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Local treatment improves the outcomes for oligometastatic disease (OMD, i.e. an intermediate state between locoregional and widespread disseminated disease). However, consensus about the definition, diagnosis and treatment of oligometastatic oesophagogastric cancer is lacking. The aim of this study was to develop a multidisciplinary European consensus statement on the definition, diagnosis and treatment of oligometastatic oesophagogastric cancer. In total, 65 specialists in the multidisciplinary treatment for oesophagogastric cancer from 49 expert centres across 16 European countries were requested to participate in this Delphi study. The consensus finding process consisted of a starting meeting, 2 online Delphi questionnaire rounds and an online consensus meeting. Input for Delphi questionnaires consisted of (1) a systematic review on definitions of oligometastatic oesophagogastric cancer and (2) a discussion of real-life clinical cases by multidisciplinary teams. Experts were asked to score each statement on a 5-point Likert scale. The agreement was scored to be either absent/poor (<50%), fair (50%–75%) or consensus (≥75%). A total of 48 experts participated in the starting meeting, both Delphi rounds, and the consensus meeting (overall response rate: 71%). OMD was considered in patients with metastatic oesophagogastric cancer limited to 1 organ with ≤3 metastases or 1 extra-regional lymph node station (consensus). In addition, OMD was considered in patients without progression at restaging after systemic therapy (consensus). For patients with synchronous or metachronous OMD with a disease-free interval ≤2 years, systemic therapy followed by restaging to consider local treatment was considered as treatment (consensus). For metachronous OMD with a disease-free interval >2 years, either upfront local treatment or systemic treatment followed by restaging was considered as treatment (fair agreement). The OMEC project has resulted in a multidisciplinary European consensus statement for the definition, diagnosis and treatment of oligometastatic oesophagogastric adenocarcinoma and squamous cell cancer. This can be used to standardise inclusion criteria for future clinical trials. [Display omitted] • A European consensus statement for oesophagogastric oligometastatic disease (OMD) was developed. • 1 organ with ≤3 metastases or 1 involved extra-regional lymph node station is OMD. • No progression at restaging after systemic therapy remains OMD. • This consensus statement requires prospective validation in a clinical study. [ABSTRACT FROM AUTHOR]

For patients with advanced thymic epithelial tumours (TET), there is no standard second-line treatment after platinum-based chemotherapy. Although immune checkpoint blockers (ICB) are a potential treatment strategy, their efficacy seems limited with an increased risk of immune-related adverse events (ir-AEs), thus hampering their application in daily clinical practice. We performed a meta-analysis to better evaluate the existing evidence about the activity and safety of ICB in the setting of unresectable or metastatic advanced TET previously treated with platinum-based chemotherapy. Six phase I/II trials met the eligibility criteria including a total of 166 evaluable patients (77% thymic carcinoma, 23% thymoma) evaluable for activity after being treated with pembrolizumab, nivolumab, avelumab or atezolizumab. The overall response rate to ICB was 18.4% (95% CI: 12.3–26.5), and the one-year progression-free survival rate and one-year overall survival rate were 26.0% (95% CI: 19.6–34.6) and 66.9% (95% CI: 59.6–75.2%), respectively. The incidence of grade 3–5 ir-AEs was 26.4%, with 17.1% in thymic carcinoma and 58.3% in thymoma. Despite the absence of a robust demonstration of efficacy in the context of randomised trials, our results suggest ICB as a potential strategy in patients with pretreated TET, mainly among patients with thymic carcinoma. Close monitoring is strongly advised to detect severe immune-toxicity. • Immune checkpoint blockers strategy is feasible in pre-treated thymic carcinomas. • In this population, ICB achieve a RR of 18% and one-year OS of 67%. • Close monitoring of patients is strongly advised to detect severe immune-toxicity. [ABSTRACT FROM AUTHOR]

Thymic epithelial tumors (TETs) are rare diseases, with diverse clinical behaviour and prognosis. Intermittent dosing sunitinib represents the gold-standard systemic treatment following platinum-based chemotherapy. To ensure more homogeneous drug exposure, continuous daily dosing (CDD) sunitinib is utilised in other malignancies; however, no data exist in patients with TETs. We retrospectively examined data from patients with platinum-resistant TETs receiving CDD sunitinib 37.5 mg between 1 May 2017 and 31 May 2022 within the Italian collaborative group for ThYmic MalignanciEs. Primary end-points were median progression-free survival, overall response rate (ORR), median duration of response and major treatment-related adverse events. A total of 20 consecutive patients (12 thymic carcinoma [TC], 6 B3, and 2 B2 thymoma) were evaluated. Among the 19 patients evaluable for response, ORR was 31.6% (95% CI, 12.5%–56.5%). Among patients with TC, one complete response, four partial responses, and four stable diseases were observed (ORR 41%).The overall median progression-free survival was 7.3 months (95% CI, 4.5–10.3): 7.3 months (95% CI, 4.4–NA) within patients with thymoma and 6.8 months (95% CI, 2.8–10.3) in patients with TC; median duration of response was 10.3 months (95% CI, 2.8–NA). CDD was associated with a manageable toxicity profile. Six patients (30%) experienced >G2 toxicity, nine required dose reduction and three discontinued treatment due to adverse events. CDD sunitinib showed a relevant antitumor activity and confirmed a good toxicity profile. Similar effectiveness and a better toxicity profile as compared with intermittent dosing historical data suggest that this schedule should be considered. • Intermittent sunitinib is used in platinum-refractory thymic epithelial tumours. • Continuous daily dose (CDD) sunitinib is used other cancers; no data exist in thymic epithelial tumours. • We retrospectively analysed data from patients receiving off-label CDD sunitinib. • CDD sunitinib schedule showed clinical efficacy and a favourable toxicity profile. [ABSTRACT FROM AUTHOR]

