of three fixed starting dose groups—2, 4, or 7 mg, with drug administered by fixed-dose rather than dosing by body surface area. Pharmacokinetic analyses were performed on serial blood samples taken over the first 24 h after diflomotecan administration (cycles 1 and 2). Cytochrome P450 3A4 (CYP3A4) activity was determined by an erythromycin breath test (EBT) prior to diflomotecan administration in cycles 1 and 2. Thirteen patients, were treated with a starting dose of either 2 mg ( n = 8) or 4 mg ( n = 5) of diflomotecan. Dose limiting toxicities (DLTs) were observed in 1 patient in the 2 mg starting dose level (grade 4 neutropenia which lasted for 8 days), and in 2 of 5 patients enrolled at the 4 mg starting dose level (grade 4 neutropenia for 11 days; grade 4 neutropenia leading to withdrawal from the study), and no further dose escalation was performed. Pharmacokinetic analyses revealed a less than dose-proportional increase in diflomotecan and for the two metabolites BN80942 and P-20, with a magnitude of P-20 exposure similar to the parent drug. There was a high inter-patient variability in diflomotecan exposure similar to that observed with other camptothecin derivatives. One minor response was observed in a patient with oesophageal cancer. Diflomotecan administered as a 20-min intravenous infusion 3-weekly is characterised by a variable pharmacokinetic profile. Alternative oral dosing schedules of diflomotecan have been shown to display a more predictable PK/PD and safety profile and should be selected for further evaluation in Phase II clinical trials. [ABSTRACT FROM AUTHOR]

Background: Advances in multi-modality treatment of locally advanced rectal cancer (LARC) have resulted in low local recurrence rates, but around 30% of patients will still die from distant metastatic disease. In parallel, there is increasing recognition that with radiotherapy and systemic treatment, some patients achieve a complete response and may avoid surgical resection, including in many cases, the need for a permanent stoma. Extended neoadjuvant regimes have emerged to address these concerns. The inclusion of immunotherapy in the neoadjuvant setting has the potential to further enhance this strategy by priming the local immune microenvironment and engaging the systemic immune response.Methods: PRIME-RT is a multi-centre, open label, phase II, randomised trial for patients with newly diagnosed LARC. Eligible patients will be randomised to receive either: short course radiotherapy (25 Gray in 5 fractions over one week) with concomitant durvalumab (1500 mg administered intravenously every 4 weeks), followed by FOLFOX (85 mg/m2 oxaliplatin, 350 mg folinic acid and 400 mg/m2 bolus 5-fluorouracil (5-FU) given on day 1 followed by 2400 mg/m2 5-FU infusion over 46-48 h, all administered intravenously every 2 weeks), and durvalumab, or long course chemoradiotherapy (50 Gray to primary tumour in 25 fractions over 5 weeks with concomitant oral capecitabine 825 mg/m2 twice per day on days of radiotherapy) with durvalumab followed by FOLFOX and durvalumab. The primary endpoint is complete response rate in each arm. Secondary endpoints include treatment compliance, toxicity, safety, overall recurrence, proportion of patients with a permanent stoma, and survival. The study is translationally rich with collection of bio-specimens prior to, during, and following treatment in order to understand the molecular and immunological factors underpinning treatment response. The trial opened and the first patient was recruited in January 2021. The main trial will recruit up to 42 patients with LARC and commence after completion of a safety run-in that will recruit at least six patients with LARC or metastatic disease.Discussion: PRIME-RT will explore if adding immunotherapy to neoadjuvant radiotherapy and chemotherapy for patients with LARC can prime the tumour microenvironment to improve complete response rates and stoma free survival. Sequential biopsies are a key component within the trial design that will provide new knowledge on how the tumour microenvironment changes at different time-points in response to multi-modality treatment. This expectation is that the trial will provide information to test this treatment within a large phase clinical trial. Trial registration Clinicaltrials.gov NCT04621370 (Registered 9th Nov 2020) EudraCT number 2019-001471-36 (Registered 6th Nov 2020). [ABSTRACT FROM AUTHOR]

