Routine measurement of plasma chromogranin B has limited clinical utility in the management of patients with neuroendocrine tumours.

OBJECTIVE: Chromogranin A (CgA) and B (CgB) are markers for monitoring disease status in patients with gastroenteropancreatic neuroendocrine tumours (NETs). These are specialized diagnostic tests often necessitating referral of specimens to a supraregional assay service (SAS) laboratory for analysis. The aim of this audit was to assess whether measurement of either plasma CgA or CgB alone provides sufficient clinical information in comparison with the current practice of measuring both markers together. DESIGN: A retrospective analysis was undertaken for all chromogranin tests requested for patients with a known NET diagnosis. Results were categorized based on whether plasma concentrations were elevated for one or both CgA and CgB. RESULTS: A total of 325 sequential patients with a NET diagnosis had plasma chromogranin levels measured during the period of review. Baseline CgA was elevated in 60·9% of patients. Isolated elevations in CgA (with normal CgB) were found in 44·9% of patients, whilst combined elevations in both CgA and CgB were found in 16% of patients. Combined CgA and CgB concentrations within the normal range were observed for 38·5% of patients. Only two patients (0·6%) had an isolated elevation in CgB at baseline. Both patients had a diagnosis of pancreatic NET and were radiologically stable. Plasma CgA and CgB corresponded with disease stage (localized vs metastatic). CgB in addition to CgA did not provide any significant improvement in diagnostic performance for identification of metastatic disease compared to CgA alone. CONCLUSIONS: Based on this NET population and specific assay performance characteristics, CgA alone provides sufficient information for the management of NET patients; the routine estimation of CgB in all patients is not informative in clinical practice.

Second-line chemotherapy in advanced biliary cancer: a systematic review.

The randomized NCRN phase III ABC-02 trial provided level-A evidence for first-line chemotherapy with cisplatin and gemcitabine combination in advanced biliary cancer (ABC). This systematic literature review aims to evaluate the level of evidence for the use of second-line chemotherapy for patients with ABC in terms of overall survival (OS), response, toxicity and quality of life. Eligible studies were identified using Medline, ASCO, ESMO and the World Gastrointestinal Congress databases. Searches were last updated on 15 December 2013. Eligible studies reported survival and/or response data for patients with ABC receiving second-line systemic chemotherapy. This systematic review was registered in the PROSPERO database (No. CRD42013004205). Five hundred and fifty-eight studies were identified from the searches in Medline (n = 342), ASCO (n = 160), ESMO (n = 27) and World Gastrointestinal Congress (n = 29). Twenty-five studies were eligible: 14 phase II clinical trials, 9 retrospective analyses and 2 case reports. In total, data from 761 patients were reported with median number of patients included in each study of 22 (range 9-96). The mean OS was 7.2 months [95% confidence interval (CI) 6.2-8.2] [phase II: 6.6 (95% CI 5.1-8.1); retrospective analysis: 7.7 (95% CI 6.5-8.9)]. The mean progression-free survival (PFS), response rate (RR) and disease control rate were 3.2 months (95% CI 2.7-3.7), 7.7% (95% CI 4.6-10.9) and 49.5% (95% CI 41.4-57.7), respectively. The best correlations were between OS and PFS for all studies (r = 0.54; P = 0.01) and between OS and PFS (r = 0.61; P = 0.04) and OS and RR (r = 0.62; P = 0.03) for phase II studies, respectively. Biliary tract cancer is known to be a chemo-responsive disease. There is insufficient evidence (level C) to recommend a second-line chemotherapy schedule in ABC, although the available data suggest that a cohort of patients may benefit. Further prospective and randomized studies are needed to clarify the relative value of second-line chemotherapy in this setting.

Learning curve of optical trocar access during laparoscopic pelvic surgery: A prospective study.