International guidelines recommend severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine for patients with cancer. A substantial risk of developing vaccine-related autoimmune toxicities could be hypothesised for patients with thymic epithelial tumours (TETs) due to their high risk of autoimmune disorders (ADs). Moreover, a cross-reaction between SARS-CoV-2 spike protein antibodies and various tissue proteins has been shown, and antibodies against nucleoproteins showed overlaps in the autoimmune cross-reaction with antibodies to spike protein. Due to the rarity of TETs, no data addressing this hypothesis are available. Patients with TETs who received SARS-CoV-2 vaccine, treated in 4 referral centres of the Italian Collaborative Group for ThYmic MalignanciEs (TYME) network between February 2021 and September 2021, were interviewed through a standardised 15-items questionnaire in order to describe the safety of SARS-CoV-2 vaccine in patients affected by TETs. Data from 245 doses of vaccine administered to 126 patients (41 = thymic carcinoma, 85 = thymoma; 38 with AD, of which 26 with active AD) were collected. Nine patients had a previous COVID-19-positive swab. No cases of AD reactivation or worsening of a pre-existing AD were seen in the study population. A new diagnosis of myasthenia gravis likely unrelated to the vaccine was made in two patients after the vaccination. Sixty-four patients (51%) experienced a total of 103 adverse events, all G1/G2, most commonly fatigue, new or worsening muscle pain and chills. None AE required patients' hospitalisation. SARS-CoV-2 mRNA vaccines appear to be safe in patients with TET, even in case of active or pre-existing AD. • Thymic epithelial tumours (TETs) induce higher risk for autoimmune diseases. • Evidence on safety profile of COVID vaccines in TET patients is limited. • Our data suggest that safety profile for TET patients is similar to general population. • COVID-19 vaccination is safe and strongly recommended in patients affected by TET. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with a survival rate of less than 7%, mainly due to the hepatic metastatic spread. Despite the importance of understanding PDAC metastases, central questions remain concerning their biology and chemosensitivity. Moreover, the transcriptomic divergence between primary tumor (PT) and hepatic metastases (HM) has been poorly studied and without a clear dissection of the confounding tumoral-surrounding tissue. Here, to unravel key biological features not biased by the surrounding tissue, we implemented a blind source separation based on independent component analysis, ProDenICA, on a treatment-naïve cohort of PDAC paired samples and a cohort of 305 resectable patients. In addition, a time-lapse experiment was performed to assess the gemcitabine chemosensitivity profile between the PT and HM. We identified HM's specific transcriptomic characteristics related to the upregulation of cell cycle checkpoint, mitochondria activity, and extracellular matrix reorganization, which could be associated with metastatic niche adaptation mechanisms. Furthermore, squamous lineage emerged as a key feature linked with a downregulation in the epithelial-to-mesenchymal program that can stratifies PDAC HM independent of the classical/basal-like spectrum. Remarkably, we also demonstrated that gemcitabine response is influenced by the squamous profile, being the HM more refractory to the treatment than the PT. These results pointed out divergent HM aspects compared to PT and allowed their stratification through the squamous lineage. Moreover, we unravel a clinical actionable squamous signature that predicts the gemcitabine response. • The squamous lineage has been related to a high aggressiveness and poor prognosis. • Squamousness stratifies PDAC independent of classical/basal-like phenotype. • Hepatic metastases displayed a higher squamous profile than the primary tumor. • The squamousness level predicts patients' adjuvant gemcitabine response. [ABSTRACT FROM AUTHOR]