Aim: Neoadjuvant treatment (NaT) for locally advanced rectal cancer prior to surgery has led to improved outcomes. However, the relationship between pathological response to NaT and survival is not entirely clear. The aim of this study was to assess the degree of pathological response to NaT on survival outcomes. Methods: Clinical and pathological data were collected from a prospectively maintained pathology database between 2005 and 2017. The primary outcome was the overall survival based on pathological response categorized as complete, good partial, partial and minimal. Univariate and multivariate analyses were conducted to identify variables predictive of survival. Cox proportional hazard ratios were used for survival. Results: A total of 596 patients had surgery following NaT for locally advanced rectal cancer. The median follow‐up was 4.57 years (interquartile range 2.21–8.15 years). The overall survival for complete pathological response was 75.6% vs. 37.3% for minimal response (P < 0.001). The overall survival at the end of the study in the good partial vs. partial response groups was 58.9% vs. 39% (P < 0.001). On multivariate analysis, the degree of pathological response remains an independent variable for overall and disease‐specific survival across all categories. Discussion: In addition to other pathological variables, the degree of pathological response to NaT is an independent predictor for survival outcomes. Future verification of these findings elsewhere could support NaT response being used for adjuvant therapy decision making. [ABSTRACT FROM AUTHOR]

Limited data exist on the effect of travelling time on post-diagnosis cancer care and mortality. We analysed the impact of travel time to cancer treatment centre on secondary care contact time and one-year mortality using a data-linkage study in Scotland with 17369 patients. Patients with longer travelling time and island-dwellers had increased incidence rate of secondary care cancer contact time. For outpatient oncology appointments, the incidence rate was decreased for island-dwellers. Longer travelling time was not associated with increased secondary care contact time for emergency cancer admissions or time to first emergency cancer admission. Living on an island increased mortality at one-year. Adjusting for cancer-specific secondary care contact time increased the hazard of death, and adjusting for oncology outpatient time decreased the hazard of death for island-dwellers. Those with longer travelling times experience the cancer treatment pathway differently with poorer outcomes. Cancer services may need to be better configured to suit differing needs of dispersed populations. • Patients with high travel burden encounter the cancer treatment pathway differently. • They spend more time in hospital in the first year following cancer diagnosis. • Island dwellers have fewer outpatient appointments; this negatively affects survival. • Better configuration of cancer services is needed for dispersed populations. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) in patients aged under 55 years is on the rise, constituting approximately 10% of cases. Our aim was to determine the survival and clinico-pathological details of young-onset CRC (yCRC), as well as audit the referral rate to genetic services and thus establish the incidence of inherited cancer syndromes.Methods: A retrospective case note review was conducted for patients aged under 55 years who were diagnosed with CRC between 2005 and 2015 in the North East of Scotland. Cases were identified by pathology records and data was obtained from patient notes. Analysis was performed using SPSS version 25 (IBM, New York, USA) to produce Kaplan-Meier survival estimates, descriptive statistics and markers predictive for genetic referral.Results: Data from 345 patients (age range 22-54 years) were identified. The one year, five year and overall survival rates were found to be 89, 63 and 55%, respectively. Most patients (61%) presented with advanced disease. Of 201 patients that met criteria for genetic referral, only 93 (46%) were referred to genetic services. Microsatellite instability (MSI) was identified in 14% of those referred.Conclusion: Survival in yCRC was found to be better than that in later onset disease, despite higher rates of advanced disease. Patients were under-referred to genetic services, where a significant proportion were found to be MSI positive and investigated for Lynch syndrome. [ABSTRACT FROM AUTHOR]

Background: Outcomes in locally advanced rectal cancer are improved by neoadjuvant therapy followed by surgical resection. Some patients respond completely to preoperative treatment. Therefore, predicting the pathological response to preoperative therapy is of clinical importance. Accurate prediction would allow for tailored approaches to neoadjuvant therapy. Methods: All patients undergoing resection of rectal adenocarcinoma after neoadjuvant therapy between 2006 and 2015 were included in this cohort study. Patients were identified from a prospectively collected database and data were supplemented retrospectively with full blood count at diagnosis. Specimens resected following neoadjuvant therapy were graded according to pathological response. Follow-up data was obtained from the national registry. The primary outcome was complete pathological response. Results: Of 330 patients, 71 (21.5%) responded completely to preoperative therapy. Median age was 66 and 65% were male (n = 215). White cell count (WCC) was the most predictive marker, for predicting pCR; area under the curve (AUC) 0.666. This was higher than neutrophil/platelet ratio (AUC 0.652) or neutrophil/lymphocyte ratios (AUC = 0.437). Kaplan-Meier survival analysis showed those patients with WCC > 8 had poorer survival than those with WCC < 8 (p = 0.009). Conclusion: Routinely collected haematology samples at the point of diagnosis can assist in predicting for complete response to neoadjuvant therapy. Although novel biomarkers will have a greater predictive value, this clinically available value test could help to assist in risk stratification of patients using routinely collected laboratory tests. [ABSTRACT FROM AUTHOR]

