ABSTRACT
During the past decade, health technology assessment bodies have faced new challenges in establishing the benefits of new drugs for individuals and health-care systems. A topic of increasing importance to the field of oncology is the so-called agnostic regulatory approval of targeted therapies for cancer (independent of tumour location and histology) granted on the basis of basket trials. Basket trials in oncology offer the advantage of simultaneously evaluating treatments for multiple tumours, even rare cancers, in a single clinical trial. To address the novel challenges introduced by these trials, an interdisciplinary panel was convened on behalf of the Transparency Committee of the French National Authority for Health to clarify an approach designed to guarantee a transparent, reproducible, and fair assessment of histology-agnostic treatments for reimbursement by the French National Health Insurance Fund. The requirements of this approach include the need for randomisation, clinically relevant endpoints, appropriate correction for multiple significance testing, characterisation of subgroup heterogeneity, and validation of underlying biomarker assays. A prospectively designated external control is encouraged when the implementation of a direct comparison is deemed infeasible. We also underline the importance of recording outcomes from basket trials in a registry for use as future external controls.
Subject(s)
Antineoplastic Agents/therapeutic use , Clinical Trials as Topic , Neoplasms/drug therapy , Research Design , Technology Assessment, Biomedical , Antineoplastic Agents/adverse effects , France , Government Agencies , Humans , Molecular Targeted Therapy , Neoplasms/genetics , Neoplasms/pathology , Treatment OutcomeSubject(s)
Antipsychotic Agents/adverse effects , Constipation/prevention & control , Laxatives/therapeutic use , Polyethylene Glycols/therapeutic use , Surface-Active Agents/therapeutic use , Administration, Rectal , Clopenthixol/adverse effects , Clozapine/adverse effects , Constipation/chemically induced , Constipation/drug therapy , Constipation/physiopathology , Drug Administration Schedule , Drug Monitoring , Drug Therapy, Combination/adverse effects , Humans , Intensive Care Units , Laxatives/administration & dosage , Laxatives/adverse effects , Methotrimeprazine/adverse effects , Plant Gums/administration & dosage , Plant Gums/adverse effects , Plant Gums/therapeutic use , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/adverse effects , Severity of Illness Index , Sterculia/chemistry , Surface-Active Agents/administration & dosage , Surface-Active Agents/adverse effectsSubject(s)
Choice Behavior , Colonoscopy/methods , Adolescent , Adult , Aged , Aged, 80 and over , Anesthesia, General , Feasibility Studies , Female , Humans , Male , Middle Aged , Patient Satisfaction , Retrospective StudiesABSTRACT
We report 3 new cases of Mitochondrial-Neuro-Gastro-Intestinal Encephalomyopathy (MNGIE) (or Pseudo-Obstruction-Leukoencephalopathy-Intestinal-Pseudoobstruction Syndrome [POLIP]), a rare disease that associates chronic intestinal pseudo-obstruction (CIPO) and neurological symptoms. A review of the 72 reported cases together with these 3 cases revealed that this condition was associated with (a) a specific cluster of neurological symptoms including leukoencephalopathy (96%), polyneuropathy (96%), ophthalmoplegia (91%) and hearing loss (55%); (b) a CIPO syndrome with the presence of small bowel diverticulae (53%); and (c) mitochondrial cytopathy in 36 of the 37 tested patients (2 of our 3 cases), and thymidine phosphorylase gene mutations in all the 37 tested patients (2 of our cases). The etiology of POLIP/MNGIE syndrome appears therefore to be due to a mitochondrial cytopathy secondary to thymidine phosphorylase gene mutation(s). In 3 cases, including 2 of our 3 patients, mitochondrial abnormalities were evidenced at the ultrastructural level in digestive smooth muscle demonstrating that the pathogenesis of gastrointestinal involvement was directly related to mitochondrial alterations in digestive smooth muscle cells.
Subject(s)
Intestinal Mucosa/metabolism , Intestinal Pseudo-Obstruction/metabolism , Mitochondria/metabolism , Mitochondrial Encephalomyopathies/metabolism , Muscle, Smooth/metabolism , Adult , Female , Humans , Intestinal Pseudo-Obstruction/diagnosis , Intestines/pathology , Male , Mitochondrial Encephalomyopathies/diagnosis , Mitochondrial Encephalomyopathies/genetics , Muscle, Smooth/pathology , Mutation , Thymidine Phosphorylase/geneticsABSTRACT
We report two cases of spontaneous regression of hepatocellular carcinoma. Firstly, a 64-year-old man with alcohol related cirrhosis developed multiple liver tumours with elevation of the alpha-fetoprotein level at 915 ng/ml. A spontaneous regression of all the tumoural masses but one and normalization of the alpha-fetoprotein level was observed after intraperitoneal spread of the malignancy. Resection of the remaining tumour 9 months later confirmed a hepatocellular carcinoma. Secondly, a 70-year-old woman with alcohol related cirrhosis developed multiple liver tumours with elevation of the alpha-fetoprotein level to 4000 ng/ml; a regression of all the tumoural masses but one and a decrease of the alpha-fetoprotein level to 400 ng/ml was observed after intraperitoneal spread of the malignancy and treatment with tamoxifen. We discuss a possible immune mechanism of tumoural regression with a review of similar cases described in the literature.