Despite the extensive use of the combination of cytotoxic chemotherapy and programmed cell death protein 1/programmed death-ligand 1 checkpoint inhibitors for cancer treatment, the incidence and characteristics of pneumonitis caused by this combination therapy have not been examined in clinical settings. We conducted a 36-centre, retrospective cohort study in patients with chemo-naïve advanced non-squamous non-small cell lung cancer who received a combination of platinum, pemetrexed and pembrolizumab between December 2018 and June 2019. The study comprised 299 patients. The most frequent grade ≥3 non-hematologic adverse event was pneumonitis. There were 37 patients (12.4%, 95% CI 8.9–16.7) with all-grade pneumonitis and 10 (3.3%, 95% CI 1.6–6.1) with grade ≥3 pneumonitis. Of these, 21 (7.0%, 95% CI 4.4–10.5) and 9 patients (3.0%, 95% CI 1.4–5.6) developed all-grade and grade ≥3 pneumonitis within 90 days after initiating the combination therapy, respectively. The median time to treatment failure and progression-free survival was 5.9 (95% CI 5.0–6.8) and 7.5 (95% CI 6.5–8.7) months, respectively. In the survival analysis after adjusting for immortal time bias, pneumonitis was independently associated with shorter progression-free survival (HR 1.99, 95% CI 1.07–3.69, P = 0.03) and overall survival (HR 3.03, 95% CI 1.12–8.20, P = 0.03). Treatment-related pneumonitis occurred at a higher rate in the real-world population than that reported previously; it led to worse survival outcomes. Pneumonitis requires more attention. Additional studies are required to improve the safety of this combination therapy. UMIN000038084 • Data on pembrolizumab plus chemotherapy-induced pneumonitis are limited. • We conducted a 36-centre, retrospective cohort study. • Treatment-related pneumonitis occurred at a higher rate in real-world settings. • After adjusting for immortal time bias, pneumonitis led to worse survival outcomes. • Our findings indicate that pneumonitis requires the careful attention of clinicians. [ABSTRACT FROM AUTHOR]

To study the association between hospital volume and outcomes in patients with invasive epithelial ovarian cancer (EOC). This study included 3988 patients diagnosed with invasive EOC between 2014 and 2018, selected from the population-based database of the Belgian Cancer Registry (BCR), and coupled with health insurance and vital status data. The associations between hospital volume and observed survival since diagnosis were assessed with Cox proportional hazard models, while volume associations with 30-day post-operative mortality and complicated recovery were evaluated using logistic regression models. Treatment for EOC was very dispersed with half of the 100 centres treating fewer than six patients per year. The median survival of patients treated in centres with the highest-volume quartile was 2.5 years longer than in those with the lowest-volume quartile (4.2 years versus 1.7 years). When taking the case-mix of hospitals into account, patients treated in the lowest volume centres had a 47% higher hazard to die than patients treated in the highest volume centres (HR: 1.47, 95% CI: 1.11–1.93, p = 0.006) over the first five years after incidence. A similar association was found when focussing on the surgical volume of the hospitals and considering only operated patients with invasive EOC. Lastly, the 30-day post-operative mortality decreased significantly with increasing surgical volume. The large dispersion of care and expertise within Belgium and the volume-outcome associations observed in this study support the implementation of the concentration of care for patients with invasive EOC in reference centres. • Treatment for invasive epithelial ovarian cancer was very dispersed in Belgium. • Median survival in high-volume centres was 2.5 year longer than in low-volume ones. • The 30-day post-operative mortality decreased with increasing surgical volume. • This study supports the concentration of care for patients with ovarian cancer. [ABSTRACT FROM AUTHOR]

Myoepithelial carcinoma occurs mainly in salivary glands but rarely can also occur in soft tissues or bone. In this paper, we evaluated the role of surgical margins, radiotherapy, and chemotherapy in myoepithelial carcinoma of soft tissue and bone (MC-SB) treated at our Institute. Medical records of 33 patients presenting with MC-SB between 1998 and 2015 at our institution were retrospectively analysed, and diagnosis and treatment were studied. The median follow-up was 58.5 months. Twenty patients had tumours originating in soft tissues and 13 in bone. Eight patients (24.2%) had metastases at diagnosis, the remaining 25 had localised disease. Thirty-two underwent resection of the primary lesion. In 29 surgical margins were evaluated: wide in 28 with 10/28 who recurred (35.7%) and marginal resection in 1 who also recurred. Six patients received adjuvant radiotherapy. Metastases developed in 15/25 patients (60%) with localised disease at onset. Chemotherapy was administered in patients with metastatic advanced disease. Cisplatin+doxorubicin was administered in six patients as first-line chemotherapy with an objective response in 5/6 patients with a median 4-month duration. Five-year overall survival rate was 62.6% in patients with localised tumours and 12.5% in those metastatic at diagnosis. MC-SB showed a high incidence of local recurrences and metastases. Despite different chemotherapy regimens, the outcome remains poor in patients with metastatic disease. Due to the absence of a standard protocol, we encourage treatment by multidisciplinary teams in referral centres with renowned expertise. • Being rare, reports on soft tissue and bone myoepithelial carcinoma are scarce. • Despite wide margins, local recurrences and metastases frequently occur. • Neoadjuvant or adjuvant radiotherapy should be considered in prospective studies. • Platinum-based agents, doxorubicin, paclitaxel are used in advanced disease. • Multidisciplinary treatment should be encouraged in selected referral centres. [ABSTRACT FROM AUTHOR]