Purpose: Transcriptomic profiling of colorectal cancer (CRC) has led to the identification of four consensus molecular subtypes (CMS1 to 4) that have prognostic value in stage II and III disease. More recently, the Colorectal Cancer Intrinsic Subtypes (CRIS) classification system has helped to define the biology specific to the epithelial component of colorectal tumors; however, the clinical value of these classification systems in the prediction of response to standard-of-care adjuvant chemotherapy remains unknown. Patients and Methods: Using samples from four European sites, we assembled a novel cohort of patients with stage II and III CRC (n = 156 samples) and performed transcriptomic profiling and targeted sequencing and generated a tissue microarray to enable integrated multiomics analyses. We also accessed data from two published cohorts of patients with stage II and III CRC: GSE39582 and GSE14333 (n = 479 and n = 185 samples, respectively). Results: The epithelial-rich CMS2 subtype of CRC benefitted significantly from treatment with adjuvant chemotherapy in both stage II and III disease (P =.02 and P <.001, respectively), whereas the CMS3 subtype significantly benefitted in stage III only (P =.001). After CRIS substratification of CMS2, we observed that only the CRIS-C subtype significantly benefitted from treatment with adjuvant chemotherapy in stage II and III disease (P =.0081 and P <.001, respectively), whereas the CRIS-D subtype significantly benefitted in stage III only (P =.0034). We also observed that CRIS-C patients with low levels of CD8+ tumor-infiltrating lymphocytes were most at risk for relapse in both stage II and III disease (log-rank P =.0031; hazard ratio, 12.18 [95% CI, 1.51 to 98.58]). Conclusion: Patient stratification using a combination of transcriptional subtyping and CD8 immunohistochemistry analyses is capable of identifying patients with poor prognostic stage II and III disease who benefit from adjuvant standard-of-care chemotherapy. These findings are particularly relevant for patients with stage II disease, where the overall benefit of adjuvant chemotherapy is marginal. [ABSTRACT FROM AUTHOR]

A phase 1 dose-escalation trial assessed the chemotherapeutic potential of ammoniumperfluorooctanoate (APFO). Forty-nine primarily solid-tumor cancer patients who failed standard therapy received weekly APFO doses (50-1200mg) for 6 weeks. Clinical chemistries and plasma PFOA (anionic APFO) were measured predose and weekly thereafter. Several clinical measures including total cholesterol, high-density lipoproteins (HDLs), thyroid stimulating hormone (TSH), and free thyroxine (fT4), relative to PFOA concentrations were examined by: Standard statistical analyses using generalized estimating equations (GEE) and a probabilistic analysis using probability distribution functions (pdf) at various PFOA concentrations; and a 2-compartment pharmacokinetic/pharmacodynamic (PK/PD) model to directly estimatemean changes. Based on the GEE, the average rates of change in total cholesterol and fT4 associated with increasing PFOA were approximately -1.2x10-3mmol/l/lMand 2.8x10-3pmol/l/lM, respectively. The PK/PDmodel predictedmore closely the trends observed in the data as well as the pdfs of biomarkers. A decline in total cholesterol was observed, with a clear transition in shape and range of the pdfs, manifested by the maximum value of the Kullback-Leibler (KL) divergence, that occurred at plasma PFOA between 420 and 565lM (175 000- 230 000 ng/ml). High-density lipoprotein was unchanged. An increase in fT4 was observed at a higher PFOA transition point, albeit TSH was unchanged. Our findings are consistent with some animalmodels and maymotivate re-examination of the epidemiologic studies to PFOA at levels several orders of magnitude lower than this study. These observational studies have reported contrary associations, but currently understood biology does not support the existence of such conflicting effects. [ABSTRACT FROM AUTHOR]

