Image-guided Adaptive Radiotherapy in Cervical Cancer.

This paper reviews the conceptual, methodological, and technical innovations underpinning strategies for adaptive target volume selection and risk-adapted dose prescription in cervical cancer. An adaptive target volume concept has been developed which reflects tumor shrinkage at the end of initial chemo-radiation, which serves for an image-guided boost delivered through brachytherapy, with a risk-adapted dose prescription to different gross tumor- and clinical target volumes defined at diagnosis and after 40-50Gy external beam radiotherapy, and adaptation of the treatment technique according to the topography of the tumor after response and adjacent organs at risk. Clinical results of these innovations are presented based on prospective and retrospective multi-center trials (IntErnational study on MRI-based BRachytherapy in locally Advanced CErvical cancer [EMBRACE], retroEMBRACE) with large patient cohorts (n = 1416, n = 731).

Patient-reported outcomes in patients with resected, high-risk melanoma with BRAF or BRAF mutations treated with adjuvant dabrafenib plus trametinib (COMBI-AD): a randomised, placebo-controlled, phase 3 trial.

Background: In the phase 3 COMBI-AD study, patients with resected, stage III melanoma with BRAF or BRAF mutations received adjuvant dabrafenib plus trametinib or placebo. The primary analysis showed that dabrafenib plus trametinib significantly improved relapse-free survival at 3 years. These results led to US Food and Drug Administration approval of dabrafenib plus trametinib as adjuvant treatment for patients with resected stage III melanoma with BRAF or BRAF mutations.

Pharmacogenetics implementation in the clinics: information and guidelines for germline variants.

The aim of this work was to supply an overview of the germline Pharmacogenetics that can be already implemented in the oncology clinical practice. An explanation of the three pillars considered necessary for determining which genetic polymorphisms should be used has been provided. These are PharmGKB single nucleotide polymorphism (SNP)-Drug Clinical Annotations with levels of evidence 1 or 2; the genetic information provided in the drug labels by the drug regulatory main agencies (Food and Drug Administration and European Medicines Agency, mainly); and the guidelines elaborated by international expert consortia (mainly Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group).

[Diagnostic and treatment pitfalls and guidelines for variants of squamous cell carcinomas of the head and neck: on behalf of the REFCOR].

Among the 20,000 new cases of head and neck neoplasms in France each year, squamous cell carcinomas (HNSCC) represent about 90 % of the cases. Among these, variants of conventional squamous cell carcinomas represent between 5% and 10% of cases. Patient history and risk factors are often similar from those of conventional HSNCC.

ACCELERATE and European Medicine Agency Paediatric Strategy Forum for medicinal product development for mature B-cell malignancies in children.

Paediatric Strategy Forums have been created by the multistakeholder organisation, ACCELERATE, and the European Medicines Agency to facilitate dialogue between all relevant stakeholders and suggest strategies in critical areas of paediatric oncology drug development. As there are many medicines being developed for B-cell malignancies in adults but comparatively few in children with these malignancies, a Paediatric Strategy Forum was held to discuss the best approach to develop these products for children. It was concluded that as current frontline therapy is highly successful, despite associated acute toxicity, de-escalation of this or substitution of presently used drugs with new medicines can only be undertaken when there is an effective salvage regimen, which is currently not available.

The influence of obesity-related factors in the etiology of renal cell carcinoma-A mendelian randomization study.

Background: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation.

Radiotherapy for retroperitoneal liposarcoma: A report from the Transatlantic Retroperitoneal Sarcoma Working Group.

Background: The current study investigated the role of radiotherapy (RT) in patients with primary nonmetastatic retroperitoneal liposarcomas.

Methods: A total of 607 patients with localized retroperitoneal well-differentiated liposarcomas (WDLPS) and dedifferentiated liposarcomas (DDLPS) underwent surgical resection with or without RT at 8 high-volume sarcoma centers (234 patients with WDLPS, 242 patients with grade 1 to 2 DDLPS, and 131 patients with grade 3 DDLPS; grading was performed according to the National Federation of Centers for the Fight Against Cancer [Federation Nationale des Centres de Lutte Contre le Cancer; FNCLCC]). RT was administered in 19.