Classification of thymic epithelial tumours (TETs) is known to be challenging; however, the level of discordances at a nationwide level between initial and expert diagnosis and their clinical consequences are currently unknown. RYTHMIC is a national network dedicated to the management of TET based on initial histological diagnosis, followed by an additional expert review of all cases. Our aim was to evaluate the discordances between initial and expert diagnoses and whether they would have led to different clinical management. We conducted a retrospective analysis of the cohort of patients discussed at RYTHMIC tumour board from January 2012 to December 2016. Assessment of disagreement was made for histological typing and for staging. The discordances were classified as major or minor based on whether they would have changed or not the proposed therapeutic strategy, respectively. Follow-up of the patients with major discordances was conducted until December 2018. Four hundred sixty-seven patients were reviewed, and 183 (39%) discordances were identified either related to histological subtype (132) and/or stage (72). Major discordances were identified in 27 patients (6%). They included 16 patients with TET for whom treatment recommendation based on the central review would have been post-operative radiotherapy, whereas it had not been the case. However, follow-up did not show any progression among the 15 patients with high-grade histology and/or stage resected thymomas. On the other hand, among the remaining 11 patients including 7 with a diagnosis other than TET, the overall management or follow-up would have been completely different with the expert diagnosis. Our real-life cohort reveals a high level of discordances considering TET diagnosis and supports expert review for optimal clinical management. • We analysed the impact of expert pathologic review of thymic epithelial tumours (TETs) in a nationwide network. • A cohort of 467 patients with TET was studied in a real-life setting. • We identified an overall discordance rate of 39% considering histotype and/or stage. • Change for post-operative radiotherapy or disease management involved 6% of patients. • Expert pathologic review of TET contributes to a better treatment decision-making. [ABSTRACT FROM AUTHOR]

Background In recurrent or metastatic (R/M) skin squamous cell cancer (sSCC) not amenable to radiotherapy (RT) or surgery, chemotherapy (CT) has a palliative intent and limited clinical responses. The role of oral pan-HER inhibitor dacomitinib in this setting was investigated within a clinical trial. Methods Patients with diagnosis of R/M sSCC were treated. Dacomitinib was started at a dose of 30 mg daily (QD) for 15 d, followed by 45 mg QD. Primary end-point was response rate (RR). Tumour samples were analysed through next-generation sequencing using a custom panel targeting 36 genes associated with sSCC. Results Forty-two patients (33 men; median age 77 years) were treated. Most (86%) received previous treatments consisting in surgery (86%), RT (50%) and CT (14%). RR was 28% (2% complete response; 26% partial response), disease control rate was 86%. Median progression-free survival and overall survival were 6 and 11 months, respectively. Most patients (93%) experienced at least one adverse event (AE): diarrhoea, skin rash (71% each), fatigue (36%) and mucositis (31%); AEs grade 3–4 occurred in 36% of pts. In 16% of cases, treatment was discontinued because of drug-related toxicity. TP53 , NOTCH1/2 , KMT2C/D , FAT1 and HER4 were the most frequently mutated genes. BRAF , NRAS and HRAS mutations were more frequent in non-responders, and KMT2C and CASP8 mutations were restricted to this subgroup. Conclusions In sSCC, dacomitinib showed activity similar to what was observed with anti–epidermal growth factor receptor agents, and durable clinical benefit was observed. Safety profile was comparable to previous experiences in other cancers. Molecular pt selection could improve therapeutic ratio. [ABSTRACT FROM AUTHOR]

Background This randomised phase III study was conducted to investigate the efficacy of extended nodal irradiation (ENI) and/or erlotinib in inoperable oesophageal squamous cell cancer (ESCC). Patients and methods Patients with histologically confirmed locally advanced ESCC or medically inoperable disease were randomly assigned (ratio 1:1:1:1) to one of four treatment groups: group A, radiotherapy adoption of ENI with two cycles of concurrent TP chemotherapy (paclitaxel 135 mg/m 2 day 1 and cisplatin 20 mg/m 2 days 1–3, every 4 weeks) plus erlotinib (150 mg per day during chemoradiotherapy); group B, radiotherapy adoption of ENI with two cycles of concurrent TP; group C, radiotherapy adoption of conventional field irradiation (CFI) with two cycles of concurrent TP plus erlotinib; group D, radiotherapy adoption of CFI with two cycles of concurrent TP. Results A total of 352 patients (88 assigned to each treatment group) were enrolled. The 2-year overall survival rates of group A, B, C and D were 57.8%, 49.9%, 44.9% and 38.7%, respectively ( P = 0.015). Group A significantly improved 2-year overall survival compared with group D. The ENI significantly improved overall survival in patients with inoperable ESCC ( P = 0.014). The addition of erlotinib significantly decreased loco-regional recurrence ( P = 0.042). Aside from rash and radiation oesophagitis, the incidence of grade 3 or greater toxicities did not differ among 4 groups. Conclusion Chemoradiotherapy with ENI and erlotinib might represent a substantial improvement on the standard of care for inoperable ESCC. ENI alone should be adopted in concurrent chemoradiotherapy for ESCC patients. [ABSTRACT FROM AUTHOR]