Purpose: Etirinotecan pegol (EP) is a long-acting topoisomerase-I inhibitor designed to provide sustained exposure to SN-38 (active metabolite of irinotecan). This phase II study compared EP versus irinotecan as second-line treatment for KRAS-mutant, irinotecan-naïve, metastatic colorectal cancer (mCRC).Methods: Patients were randomized to EP 145 mg/m2 or irinotecan 350 mg/m2 Q21d until disease progression/unacceptable toxicity. The primary endpoint was progression-free survival (PFS) with response determined by central radiologic review (RECIST version 1.1).Results: The study was terminated before completing accrual due to evolving standards of care. Eighty-three patients were randomized. Median PFS was longer with EP versus irinotecan (4.0 versus 2.8 months, respectively; HR 0.65; 95% CI 0.40-1.04; P = 0.07). Six-month PFS rates were 32.8 and 15.4%, respectively. Median OS was 9.6 and 8.4 months in EP and irinotecan arms, respectively (HR 0.91; 95% CI 0.56-1.49). ORRs were 10 and 5%, respectively (P = 0.676); median DOR was significantly longer in EP arm (7.9 versus 1.4 months; P = 0.018). The most common grade-3/4 adverse events for EP and irinotecan were diarrhea (21 vs 20%), neutropenia (10 vs 22%), abdominal pain (14 vs 5%), nausea (14 vs 2%), and vomiting (12 vs 7%), respectively.Conclusion: EP is active and safe for second-line treatment of KRAS-mutant, irinotecan-naïve mCRC. [ABSTRACT FROM AUTHOR]

Background: The influence of EGFR pathway mutations on cetuximab-containing rectal cancer preoperative chemoradiation (CRT) is uncertain.Methods: In a prospective phase II trial (EXCITE), patients with magnetic resonance imaging (MRI)-defined non-metastatic rectal adenocarinoma threatening/involving the surgical resection plane received pelvic radiotherapy with concurrent capecitabine, irinotecan and cetuximab. Resection was recommended 8 weeks later. The primary endpoint was histopathologically clear (R0) resection margin. Pre-planned retrospective DNA pyrosequencing (PS) and next generation sequencing (NGS) of KRAS, NRAS, PIK3CA and BRAF was performed on the pre-treatment biopsy and resected specimen.Results: Eighty-two patients were recruited and 76 underwent surgery, with R0 resection in 67 (82%, 90%CI: 73-88%) (four patients with clinical complete response declined surgery). Twenty-four patients (30%) had an excellent clinical or pathological response (ECPR). Using NGS 24 (46%) of 52 matched biopsies/resections were discrepant: ten patients (19%) gained 13 new resection mutations compared to biopsy (12 KRAS, one PIK3CA) and 18 (35%) lost 22 mutations (15 KRAS, 7 PIK3CA). Tumours only ever testing RAS wild-type had significantly greater ECPR than tumours with either biopsy or resection RAS mutations (14/29 [48%] vs 10/51 [20%], P=0.008), with a trend towards increased overall survival (HR 0.23, 95% CI 0.05-1.03, P=0.055).Conclusions: This regimen was feasible and the primary study endpoint was met. For the first time using pre-operative rectal CRT, emergence of clinically important new resection mutations is described, likely reflecting intratumoural heterogeneity manifesting either as treatment-driven selective clonal expansion or a geographical biopsy sampling miss. [ABSTRACT FROM AUTHOR]

Aims bcl-2-associated transcription factor 1 ( BCLAF1) is a nuclear protein that binds to bcl-related proteins and can induce apoptosis and autophagy. The aim of this study was to investigate the expression of BCLAF1 in a series of rectal cancers following neoadjuvant therapy. Methods and results Immunohistochemistry was performed on a post-neoadjuvant therapy rectal cancer tissue microarray. It contained rectal cancers ( n = 248), lymph node metastases ( n = 76), and non-neoplastic rectal mucosal samples ( n = 73). A monoclonal antibody against BCLAF1 that we have developed was used. Non-neoplastic rectal epithelium showed nuclear localization of BCLAF1 in both crypt and surface epithelial cells, whereas rectal cancers showed both nuclear and cytoplasmic BCLAF1 expression. Most rectal cancers showed moderate or strong nuclear immunoreactivity, but showed weak cytoplasmic immunoreactivity. Cytoplasmic BCLAF1 expression was increased in primary rectal cancers as compared with non-neoplastic rectal mucosa ( P = 0.008). Negative and weak nuclear BCLAF1 expression was associated with a poor prognosis [hazard ratio ( HR) 0.502, 95% confidence interval ( CI) 0.269-0.939, χ2 = 4.876, P = 0.027]. Nuclear BCLAF1 expression was independently prognostic in a multivariate model ( HR 0.431, 95% CI 0.221-0.840, P = 0.013). Conclusions This study has shown that both cytoplasmic BCLAF1 expression and nuclear BCLAF1 expression are increased in post-neoadjuvant therapy rectal cancer, and that negative and weak nuclear BCLAF1 expression are independently associated with a poor prognosis. [ABSTRACT FROM AUTHOR]