INTRODUCTION: The optical trocar access (OTA) is a modified closed technique that aims to minimize the risk of vascular or bowel injuries while reducing the likelihood of gas leakage. A learning curve (LC) effect for OTA has been invoked with n = 30 procedures being considered as a threshold to define expertise. We aim to evaluate the impact of the LC within the first thirty cases of OTA performed by a trainee. METHODS: This is a prospective randomized study on 60 patients elected to laparoscopic gynecological surgery. Patients were randomized to have OTA insertion by a junior surgeon or by an expert. LC was evaluated by: 1) insertion time; number of: 2) corrections by the senior; 3) times the tip of the trocar stopped in the preperitoneal layer; 4) mistakes of skin incision; 5) times the tip of the trocar ends under the omentum; 6) complications. To analyze the LC within the first 30 cases, procedures were stratified in 3 groups (cases 1-10; 11-20; 21-30) for both trainee and expert and LC variables were compared. RESULTS: Overall, mean OTA insertion time was 56 s. No major intra- and post-operative complications were recorded. Mean insertion time was statistically significantly longer for the trainee compared to the expert within the first 10 cases (91 vs 33 s respectively, P = .01). For cases 11-20 and 21-30, time advantage of the senior surgeon is less evident (P = .05). The number of times the tip of the trocar stopped in the preperitoneal layer was similar between groups, as well as times the tip of the trocar ends under the omentum. CONCLUSIONS: OTA is a fast and simple way to achieve the pneumoperitoneum and first trocar insertion as a single step. The current series confirms the effectiveness of the technique since the beginning of the LC.

Management of non-hepatic distant metastases in neuroendocrine neoplasms.

Neuroendocrine neoplasms represent an uncommon disease with an increasing incidence. Thanks to improvements in diagnostic and therapeutic methods, metastases previously considered uncommon, such as bone metastases, or even very rare, such as brain, orbital and cardiac metastases, are more frequently found in daily practice. Due to the great heterogeneity of these neoplasms, there is a lack of high-quality evidence on the management of patients with these types of metastases. The aim of this review is to provide the current state of the art, reviewing neuroendocrine neoplasm specific studies and useful information from other tumor types and to propose a treatment recommendation with algorithms to consider in daily clinical practice.

The management of hepatocellular carcinoma. Current expert opinion and recommendations derived from the 24th ESMO/World Congress on Gastrointestinal Cancer, Barcelona, 2022.

This article summarises expert discussion on the management of patients with hepatocellular carcinoma (HCC), which took place during the 24th World Gastrointestinal Cancer Congress (WGICC) in Barcelona, July 2022. A multidisciplinary approach is mandatory to ensure an optimal diagnosis and staging of HCC, planning of curative and therapeutic options, including surgical, embolisation, ablative strategies, or systemic therapy. Furthermore, in many patients with HCC, underlying liver cirrhosis represents a challenge and influences the therapeutic options.

How I treat biliary tract cancer.

Management of biliary tract cancers (BTCs) is rapidly evolving. Curative management relies on surgical resection followed by adjuvant capecitabine for cholangiocarcinoma and gallbladder cancers. Unfortunately relapse rate remains high, and better adjuvant strategies are urgently required. A majority of patients are diagnosed with advanced disease, when chemotherapy with cisplatin and gemcitabine followed by second-line 5-FU and oxaliplatin /irinotecan is the cornerstone of treatment for most patients in the absence of targetable alterations. Targeted therapies, including therapies for tumours with fibroblast growth factor receptor-2 (FGFR-2) fusions, isocitrate dehydrogenase-1 (IDH-1) mutations, B-Raf proto-oncogene serine/threonine kinase (BRAF) V600E mutations, neurotrophic tyrosine receptor kinase (NTRK) fusions, Human epidermal growth factor-2 (HER-2) amplifications, and/or microsatellite instability are rapidly changing the treatment paradigm for many patients with advanced BTC, especially for patients with intrahepatic cholangiocarcinoma. Because of this, molecular profiling should be considered early on patients pathway to allow adequate planning of therapy. Ongoing research is likely to clarify the role of immunotherapy, liver-directed therapy, and liver transplant for BTCs in the future.

Setup of multidisciplinary team discussions for patients with cholangiocarcinoma: current practice and recommendations from the European Network for the Study of Cholangiocarcinoma (ENS-CCA).