Introduction Therapeutic inhibition of the human epidermal receptor 3 (ERBB3, HER3) has been challenged by the low frequency of ERBB3 somatic alterations across cancer types. We have evaluated the clinical utility to use available inhibitors of the HER family in the context of ERBB3 mutations. Patients and methods In this study, we have selected patients with somatic ERBB3 alterations detected in their tumours from the molecular screening programs running at our institution. Techniques used for molecular screening were targeted next generation sequencing, comparative genomic hybridisation and/or whole exome sequencing on fresh frozen tumour biopsies. Results On the 844 patients with a molecular portrait of their tumours, 31 (3.7%) had a somatic mutation of ERBB3 . Overall, 9 patients received available inhibitors of HER family, including trastuzumab and/or lapatinib or afatinib. Sixteen patients received other molecularly targeted agents, including the Mammalian Target Of Rapamycin (mTOR), the Phosphatidylinositol-4,5-Bisphosphate 3-Kinase (PI3K) or NOTCH inhibitors or chemotherapy, and 4 patients failed being treated. Thirteen different histological subtypes were affected by ERBB3 mutations; top ones were colorectal carcinomas (6 patients), non-small cell lung cancers (4 patients, including a squamous cell carcinoma), head and neck squamous cell carcinomas (3 patients) and breast carcinomas (3 patients). The presence of a mutation in the tyrosine kinase domain of the ERBB3/HER3 protein detected in four patients' tumours was significantly related to good progression-free survival (hazard ratio [HR] = 0.18, p value = 0.022) and overall survival (HR = 0.19, p value = 0.03) in univariate analysis. Treatment of these four patients included at least a tyrosine kinase inhibitor lapatinib or afatinib. Conclusion Our exploratory analysis suggests that mutations in the tyrosine kinase domain of the HER3 protein are related to a favourable outcome under HER family inhibitors. [ABSTRACT FROM AUTHOR]

Despite the support for including patient-reported outcomes (PROs) and health-related quality of life in clinical trials, there have been deficiencies in how these have been assessed and reported in epithelial ovarian cancer (EOC) clinical trials. To redress this, the 5th Ovarian Cancer Consensus Conference, included a plenary session entitled ‘How to include PROs in clinical trials’. The perspective is a summary of the recommendations made by the Gynecologic Cancer InterGroup unanimously agreed on the importance of PROs and PRO end-points in EOC clinical trials. They recognised that effort must be made to ensure the integrity of collection of PRO data and to avoid missing data. PRO end-points should be based on the PRO hypotheses, be context specific and reflect the patient population and the objectives of treatment (e.g. first line, maintenance therapy, early or late relapse). The PRO end-points inform the choice of PRO measures used in the trial and how the results are analysed and reported. There was agreement that progression-free survival should be supported by PROs among patients with late relapse (platinum sensitive) and that progression-free survival alone was not sufficient as the primary end-point of clinical trials in patients with platinum resistant/refractory EOC and PROs should be included as either the primary/co-primary end-point in this subset of patients. Novel approaches to measure the benefit of palliative chemotherapy such as time until definitive deterioration of Health-Related Quality of Life were recommended. There was consensus to endorse the ISOQOL and CONSORT-PRO guidelines on the inclusion and reporting of PRO endpoints in protocols and that all future EOC Gynecologic Cancer InterGroup trials should adhere to these. [ABSTRACT FROM AUTHOR]

Increasingly, squamous cell carcinoma of the oropharynx (OPSCC) is attributable to transformation resulting from high-risk human papillomavirus (HPV) infection. Such cancers are significantly more responsive to treatment than traditional tobacco- and alcohol-associated squamous cell cancers of the head and neck. Conventional management with definitive chemoradiation, surgery and adjuvant radiation, or radiation given with altered fractionation schemes, while effective, incurs long-term morbidity that escalates with treatment intensity and significantly impairs quality of life. Recent trials have suggested that less intensive treatment regimens may achieve similar efficacy with decreased toxicity. In this article, we review the primary strategies used for de-escalation of treatment, which include the reduction of radiation dose, substitution and/or elimination of concurrent radiosensitising chemotherapy, and the use of minimally invasive surgery. We discuss the rationale behind these approaches and the preliminary data demonstrating the success of de-escalation, as well as potential considerations raised by treatment de-intensification in HPV-associated OPSCC. [ABSTRACT FROM AUTHOR]