The presence of lymph node metastasis is a key prognostic factor in colorectal cancer and lymph node yield is an important parameter in assessing the quality of histopathology reporting of colorectal cancer excision specimens. This study assesses the trend in lymph node evaluation over time in a single institution and the relationship with the identification of lymph node positive tumours. It compares the lymph node yield of a contemporary dataset compiled from the histopathology reports of 2178 patients who underwent surgery for primary colorectal cancer between 2005 and 2012 with that of a historic dataset compiled from the histopathology reports of 1038 patients who underwent surgery for colorectal cancer at 5 yearly intervals from 1975 to 2000. The mean lymph node yield was 14.91 in 2005 rising to 21.38 in 2012. In 2012 92.9% of all cases had at least 12 lymph nodes examined. Comparison of the mean lymph node yield and proportion of Dukes C cases shows a significant increase (Pearson correlation = 0.927, p = 0.001) in lymph node yield while there is no corresponding significant trend in the proportion of Dukes C cases (Pearson correlation = −0.138, p = 0.745). This study shows that there is increasing yield of lymph nodes from colorectal cancer excision specimens. However, this is not necessarily associated with an increase number of lymph node positive cancers. Further risk stratifying of colorectal cancer requires consideration of other pathological parameters especially the presence of extramural venous invasion and relevant biomarkers. [ABSTRACT FROM AUTHOR]

Background: People living with colorectal cancer are at risk of anxiety and depression. We investigated what factors were most highly associated with these. Methods: Four hundred and ninety-six people with colorectal cancer completed the Hospital Anxiety and Depression Scale (HADS). Data on functioning, symptoms, illness perceptions and social difficulties were collected by questionnaire. Case-note-identified disease, treatment and co-morbidity data were recorded. Multiple logistic regression identified factors independently predictive of anxiety and depression caseness. Results: Self-reported history of anxiety/depression predicted anxiety but not depression caseness. Depression caseness predicted anxiety caseness ( p = 0.043), as did poorer self-reported cognitive functioning ( p = 0.001), dyspnoea ( p = 0.015) or diarrhoea ( p = 0.021), reporting a high negative life and emotional impact ( p < 0.001) and having difficulties with finance ( p = 0.007). Having neo-adjuvant radiotherapy increased the odds of depression caseness ( p = 0.007), as did poorer physical ( p = 0.007), cognitive ( p < 0.001) and social ( p < 0.001) functioning, having constipation ( p = 0.011), reporting a high negative life and emotional impact ( p < 0.001), having difficulties with personal care ( p = 0.022) and communicating with others ( p = 0.014). Conclusion: Levels of anxiety caseness were similar to those of non-clinical samples, but depression caseness was higher, particularly in those who had received neo-adjuvant radiotherapy. Most factors associated with possible or probable depression may be modified with appropriate intervention. [ABSTRACT FROM AUTHOR]

Correction to: Radiat Oncol (2021) 16:163. https://doi.org/10.1186/s13014-021-01888-1 After publication of this article [[1]], the authors reported that the Funding information section was incomplete. Durvalumab (MEDI 4736) in combination with extended neoadjuvant regimens in rectal cancer: a study protocol of a randomised phase II trial (PRIME-RT). [Extracted from the article]

Sound processing properties for calling song (CS) models, as described for the prothoracic L3 auditory neurone in Acheta domesticus, are investigated for the homologous auditory neurone 2 (AN2) in female Gryllus bimaculatus De Geer. AN2 of G. bimaculatus responds selectively to the syllable period (SP) of models of a male CS. The selectiveness of this response parallels the selectivity of phonotaxis females perform in response to the same SPs. Both, the responses of AN2 and female behaviour show clear interindividual variability. The SP-selective responses of AN2 result from an SP-dependent reduction in the spiking to subsequent syllables of the model CSs, measured as the percentage decrement. This SP-dependent response does not primarily result from inbuilt properties of the AN2 membrane. Rather, it is dependent on inhibitory input to the AN2. However, clear inhibitory postsynaptic potentials in dendritic recordings of the AN2 are not encountered. This immediate response of AN2 to CSs is followed by an increased rate of tonic firing between stimulus CSs, which is termed the prolonged response, and is dependent on the carrier frequencies that make up the male CSs. With stimulation on the contralateral side of the soma of AN2s, more than 50% of AN2s exhibit a prolonged response. However, with stimulation from the ipsilateral side of the soma, most AN2s exhibit a prolonged response. The prolonged response of AN2 at 5 kHz may be even more sensitive than the immediate response. Thus, the AN2 neurone could provide a basis for phonotaxis that is selective for both the SPs and the carrier frequencies of potentially attractive calling songs. [ABSTRACT FROM AUTHOR]