BACKGROUND: Cholangiocarcinomas (CCAs) are a rare group of malignancies characterized by dismal prognosis. There are currently no standardized guidelines for multidisciplinary teams (MDTs) in CCAs. MATERIAL AND METHODS: An online survey was built with the aim of defining the current practice of MDTs in CCAs and identifying possible areas of improvement, providing minimum standards of practice for an ideal CCA MDT. Analysis of the replies regarding current and ideal MDT practice was carried out by calculating weighted average (WA) of likelihood of every item. The survey was shared with members of the European Network for the Study of Cholangiocarcinoma and other medical centers with expertise in biliary tract cancer part of the EURO-CHOLANGIO-NET (European Cholangiocarcinoma Network: https://eurocholangionet.eu/) COST Action CA18122 initiative. RESULTS: The role of the MDT coordinator was a recognized priority in an ideal well-functioning MDT (WA 3.31/4), together with providing minimum clinical information before the meeting to secure adequate case preparation (WA 3.54/4). Optimal frequency of MDT meetings was weekly according to 76.92% of the participants; 73.06% believed that ideally all newly diagnosed patients and each new treatment should be discussed, although that happened only in less than half of the MDTs (46.15%) in current practice. Most participants stated that they always (46.15%) or often (50.00%) used guidelines, mainly international (61.00%) (European and American), followed by national/local (39.00%). We defined the ideal setup of a CCA MDT, identifying specialists whose presence is mandatory with WA >3.0 (oncologist, clinician responsible for patient's care, surgeon, diagnostic and interventional radiologist, hepatologist, pathologist, endoscopist and gastroenterologist) and those whose presence would be recommended with a WA <3.0 (palliative care, nurse, dietitian, basic researcher, psychologist and social worker). CONCLUSIONS: Our identified minimum requirements should be taken into account at the time of CCA MDT setup and quality assessment.

Impact of COVID-19 on social media as perceived by the oncology community: results from a survey in collaboration with the European Society for Medical Oncology (ESMO) and the OncoAlert Network.

BACKGROUND: The COVID-19 pandemic has impacted all aspects of modern-day oncology, including how stakeholders communicate through social media. We surveyed oncology stakeholders in order to assess their attitudes pertaining to social media and how it has been affected during the pandemic. MATERIALS AND METHODS: A 40-item survey was distributed to stakeholders from 8 July to 22 July 2020 and was promoted through the European Society for Medical Oncology (ESMO) and the OncoAlert Network. RESULTS: One thousand and seventy-six physicians and stakeholders took part in the survey. In total, 57.3% of respondents were medical oncologists, 50.6% aged <40 years, 50.8% of female gender and mostly practicing in Europe (51.5%). More than 90% of respondents considered social media a useful tool for distributing scientific information and for education. Most used social media to stay up to date on cancer care in general (62.5%) and cancer care during COVID-19 (61%) given the constant flow of information. Respondents also used social media to interact with other oncologists (78.8%) and with patients (34.4%). Overall, 61.1% of respondents were satisfied with the role that social media was playing during the COVID-19 pandemic. On the other hand, 41.1% of respondents reported trouble in discriminating between credible and less credible information and 30% stated social networks were a source of stress. For this reason, one-third of respondents reduced its use during the COVID-19 pandemic. Regarding meeting attendance, a total of 59.1% of responding physicians preferred in-person meetings to virtual ones, and 51.8% agreed that virtual meetings and social distancing could hamper effective collaboration. CONCLUSION: Social media has a useful role in supporting cancer care and professional engagement in oncology. Although one-third of respondents reported reduced use of social media due to stress during the COVID-19 pandemic, the majority found social media useful to keep up to date and were satisfied with the role social media was playing during the pandemic.

Structural Bases of Atypical Whisker Responses in a Mouse Model of CDKL5 Deficiency Disorder.