Background We conducted a phase III, non-inferiority trial comparing upfront primary debulking surgery (PDS) and interval debulking surgery (IDS) following neoadjuvant chemotherapy (NAC) for stage III/IV ovarian, tubal, and peritoneal cancers (JCOG0602). Two earlier studies, EORTC55971 and CHORUS, demonstrated non-inferior survival of patients treated with NAC. However, they could not evaluate true treatment invasiveness because of adding diagnostic laparotomy or laparoscopy before treatment in over 30% of both arms of EORTC55971 and in 16% of NAC arm of CHORUS. Methods Patients were randomised into the standard arm (PDS followed by eight cycles of paclitaxel and carboplatin [TC]) and NAC arm (four cycles of TC, IDS, and four cycles of TC). In the standard arm, IDS was optional for patients who had undergone suboptimal or incomplete PDS. Treatment invasiveness was compared between arms (UMIN000000523). Results Between November 2006 and October 2011, 301 patients were randomised. In the standard arm, 147/149 underwent PDS and 49 underwent IDS. In the NAC arm, 130/152 underwent IDS. The NAC arm required fewer surgeries (mean 0.86 versus 1.32, p < 0.001) and shorter total operation time (median 273 min versus 341 min, p < 0.001) than the standard arm and required a lower frequency of abdominal organ resection (23.7% versus 37.6%, p = 0.012) or distant metastases resection (3.9% versus 10.7%, p = 0.027). In the NAC arm IDS, blood/ascites loss was smaller (median 787 ml versus 3235 ml, p < 0.001) and albumin transfusion and G3/4 adverse events after surgery in total were less frequent (26.2% versus 58.5%, p < 0.001; 4.6% versus 15.0%, p = 0.005, respectively). Conclusion Our findings demonstrated that NAC treatment is less invasive than standard treatment. NAC treatment may become the new standard treatment for advanced ovarian cancer when non-inferior survival is confirmed in the planned primary analysis in 2017. [ABSTRACT FROM AUTHOR]

Aim The aim of this study was to investigate if biomarkers of individual drug metabolism, respectively, the erlotinib/O-desmethyl-erlotinib metabolic ratio, may be a predictive factor for the severity of erlotinib-mediated skin rash in epidermal growth factor receptor (EGFR) inhibitor-treated patients suffering from epithelial cancers. This is especially important since it is known that the severity of skin rash has a prognostic value on outcome and survival in cancer patients experiencing skin rash under treatment with EGFR inhibitors. Methods From 2008 to 2014, 96 patients, n = 63 suffering from histologically confirmed non-small-cell lung cancer and n = 33 from pancreatic adenocarcinoma were observed for the occurrence and severity of skin rash after the onset of treatment with erlotinib. The primary end-points (occurrence and severity of skin rash, progression-free survival [PFS] and overall survival [OS]) were analysed with regard to erlotinib and its metabolite O-desmethyl-erlotinib trough serum concentrations measured at 4 weeks after onset of therapy by the use of correlation, multiple regression and survival analysis. Results Occurrence of skin rash was associated with PFS (p = 0.0042) and OS (p = 0.017) in the overall cohort of erlotinib-treated cancer patients. Drug-metabolising activity assessed by the erlotinib/O-desmethyl-erlotinib metabolic ratio was correlated with severity of skin rash (p = 0.023) and as well highly associated with both PFS (p = 2.1 × 10 −4 ) and OS (p = 5.8 × 10 −5 ). Conclusion The erlotinib/O-desmethyl-erlotinib metabolic ratio reflecting the individual metabolic activity of erlotinib correlated with the severity of skin rash and outcome in patients treated with EGFR tyrosine kinase inhibitors. The metabolic ratio determined in serum may be used for therapeutic monitoring in erlotinib treatment and decisions on individual dosing to rash in rash-negative patients. [ABSTRACT FROM AUTHOR]

Background: Primary malignant brain tumours are rare but represent a serious health burden due to their poor survival. This manuscript describes the survival of malignant brain tumours in adults diagnosed 2000-2007 in Europe. Methods: For this study we analysed patients archived in 86 European population-based cancer registries, followed up to 31st December 2008. Only primary malignant neuroepithelial brain tumours (with pathological confirmation) and primary malignant unspecified brain tumours without pathological confirmation were included. We estimated 1-year and 5-year relative survival (RS) weighted by age group and country. We also estimated country-specific and age-specific survival, together with survival differences between time periods (for 1999-2001, 2002-2004 and 2005-2007). Results: Glioblastoma represents 49% of all brain tumours, followed by other/unspecified astrocytoma (18%), oligodendroglioma/oligoastrocytoma (9%), ependymoma (1.5%) and embryonal tumours (1%). Five-year RS was 20% for all tumours combined, but ranged from 58% for ependymoma to only 6% for glioblastoma and sharply decreased with increasing age. Differences between countries were relatively small, but generally RS in Ireland/United Kingdom (UK) and Eastern Europe was below the average. An increase in 1-year RS (up to 10-12%) was noted over time, being largest in Central and Northern Europe in patients between 45 and 74 years of age. Conclusions: Despite an increase in 1-year RS in most European regions, the survival of primary malignant brain tumours is still poor. Disparities between countries were evident, being even larger at the end of the study period than at the beginning, suggesting differences in availability of the latest treatment modalities. [ABSTRACT FROM AUTHOR]