Earlier studies of phonotaxis by female crickets describe this selective behavioural response as being important in the females' choices of conspecific males, leading to reproduction. In the present study, moderate (30+) to very large data sets of phonotactic behaviour by female Acheta domesticus L., Gryllus bimaculatus DeGeer, Gryllus pennsylvanicus Burmeister and Gryllus veletis Alexander demonstrate substantially greater plasticity in the behavioural choices, as made by females of each species, for the syllable periods (SP) of model calling songs (CS) than has been previously described. Phonotactic choices by each species range from the very selective (i.e. responding to only one or two SPs) to very unselective (i.e. responding to all SPs presented). Some females that do not respond to all SPs prefer a range that includes either the longest or shortest SP tested, which fall outside the range of SPs produced by conspecific males. Old female A. domesticus and G. pennsylvanicus are more likely to be unselective for SPs than are young females. Each species includes females that do not respond to a particular SP when responding to CSs with longer and shorter SPs. The results suggest that the plasticity of phonotactic behaviour collectively exhibited by the females of each species does not ensure that choices of a male's CS effectively focus the female's phonotactic responses on CSs that represent the conspecific male. The phonotactic behaviour collectively exhibited by females of each species does not readily fit any of the models for selective processing by central auditory neurones that have been proposed to underlie phonotactic choice. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: Evidence on which to base decisions about the management of radiation skin reactions is lacking. The purpose of this study was to investigate whether sucralfate or aqueous cream reduced acute skin toxicity during radiotherapy to the head and neck, breast or anorectal area (phase A), and to evaluate the effect of hydrogels and dry dressings on moist desquamation (phase B). This paper presents the results of phase A. Patients and methods: Three hundred and fifty seven patients were randomised to apply aqueous cream, sucralfate cream or no cream to the irradiated area from day one of radical radiotherapy treatment. All patients were instructed to wash using unperfumed soap. Acute skin toxicity was measured using a modified radiation therapy oncology group (RTOG) score, reflectance spectrophotometry, patient diary card and dermatology life quality index (DLQI). A cost minimisation approach was used to compare the costs of each skin care approach. Results: No consistent differences were found in the severity of skin reactions or levels of discomfort suffered by patients in each of the randomised groups. Patients with a higher body mass index, who smoked, received concomitant chemotherapy, boost or bolus during treatment were more likely to develop skin reactions. Conclusions: There is no evidence to support the prophylactic application of either of the creams tested for the prevention of radiation skin reactions. Our results show that it is possible to predict which patients are at greatest risk of skin reactions. We suggest that known risk factors should be incorporated into future study protocols. [Copyright &y& Elsevier]

Purpose: BBR 3464 is a novel trinuclear platinum anticancer agent with a broad spectrum of preclinical antitumour activity. A phase I, open-label dose-escalating study was performed to determine the maximum tolerated dose (MTD) of BBR 3464 administered in combination with protracted venous infusional (PVI) 5-fluorouracil (5-FU) for up to six courses in patients with locally advanced and/or metastatic cancer.Methods: Dose escalation was based on observation of toxicity at each dose level. BBR 3464 (0.6 mg/m(2) escalated to 0.75 mg/m(2)) was studied in combination with PVI 5-FU (200 mg/m(2) per day).Results: Entered into the study were 14 patients. The most frequent toxicities were nausea, neutropenia, fatigue and diarrhoea. The protocol-defined MTD was not determined as 11/14 patients experienced grade 3 or 4 neutropenia that interrupted the planned administration of PVI 5-FU on day 15 (of 21). Although these events were not dose-limiting, as defined in the protocol, they imposed limitations on the dose of PVI 5-FU administered. Antitumour activity was observed: a partial response in one patient (7%) with invasive breast cancer. Stable disease was confirmed in three patients (21%). These four patients all completed the planned six courses of combined therapy.Conclusions: In light of the lack of septic events associated with the recorded neutropenia, it may be possible to safely continue PVI 5-FU despite the grade 3 or 4 neutropenia or modify the PVI schedule and administer therapy on days 1-15 of the 21-day cycle, but these modifications were not considered in this study. [ABSTRACT FROM AUTHOR]