Iterative cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastases: A multi-institutional experience.

Background And Objectives: The aims of this multi-institutional study were to assess the feasibility of iterative cytoreductive surgery (iCRS)/hyperthermic intraperitoneal chemotherapy, iCRS in colorectal peritoneal carcinomatosis (CRPC), evaluate survival, recurrence, morbidity and mortality outcomes, and identify prognostic factors for overall survival.

Methods: Patients with CRPC that underwent an iCRS, with or without intraperitoneal chemotherapy, from June 1993 to July 2016 at 13 institutions were retrospectively analyzed from prospectively maintained databases.

Results: The study comprised of 231 patients, including 126 females (54.

Survival Outcomes in Patients With Previously Untreated BRAF Wild-Type Advanced Melanoma Treated With Nivolumab Therapy: Three-Year Follow-up of a Randomized Phase 3 Trial.

Importance: This analysis provides long-term follow-up in patients with BRAF wild-type advanced melanoma receiving first-line therapy based on anti-programmed cell death 1 receptor inhibitors.

Objective: To compare the 3-year survival with nivolumab vs that with dacarbazine in patients with previously untreated BRAF wild-type advanced melanoma.

Design, Setting, And Participants: This follow-up of a randomized phase 3 trial analyzed 3-year overall survival data from the randomized, controlled, double-blind CheckMate 066 phase 3 clinical trial.

Human CD4- invariant NKT lymphocytes regulate graft versus host disease.

Despite increasing evidence for a protective role of invariant (i) NKT cells in the control of graft-versus-host disease (GVHD), the mechanisms underpinning regulation of the allogeneic immune response in humans are not known. In this study, we evaluated the distinct effects of human expanded and flow-sorted human CD4 and CD4 iNKT subsets on human T cell activation in a pre-clinical humanized NSG mouse model of xenogeneic GVHD. We demonstrate that human CD4 but not CD4 iNKT cells could control xenogeneic GVHD, allowing significantly prolonged overall survival and reduced pathological GVHD scores without impairing human T cell engraftment.

Synthetically Lethal Interactions of ATM, ATR, and DNA-PKcs.

Synthetic lethality occurs when simultaneous perturbations of two genes or molecular processes result in a loss of cell viability. The number of known synthetically lethal interactions is growing steadily. We review here synthetically lethal interactions of ataxia-telangiectasia mutated (ATM), ATM- and Rad3-related (ATR), and DNA-dependent protein kinase catalytic subunit (DNA-PKcs).

Longer Follow-Up Confirms Relapse-Free Survival Benefit With Adjuvant Dabrafenib Plus Trametinib in Patients With Resected V600-Mutant Stage III Melanoma.

Purpose: Dabrafenib plus trametinib improved relapse-free survival (RFS) versus placebo (hazard ratio [HR], 0.47; < .001) in patients with resected V600-mutant stage III melanoma (BRF115532; COMBI-AD; ClinicalTrials.

Starting the fight in the tumor: expert recommendations for the development of human intratumoral immunotherapy (HIT-IT).

A European Society for Medical Oncology (ESMO)-sponsored expert meeting was held in Paris on 8 March 2018 which comprised 11 experts from academia, 11 experts from the pharmaceutical industry and 2 clinicians who were representatives of ESMO. The focus of the meeting was exclusively on the intratumoral injection/delivery of immunostimulatory agents with the aim of harmonizing the standard terms and methodologies used in the reporting of human intratumoral immunotherapy (HIT-IT) clinical trials to ensure quality assurance and avoid a blurring of the data reported from different studies. The goal was to provide a reference document, endorsed by the panel members that could provide guidance to clinical investigators, pharmaceutical companies, ethics committees, independent review boards, patient advocates and the regulatory authorities and promote an increase in the number and quality of HIT-IT clinical trials in the future.

The 'Survivorship Passport' for childhood cancer survivors.