Cutaneous squamous cell carcinoma (cSCC) is one of the most common cancers in Caucasian populations, accounting for 20% of all cutaneous malignancies. A unique collaboration of multi-disciplinary experts from the European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO) and the European Organization of Research and Treatment of Cancer (EORTC) was formed to make recommendations on cSCC diagnosis and management, based on a critical review of the literature, existing guidelines and the expert’s experience. The diagnosis of cSCC is primarily based on clinical features. A biopsy or excision and histologic confirmation should be performed in all clinically suspicious lesions in order to facilitate the prognostic classification and correct management of cSCC. The first line treatment of cutaneous SCC is complete surgical excision with histopathological control of excision margins. The EDF–EADO–EORTC consensus group recommends a standardised minimal margin of 5 mm even for low-risk tumours. For tumours, with histological thickness of >6 mm or in tumours with high risk pathological features, e.g. high histological grade, subcutaneous invasion, perineural invasion, recurrent tumours and/or tumours at high risk locations an extended margin of 10 mm is recommended. As lymph node involvement by cSCC increases the risk of recurrence and mortality, a lymph node ultrasound is highly recommended, particularly in tumours with high-risk characteristics. In the case of clinical suspicion or positive findings upon imaging, a histologic confirmation should be sought either by fine needle aspiration or by open lymph node biopsy. In large infiltrating tumours with signs of involvement of underlying structures, additional imaging tests, such as CT or MRI imaging may be required to accurately assess the extent of the tumour and the presence of metastatic spread. Current staging systems for cSCC are not optimal, as they have been developed for head and neck tumours and lack extensive validation or adequate prognostic discrimination in certain stages with heterogeneous outcome measures. Sentinel lymph node biopsy has been used in patients with cSCC, but there is no conclusive evidence of its prognostic or therapeutic value. In the case of lymph node involvement by cSCC, the preferred treatment is a regional lymph node dissection. Radiation therapy represents a fair alternative to surgery in the non-surgical treatment of small cSCCs in low risk areas. It generally should be discussed either as a primary treatment for inoperable cSCC or in the adjuvant setting. Stage IV cSCC can be responsive to various chemotherapeutic agents; however, there is no standard regimen. EGFR inhibitors such as cetuximab or erlotinib, should be discussed as second line treatments after mono- or polychemotherapy failure and disease progression or within the framework of clinical trials. There is no standardised follow-up schedule for patients with cSCC. A close follow-up plan is recommended based on risk assessment of locoregional recurrences, metastatic spread or development of new lesions. [ABSTRACT FROM AUTHOR]

Background Genetic polymorphisms in the 3′ untranslated regions (3′ UTRs) targeted by miRNAs alter the strength of miRNA binding in a manner that affects the behaviour of individual miRNAs. An insertion (Ins)/deletion (Del) polymorphism (rs3783553) in the 3′ UTR of IL-1α may disrupt a binding site for miRNA-122. IL-1α plays an important role in inflammation, immunity and defense against infection. Thus, we hypothesised that the rs3783553 polymorphism affects individual susceptibility to human papillomavirus (HPV)-associated oral squamous cell carcinoma (OSCC). Methods We genotyped the rs3783553 polymorphism; and determined HPV16 L1 serology, tumour HPV16 DNA and serum IL-1α expression. Univariate/multivariable logistic regression models were used to calculate associations. Results We found that HPV16 L1 seropositivity alone was associated with an increased risk of OSCC (Odds ratio (OR), 3.1; 95% confidence interval (CI), 2.1–4.6), and the risk of HPV16-associated OSCC was modified by the rs3783553 polymorphism. Patients with both HPV16 L1 seropositivity and Del/Del genotype for the rs3783553 had the highest risk of OSCC when using patients with HPV16 L1 seronegativity and Ins/Del + Ins/Ins genotypes as a comparison group. Notably, that effect modification was particularly pronounced in several subgroups (e.g. SCCOP, never-smokers and never-drinkers). The patients with Del/Del genotype were approximately 3.0 times more likely to have HPV16-positive squamous cell carcinoma of the oropharynx (SCCOP) tumours compared to those patients with Ins/Del + Ins/Ins genotypes. Additionally, functional relevance of this variant was characterised to explore the genotype–phenotype correlation. Conclusion These results suggest that IL-1α 3′ UTR rs3783553 polymorphism may be functional and influence susceptibility to HPV16-associated OSCC, particularly for SCCOP. Validation of our findings is warranted. [ABSTRACT FROM AUTHOR]

Abstract: Epithelial ovarian cancer (EOC) in pregnancy is a rare situation. Due to its low incidence with a consecutive lack of clinical trials many questions regarding indication of different treatment approaches are unanswered. This article discusses the current literature to elaborate recommendations for the management of EOC during pregnancy. A literature search of diagnostic approaches and treatment strategies for EOC complicated by pregnancy was performed. We reviewed the available information with emphasis on surgery as well as chemotherapeutical treatment options. EOC in pregnancy is often diagnosed at early stage and no data support that concurrent pregnancy influences the growth rate or propensity for spread of EOC. Radical cytoreduction of all visible tumour followed by subsequent systemic chemotherapy is the standard treatment of EOC in most non-pregnant women. In pregnant women, however, chemotherapy as well as radical surgery should be avoided in the first trimester because of teratogenesis and high abortion rates. Besides induced abortion followed by classic management of EOC, pregnancy preserving surgery, followed by chemotherapy in the second or third trimester, timely delivery as well as neo-adjuvant chemotherapy with subsequent completing surgery appear to be viable treatment options. Conclusions: Since there is only very limited information regarding the optimal therapeutic approach to EOC during pregnancy, each case needs to be addressed individually. Treatment in specialised centres should be intended especially in this rare and challenging situation. [Copyright &y& Elsevier]

