Ovarian cancer cell line panel (OCCP): Clinical importance of in vitro morphological subtypes

Epithelial ovarian cancer is a highly heterogeneous disease and remains the most lethal gynaecological malignancy in the Western world. Therapeutic approaches need to account for inter-patient and intra-tumoural heterogeneity and detailed characterization of in vitro models representing the different histological a

International assessment and validation of the prognostic role of lymph node ratio in patients with resected pancreatic head ductal adenocarcinoma

Background: Lymph node ratio (LNR; positive/harvested lymph nodes) was identified as overall survival predictor in several cancers, including pancreatic adenocarcinoma. It remains unclear if LNR is predictive of overall survival in pancreatic adenocarcinoma patients staged pN2. This study assessed the prognostic overall survival role of LNR in pancreatic adenocarcinoma patients in relation with lymph node involvement.Methods: A retrospective international study in six different centers (Europe and United States) was performed. Pancreatic adenocarcinoma patients who underwent pancreatoduodenectomy from 2000 to 2017 were included. Patients with neoadjuvant treatment, metastases, R2 resections, or missing data regarding nodal status were excluded. Survival curves were calculated using Kaplan-Meier method and compared using log-rank test. Multivariable Cox regressions were performed to find independent overall survival predictors adjusted for potential confounders.Results: A total of 1,327 patients were included. Lymph node involvement (pN+) was found in 1,026 patients (77%), 561 pN1 (55%) and 465 pN2 (45%). Median LNR in pN+ patients was 0.214 (IQR: 0.105-0.364). On multivariable analysis, LNR was the strongest overall survival predictor in the entire cohort (HR 5.5, 95% CI: 3.1-9.9, P= 0.225 in the entire cohort and pN+ patients. Similar results were found in pN2 patients (worse overall survival when LNR >= 0.225).Conclusions: LNR appeared as an important prognostic factor in patients undergoing surgery for pancreatic adenocarcinoma and permitted to stratify overall survival in pN2 patients. LNR should be routinely used in complement to TNM stage to better predict patient prognosis.Surgical oncolog

TP53 mutated glioblastoma stem-like cell cultures are sensitive to dual mTORC1/2 inhibition while resistance in TP53 wild type cultures can be overcome by combined inhibition of mTORC1/2 and Bcl-2

Background: Glioblastoma is the most malignant tumor of the central nervous system and still lacks effective treatment. This study explores mutational biomarkers of 11 drugs targeting either the RTK/Ras/PI3K, the p53 or the Rb pathway using 25 patient-derived glioblastoma stem-like cell cultures (GSCs). Results: We found that TP53 mutated GSCs were approximately 3.5 fold more sensitive to dual inhibition of mammalian target of rapamycin complex 1 and 2 (mTORC1/2) compared to wild type GSCs. We identified that Bcl-2(Thr56/Ser70) phosphorylation contributed to the resistance of TP53 wild type GSCs against dual mTORC1/2 inhibition. The Bcl-2 inhibitor ABT-263 (navitoclax) increased sensitivity to the mTORC1/2 inhibitor AZD8055 in TP53 wild type GSCs, while sensitivity to AZD8055 in TP53 mutated GSCs remained unchanged. Conclusion: Our data suggest that Bcl-2 confers resistance to mTORC1/2 inhibitors in TP53 wild type GSCs and that combined inhibition of both mTORC1/2 and Bcl-2 is worthwhile to explore further in TP53 wild type glioblastomas, whereas in TP53 mutated glioblastomas dual mTORC1/2 inhibitors should be explored

European guideline on IgG4-related digestive disease – UEG and SGF evidence-based recommendations

The overall objective of these guidelines is to provide evidence-based recommendations for the diagnosis and management of immunoglobulin G4 (IgG4)-related digestive disease in adults and children. IgG4-related digestive disease can be diagnosed only with a comprehensive work-up that includes histology, organ morphology at imaging, serology, search for other organ involvement, and response to glucocorticoid treatment. Indications for treatment are symptomatic patients with obstructive jaundice, abdominal pain, posterior pancreatic pain, and involvement of extra-pancreatic digestive organs, including IgG4-related cholangitis. Treatment with glucocorticoids should be weight-based and initiated at a dose of 0.6–0.8 mg/kg body weight/day orally (typical starting dose 30-40 mg/day prednisone equivalent) for 1 month to induce remission and then be tapered within two additional months. Response to initial treatment should be assessed at week 2–4 with clinical, biochemical and morphological markers. Maintenance treatment with glucocorticoids should be considered in multi-organ disease or history of relapse. If there is no change in disease activity and burden within 3 months, the diagnosis should be reconsidered. If the disease relapsed during the 3 months of treatment, immunosuppressive drugs should be added