Background: Currently, there are between 300,000 and 500,000 childhood cancer survivors (CCSs) in Europe. A significant proportion is at high risk, and at least 60% of them develop adverse health-related outcomes that can appear several years after treatment completion. Many survivors are unaware of their personal risk, and there seems to be a general lack of information among healthcare providers about pathophysiology and natural history of treatment-related complications.

Increased expression of the thyroid hormone nuclear receptor TRα1 characterizes intestinal tumors with high Wnt activity.

Our previous work demonstrated a key function of the thyroid hormone nuclear receptor TRα1, a T3-modulated transcription factor, in controlling intestinal development and homeostasis the Wnt and Notch pathways. Importantly, increased expression of TRα1 in the intestinal epithelium in a mutated genetic background (-TRα1/Apc mice) accelerated tumorigenesis and contributed to a more aggressive tumor phenotype compared to that of the mutants alone. Therefore, the aim of this study was to determine the relevance of this synergistic effect in human colorectal cancers and to gain insights into the mechanisms involved.

Serotonin uptake is required for Rac1 activation in Kras-induced acinar-to-ductal metaplasia in the pancreas.

Pancreatic ductal adenocarcinoma (PDAC), which is the primary cause of pancreatic cancer mortality, is poorly responsive to currently available interventions. Identifying new targets that drive PDAC formation and progression is critical for developing alternative therapeutic strategies to treat this lethal malignancy. Using genetic and pharmacological approaches, we investigated in vivo and in vitro whether uptake of the monoamine serotonin [5-hydroxytryptamine (5-HT)] is required for PDAC development.

Management and outcome of colorectal cancer during pregnancy: report of 41 cases.

Background: Colorectal cancer in pregnancy is rare, with an incidence of 0.8 per 100,000 pregnancies. Advanced disease (stage III or IV) is diagnosed more frequently in pregnant patients.

Transoral robotic-assisted supracricoid partial laryngectomy with cricohyoidoepiglottopexy: Procedure development and outcomes of initial cases.

Background: We report on the feasibility and functional outcome of transoral robotic (TORS) supracricoid partial laryngectomy (SCPL) with cricohyoidoepiglottopexy (CHEP).

Methods: Cadaveric studies and functional outcome at 3 years using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-H&N35), the Functional Outcome Swallowing Scale (FOSS), the Performance Status Scale for Head and Neck Cancer (PSS-HN), computerized voice analysis, and videotape recordings. Data were compared with a historical cohort of open CHEPs/cricohyoidopexies (CHPs).

Impact on testicular function of a single ablative activity of 3.7 GBq radioactive iodine for differentiated thyroid carcinoma.

Study Question: What are the consequences of radioactive iodine (RAI) therapy for testicular function?

Summary Answer: A single activity of 3.7 GBq RAI for differentiated thyroid carcinoma (DTC) treatment in young men transiently altered Sertoli cell function and induced sperm chromosomal abnormalities.

What Is Known Already: Few studies, mainly retrospective, have reported the potential impacts of RAI on endocrine and exocrine testicular function.

Combined HAT/EZH2 modulation leads to cancer-selective cell death.

Epigenetic alterations have been associated with both pathogenesis and progression of cancer. By screening of library compounds, we identified a novel hybrid epi-drug MC2884, a HAT/EZH2 inhibitor, able to induce cancer-selective cell death in both solid and hematological cancers , and xenograft models. Anticancer action was due to an epigenome modulation by H3K27me3, H3K27ac, H3K9/14ac decrease, and to caspase-dependent apoptosis induction.

Laser debulking or tracheotomy in airway management prior to total laryngectomy for T4a laryngeal cancer.

Purpose: Retrospective studies have shown that tracheotomy prior to total laryngectomy (TL) is associated with decreased survival. We sought to investigate whether this is due to higher local invasiveness associated with obstructive disease or whether it is the result of tracheotomy itself.

Methods: We reviewed patients with a T4a (AJCC 7th edition) laryngeal squamous-cell carcinoma treated with a primary TL followed by adjuvant radiotherapy between 2001 and 2013.