Mutations in the CDKL5 (cyclin-dependent kinase-like 5) gene cause CDKL5 Deficiency Disorder (CDD), a severe neurodevelopmental syndrome where patients exhibit early-onset seizures, intellectual disability, stereotypies, limited or absent speech, autism-like symptoms and sensory impairments. Mounting evidences indicate that disrupted sensory perception and processing represent core signs also in mouse models of CDD; however we have very limited knowledge on their underlying causes. In this study, we investigated how CDKL5 deficiency affects synaptic organization and experience-dependent plasticity in the thalamo-cortical (TC) pathway carrying whisker-related tactile information to the barrel cortex (BC). By using synapse-specific antibodies and confocal microscopy, we found that Cdkl5-KO mice display a lower density of TC synapses in the BC that was paralleled by a reduction of cortico-cortical (CC) connections compared to wild-type mice. These synaptic defects were accompanied by reduced BC activation, as shown by a robust decrease of c-fos immunostaining, and atypical behavioral responses to whisker-mediated tactile stimulation. Notably, a 2-day paradigm of enriched whisker stimulation rescued both number and configuration of excitatory synapses in Cdkl5-KO mice, restored cortical activity and normalized behavioral responses to wild-type mice levels. Our findings disclose a novel and unsuspected role of CDKL5 in controlling the organization and experience-induced modifications of excitatory connections in the BC and indicate how mutations of CDKL5 produce failures in higher-order processing of somatosensory stimuli. This article is part of a Special Issue entitled: Animal Models of Neurodevelopmental Disorders.

Antiviral activity and safety of aplaviroc, a CCR5 antagonist, in combination with lopinavir/ritonavir in HIV-infected, therapy-naïve patients: results of the EPIC study (CCR100136).

BACKGROUND: This phase IIb study explored the antiviral activity and safety of the investigational CC chemokine receptor 5 (CCR5) antagonist aplaviroc (APL) in antiretroviral-naïve patients harbouring R5- or R5X4-tropic virus. METHODS: A total of 191 patients were randomized 2:2:2:1 to one of three APL dosing regimens or to lamivudine (3TC)/zidovudine (ZDV) twice daily (bid), each in combination with lopinavir/ritonavir (LPV/r) 400 mg/100 mg bid. Efficacy, safety and pharmacokinetic parameters were assessed. RESULTS: This study was terminated prematurely because of APL-associated idiosyncratic hepatotoxicity. A total of 141 patients initiated treatment early enough to have been able to complete 12 weeks on treatment [modified intent-to-treat (M-ITT) population]; of these, 133 completed the 12-week treatment phase. The proportion of subjects in the M-ITT population with HIV-1 RNA <400 copies/mL at week 12 was 50, 48, 54 and 75% in the APL 200 mg bid, APL 400 mg bid, APL 800 mg once a day (qd) and 3TC/ZDV arms, respectively. Similar responses were seen in the few subjects harbouring R5X4-tropic virus (n=17). Common clinical adverse events (AEs) were diarrhoea, nausea, fatigue and headache. APL demonstrated nonlinear pharmacokinetics with high interpatient variability. CONCLUSIONS: While target plasma concentrations of APL were achieved, the antiviral activity of APL+LPV/r did not appear to be comparable to that of 3TC/ZDV+LPV/r.

Urgent need for consensus: international survey of clinical practice exploring use of platinum-etoposide chemotherapy for advanced extra-pulmonary high grade neuroendocrine carcinoma (EP-G3-NEC).

BACKGROUND: Platinum-etoposide (PE) chemotherapy (CH) is a globally established combination for extra-pulmonary high grade neuroendocrine carcinoma (EP-G3-NEC); the optimal schedule has not been established. METHODS: An international survey was designed, and completed by clinicians with an expertise in the field to assess consistency in clinical practice. RESULTS: Seventy-five replies were received (June-Nov'17). A minority of physicians (13; 17.6%) did not take Ki-67 or morphology (9; 12.0%) into consideration for selection of CH. Most (72; 96.0%) selected PE-CH as first-line treatment for EP-G3-NEC. CH schedules varied: cisplatin-based (37/71; 52.1%), carboplatin-based (34/71; 47.9%); intravenous etoposide (64/71; 90.1%), oral etoposide (7/71; 9.9%). Choice of second-line CH depended on time to progression on PE-based first-line: if > 6 months, re-challenge with PE was the preferred choice (34; 45.9%); if < 6 months, alternative combinations such as fluoropyrimidine/irinotecan (21; 29.2%) or temozolomide/capecitabine (22; 30.6%) were used. CONCLUSION: Significant variation in PE regimen employed exists. Standardising clinical practice would facilitate clinical trial development.