Clinical added value of MRI to CT in patients scheduled for local therapy of colorectal liver metastases (CAMINO):study protocol for an international multicentre prospective diagnostic accuracy study

Abstract Background Abdominal computed tomography (CT) is the standard imaging method for patients with suspected colorectal liver metastases (CRLM) in the diagnostic workup for surgery or thermal ablation. Diffusion-weighted and gadoxetic-acid-enhanced magnetic resonance imaging (MRI) of the liver is increasingly used to improve the detection rate and characterization of liver lesions. MRI is superior in detection and characterization of CRLM as compared to CT. However, it is unknown how MRI actually impacts patient management. The primary aim of the CAMINO study is to evaluate whether MRI has sufficient clinical added value to be routinely added to CT in the staging of CRLM. The secondary objective is to identify subgroups who benefit the most from additional MRI. Methods In this international multicentre prospective incremental diagnostic accuracy study, 298 patients with primary or recurrent CRLM scheduled for curative liver resection or thermal ablation based on CT staging will be enrolled from 17 centres across the Netherlands, Belgium, Norway, and Italy. All study participants will undergo CT and diffusion-weighted and gadoxetic-acid enhanced MRI prior to local therapy. The local multidisciplinary team will provide two local therapy plans: first, based on CT-staging and second, based on both CT and MRI. The primary outcome measure is the proportion of clinically significant CRLM (CS-CRLM) detected by MRI not visible on CT. CS-CRLM are defined as liver lesions leading to a change in local therapeutical management. If MRI detects new CRLM in segments which would have been resected in the original operative plan, these are not considered CS-CRLM. It is hypothesized that MRI will lead to the detection of CS-CRLM in ≥10% of patients which is considered the minimal clinically important difference. Furthermore, a prediction model will be developed using multivariable logistic regression modelling to evaluate the predictive value of patient, tumor and procedural variables on finding CS-CRLM on MRI. Discussion The CAMINO study will clarify the clinical added value of MRI to CT in patients with CRLM scheduled for local therapy. This study will provide the evidence required for the implementation of additional MRI in the routine work-up of patients with primary and recurrent CRLM for local therapy. Trial registration The CAMINO study was registered in the Netherlands National Trial Register under number NL8039 on September 20th 2019

Simultaneous resection of colorectal cancer and synchronous liver metastases: what determines the risk of unfavorable outcomes? An international multicenter retrospective cohort study

BACKGROUND: The use of a simultaneous resection (SIMR) in patients with synchronous colorectal liver metastases (sCRLM) has increased over the past decades. However, it remains unclear when a SIMR is beneficial and when it should be avoided. The aim of this retrospective cohort study was therefore to compare the outcomes of a SIMR for sCRLM in different settings, and to assess which factors are independently associated with unfavorable outcomes. METHODS: To perform this retrospective cohort study, patients with sCRLM undergoing SIMR (2004-2019) were extracted from an international multicenter database, and their outcomes were compared after stratification according to the type of liver and colorectal resection performed. Factors associated with unfavorable outcomes were identified through multivariable logistic regression. RESULTS: Overall, 766 patients were included, encompassing colorectal resections combined with a major liver resection (n=122), minor liver resection in the anterolateral (n=407), or posterosuperior segments ('Technically major', n=237). Minor and technically major resections, compared to major resections, were more often combined with a rectal resection (29.2 and 36.7 vs. 20.5%, respectively, both P=0.003) and performed fully laparoscopic (22.9 and 23.2 vs. 6.6%, respectively, both P = 0.003). Major and technically major resections, compared to minor resections, were more often associated with intraoperative transfusions (42.9 and 38.8 vs. 20%, respectively, both P = 0.003) and unfavorable incidents (9.6 and 9.8 vs. 3.3%, respectively, both P≤0.063). Major resections were associated, compared to minor and technically major resections, with a higher overall morbidity rate (64.8 vs. 50.4 and 49.4%, respectively, both P≤0.024) and a longer length of stay (12 vs. 10 days, both P≤0.042). American Society of Anesthesiologists grades ≥3 [adjusted odds ratio (aOR): 1.671, P=0.015] and undergoing a major liver resection (aOR: 1.788, P=0.047) were independently associated with an increased risk of severe morbidity, while undergoing a left-sided colectomy was associated with a decreased risk (aOR: 0.574, P=0.013). CONCLUSIONS: SIMR should primarily be reserved for sCRLM patients in whom a minor or technically major liver resection would suffice and those requiring a left-sided colectomy. These findings should be confirmed by randomized studies comparing SIMR with staged resections