Abstract: Background and aims: Little is known about the epidemiology of rare epithelial digestive cancers. The aim of this study was to report on their incidence, prevalence and survival across Europe. Methods: The analysis was carried out on 50,646 cases diagnosed from 1995 to 2002 within a population of 162,000,000 in 21 European countries. Age-standardised incidence rates were computed using the European standard population. Prevalence rates, relative survival and period survival indicators for the years 2000–2002 were calculated. The expected number of new cases per year and of prevalent cases in Europe was estimated. Results: There were large variations in gallbladder epithelial cancer incidence rates: the incidence in Eastern Europe was 7 times higher than in the UK & Ireland. Differences between incidence rates were smaller for the other sites. The estimated number of new epithelial cancers arising in the EU each year was estimated to be 11,050 for extrahepatic bile duct cancer, 10,713 for gallbladder cancer, 5427 for anal cancer and 3595 for small intestine cancer. The corresponding estimated number of total prevalent cases was 18,483, 15,620, 40,589 and 13,276. There was also a large variation in the 5-year relative survival rate. For epithelial cancer of the anal canal, this varied between 66% (Central Europe) and 44% (Eastern Europe). The corresponding rates for small intestine cancers were 33% and 20%, for extrahepatic bile duct cancers, 17% and 12% and for gallbladder cancer 13% and 10%. Conclusion: There are large variations within Europe in the incidence and survival of rare digestive cancers according to geographic area. [Copyright &y& Elsevier]

Background: Emerging data have shown that miRNA are closely related to the occurrence and development of oesophageal squamous cell carcinoma (ESCC). However, the function and mechanism of miRNA in ESCC remain elusive. We investigated the role of a novel miRNA in the malignantly transformed immortalised human oesophageal epithelial cell line induced by TPA. Methods: SHEE cells (immortalised human oesophageal epithelial cell line) and SHEEC (malignantly transformed oesophageal carcinoma cell line) were cultured. Expression of miRNAs was examined using miRNA microarray chip technology. The most significant changed miRNAs from microarray were verified by using qRT-PCR. Cell growth, cell apoptosis, and cell colony growth ability of SHEEC cells was examined after the cells were transfected with siRNAs targeting miR-483-5P. Findings: We found that expression of miR-483-5P was high in SHEEC cells. Silencing of miR-483-5P expression in malignant transformed SHEEC cells led to inhibition of cell proliferation and colony formation, and increased apoptosis. Interpretation: These findings suggest that miR-483-5P acts as an oncogene in malignantly transformed SHEE cells induced by TPA. The identification of miRNA could provide new insight into the molecular mechanisms of chemical carcinogenesis. [ABSTRACT FROM AUTHOR]

Background: Epithelial ovarian cancer (EOC) mortality rates have remained unchanged in 30years. The most common EOC subtype, high-grade serous ovarian carcinoma (HG-SOC), can be divided into four subgroups on the basis of molecular characteristics. The C5 subgroup is defined by MYCN pathway activation and carries a poor prognosis. The commonly used EOC cell lines are poor models of HG-SOC, whereas patient-derived xenografts (PDX) retain pathological and immunohistochemical features of primary tumour, providing a valuable preclinical resource for therapeutic exploration. Methods: Fourteen "C5-like" HG-SOC PDX were generated from tumour tissue transplanted into NOD/SCIDIL2R&#947null mice. Three were from a consecutive cohort of HG-SOC PDX identified by qRT-PCR of the MYCN pathway and the rest from a separate cohort by gene expression analysis. Molecular analysis done included qRT-PCR for MYCN, HMGA2, LIN28B, and sequencing of DNA repair genes. In-vivo response to cisplatin (intraperitoneal on days 1, 8, and 18) is underway, because platinum response provides prognostic information. Tumour volume is measured twice weekly and mice with tumours larger than 0.7cm³ are euthanised. PDX are deemed sensitive if response is maintained for 100 or more days; resistant if they had stable disease or relapsed in less than 100days; and refractory if they progressed on treatment. Investigation of in vivo response to compounds targeting the MYCN pathway is underway and each response is considered in light of molecular phenotype. Findings: Preliminary data revealed six "C5-like" PDX overexpressed LIN28B and eight overexpressed MYCN. Three overexpressed CCNE1 (drug resistance marker) and three PDX harboured mutations in DNA repair genes (marker of platinum sensitivity). Two PDX were sensitive to cisplatin, two were resistant, four were refractory, and one showed mixed response. Interpretation: This cohort of "C5-like" HG-SOC PDX depicts molecular complexity and treatment response heterogeneity. Use of these molecularly annotated PDX to demonstrate novel effective therapies targeting the MYCN pathway will inform clinical trial design. [ABSTRACT FROM AUTHOR]