Outcomes in patients ≥ 80 years with a diagnosis of a hepatopancreaticobiliary (HPB) malignancy.

Older patients are underrepresented in oncological clinical trials. The incidence of hepatopancreaticobiliary (HPB) malignancies is higher in older patients, but data on outcomes are lacking. This study assessed patient outcomes in those < 80 and ≥ 80 years with a HPB malignancy seen at a tertiary referral centre, The Christie NHS Foundation Trust. Data on patients with a HPB malignancy were collected retrospectively between 2012 and 2017 via on-line case-note review. Survival was calculated using the Kaplan-Meier method and prognostic factors using log-rank analysis. Of 1421 patients, 10% were ≥ 80 years. Of patients < 80 and ≥ 80 years, 56% and 57% had pancreas cancer, 39% and 36% biliary tract cancer, and 5% and 7% had hepatocellular carcinoma, respectively. Amongst patients ≥ 80 years, 75% had an Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2. Patients ≥ 80 years had higher rates of comorbidity; 28% received systemic anti-cancer therapy (SACT), compared with 62% of patients < 80 years. Best supportive care (BSC) was instituted in 44% of older patients, compared with 13% in those < 80 years. Of patients ≥ 80 years who received SACT, 82% received monotherapy. Median overall survival (OS) for patients receiving palliative SACT was 10.07 months (95% CI 8.89-11.08) and 10.10 months (95% CI 6.30-12.30) in patients < 80 and ≥ 80 years, respectively, p 0.41; ECOG PS (p < 0.001) was prognostic for OS in older patients but Adult Comorbidity Evaluation-27 comorbidity score (p = 0.07, when comparing groups of ACE score ≤ 1 and > 1) was not. Baseline factors were similar in both age cohorts, but more comorbidities were present in older patients. Older patients were less likely to receive SACT, but when they did, they had an equivalent benefit in OS to younger patients.

Identification of clinical biomarkers for patients with advanced hepatocellular carcinoma receiving sorafenib.

BACKGROUND: Identification of patients with advanced HCC-deriving preferential benefit from sorafenib is desirable, and treatment-related adverse events are potential clinical biomarkers. METHODS: Survival and toxicity data for patients with HCC treated with sorafenib at the Christie NHS Foundation Trust from 11/09 to 02/15 were collected retrospectively. RESULTS: Eighty-five eligible patients were identified. The most common grade 3 or 4 treatment-related toxicities were hypertension (HTN, 45 %), fatigue (8 %), and hand-foot syndrome (HFS, 8 %). Any-grade HFS and/or worsening HTN (HFS/HTN) were experienced by 58 % of patients. Estimated median progression-free and overall survival (OS) were 4.6 (95 % CI 2.8-5.2) and 6.5 (95 % CI 4.9-8.01) months, respectively. Child-Pugh score (p value <0.001) and the development of HFS/HTN were independent prognostic factors impacting on OS on multivariable analysis. Patients who developed HFS/HTN had median OS of 8.2 months (95 % CI 6.5-12.4) compared with 4.1 (95 % CI 2.7-5.4) for those without this toxicity (Hazard Ratio (HR) 0.4, 95 % CI 0.2-0.7, p value 0.003). The prognostic impact of HFS/HTN was confirmed by landmark analyses limited to patients who lived a minimum of 2 months (p value 0.019) or who developed HFS/HTN in the first 3 months of treatment (p value 0.006). CONCLUSION(S): The development of toxicities specific to sorafenib is associated with prolonged survival in a UK-based HCC patient series; prospective assessment of their significance is required.