Radiofrequency ablation and chemotherapy versus chemotherapy alone for locally advanced pancreatic cancer (PELICAN):study protocol for a randomized controlled trial

Contains fulltext : 239066.pdf (Publisher’s version ) (Open Access)BACKGROUND: Approximately 80% of patients with locally advanced pancreatic cancer (LAPC) are treated with chemotherapy, of whom approximately 10% undergo a resection. Cohort studies investigating local tumor ablation with radiofrequency ablation (RFA) have reported a promising overall survival of 26-34 months when given in a multimodal setting. However, randomized controlled trials (RCTs) investigating the effect of RFA in combination with chemotherapy in patients with LAPC are lacking. METHODS: The "Pancreatic Locally Advanced Unresectable Cancer Ablation" (PELICAN) trial is an international multicenter superiority RCT, initiated by the Dutch Pancreatic Cancer Group (DPCG). All patients with LAPC according to DPCG criteria, who start with FOLFIRINOX or (nab-paclitaxel/)gemcitabine, are screened for eligibility. Restaging is performed after completion of four cycles of FOLFIRINOX or two cycles of (nab-paclitaxel/)gemcitabine (i.e., 2 months of treatment), and the results are assessed within a nationwide online expert panel. Eligible patients with RECIST stable disease or objective response, in whom resection is not feasible, are randomized to RFA followed by chemotherapy or chemotherapy alone. In total, 228 patients will be included in 16 centers in The Netherlands and four other European centers. The primary endpoint is overall survival. Secondary endpoints include progression-free survival, RECIST response, CA 19.9 and CEA response, toxicity, quality of life, pain, costs, and immunomodulatory effects of RFA. DISCUSSION: The PELICAN RCT aims to assess whether the combination of chemotherapy and RFA improves the overall survival when compared to chemotherapy alone, in patients with LAPC with no progression of disease following 2 months of systemic treatment. TRIAL REGISTRATION: Dutch Trial Registry NL4997 . Registered on December 29, 2015. ClinicalTrials.gov NCT03690323 . Retrospectively registered on October 1, 2018

Implementation of contemporary chemotherapy for patients with metastatic pancreatic ductal adenocarcinoma: a population-based analysis

Background: Positive results of randomized trials led to the introduction of FOLFIRINOX in 2012 and gemcitabine with nab-paclitaxel in 2015 for patients with metastatic pancreatic ductal adenocarcinoma. It is unknown to which extent these new chemotherapeutic regimens have been implemented in clinical practice and what the impact has been on overall survival. Material and methods: Patients diagnosed with metastatic pancreatic ductal adenocarcinoma between 2007–2016 were included from the population-based Netherlands Cancer Registry. Multilevel logistic regression and Cox regression analyses, adjusting for patient, tumor, and hospital characteristics, were used to analyze variation of chemotherapy use. Results: In total, 8726 patients were included. The use of chemotherapy increased from 31% in 2007–2011 to 37% in 2012–2016 (p <.001). Variation in the use of any chemotherapy between centers decreased (adjusted range 2007–2011: 12–67%, 2012–2016: 20–54%) whereas overall survival increased from 5.6 months to 6.4 months (p <.001) for patients treated with chemotherapy. Use of FOLFIRINOX and gemcitabine with nab-paclitaxel varied widely in 2015–2016, but both showed a more favorable overall survival compared to gemcitabine monotherapy (median 8.0 vs. 7.0 vs. 3.8 months, respectively). In the period 2015–2016, FOLFIRINOX was used in 60%, gemcitabine with nab-paclitaxel in 9.7% and gemcitabine monotherapy in 25% of patients receiving chemotherapy. Conclusion: Nationwide variation in the use of chemotherapy decreased after the implementation of FOLFIRINOX and gemcitabine with nab-paclitaxel. Still a considerable proportion of patients receives gemcitabine monotherapy. Overall survival did improve, but not clinically relevant. These results emphasize the need for a structured implementation of new chemotherapeutic regimens