Platinum Sensitivity in IDH1/2 Mutated Intrahepatic Cholangiocarcinoma: Not All "BRCAness" Is Created Equal.

Preclinical data suggest that IDH1/2 mutations result in defective homologous recombination repair (HRR). We hypothesized that patients with IDH1/2mt intrahepatic cholangiocarcinoma (IHCC) would benefit more from 1 L platinum chemotherapy than patients with wildtype (WT) tumors. We performed a multicenter retrospective study of 81 patients with unresectable IHCC treated with 1 L platinum with a primary endpoint of clinical benefit rate (CBR). Patients with IDH1/2mt tumors had a similar CBR and objective response rate compared to those with IDH WT disease (59 versus 54%; p = 0.803), suggesting that a relationship between platinum sensitivity and HRR gene defects may be specific to tumor context.

PD-L1 as a biomarker of response to immune-checkpoint inhibitors.

Immune-checkpoint inhibitors targeting PD-1 or PD-L1 have already substantially improved the outcomes of patients with many types of cancer, although only 20-40% of patients derive benefit from these new therapies. PD-L1, quantified using immunohistochemistry assays, is currently the most widely validated, used and accepted biomarker to guide the selection of patients to receive anti-PD-1 or anti-PD-L1 antibodies. However, many challenges remain in the clinical use of these assays, including the necessity of using different companion diagnostic assays for specific agents, high levels of inter-assay variability in terms of both performance and cut-off points, and a lack of prospective comparisons of how PD-L1+ disease diagnosed using each assay relates to clinical outcomes. In this Review, we describe the current role of PD-L1 immunohistochemistry assays used to inform the selection of patients to receive anti-PD-1 or anti-PD-L1 antibodies, we discuss the various technical and clinical challenges associated with these assays, including regulatory issues, and we provide some perspective on how to optimize PD-L1 as a selection biomarker for the future treatment of patients with solid tumours.

Predictive Biomarkers for Immune Checkpoint Inhibitors in Advanced Non-Small Cell Lung Cancer: Current Status and Future Directions.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment paradigm for advanced non-small cell lung cancer (NSCLC). Although certain patients achieve significant, long-lasting responses from checkpoint blockade, the majority of patients with NSCLC do not and may be unnecessarily exposed to inadequate therapies and immune-related toxicities. Therefore, there is a critical need to identify biomarkers predictive of immunotherapy response. While tumor and immune cell expression of programmed death ligand-1 and, more recently, tumor mutational burden are used in clinical practice and may correlate with immunotherapy response in selected circumstances, neither consistently predicts an individual patient's likelihood of clinical benefit from ICI therapy. More recently, innovative approaches such as blood-based assays and combination biomarker strategies are under active investigation. This review will focus on the current role and challenges of programmed death ligand-1 and tumor mutational burden as predictive biomarkers for immunotherapy response in advanced NSCLC and explore promising novel biomarker strategies.

Residential Treatment and the Invention of the Emotionally Disturbed Child in Twentieth-Century America.

In the 1930s, children who were violent, depressed, psychotic, or suicidal would likely have been labeled delinquent and sent to a custodial training school for punitive treatment. But starting in the 1940s, a new group of institutions embarked on a new experiment to salvage and treat severely deviant children. In the process, psychiatrists, psychologists, and social workers at these residential treatment centers (RTCs) made visible, and indeed invented, a new patient population. This article uses medical literature, popular media, and archival sources from several RTCs to argue that staff members created what they called the "emotionally disturbed" child. While historians have described the identification of the mildly "troublesome" child in child guidance clinics, I demonstrate how a much more severely ill child was identified and defined in the process of creating residential treatment and child mental health as a professional enterprise.

An alarming solution: Bedwetting, medicine, and behavioral conditioning in mid-twentieth-century America.

This article explores the history of the bedwetting alarm, invented in 1938 by two psychologists to cure enuresis, or bedwetting, using the principles of classical conditioning. Infused with the optimism of behaviorism, the bedwetting alarm unexpectedly proved difficult to implement in practice, bearing a multitude of unanticipated complications that hindered its widespread acceptance. Introduced as a medical and psychological technology, in practice the alarm was also a child-rearing device, encouraging the kind of behavioristic attitudes that had prompted its initial development, while simultaneously promoting the child-centered approach that would become dominant in the early 1950s. The life story of the bedwetting alarm muddies the traditional account of how childrearing theories progressed in tidy succession, suggesting both that behavioristic approaches did not die out in the 1930s and that elements of permissive child-rearing were being considered earlier than we traditionally assume.

Performing a cure for schizophrenia: insulin coma therapy on the wards.

Most historians of psychiatry regard insulin coma therapy (ICT) either as an embarrassing stumble on the path to modern biological psychiatry or as one member of a long line of somatic therapies used to treat mental illness in the mid-twentieth century. This article explores the ICT era, roughly 1933-60, as a key moment in the development of American psychiatry. Developed only ten years after insulin had been embraced as a "miracle drug" for the treatment of diabetes, ICT was perceived by psychiatrists as a means of bringing their field closer to mainstream medicine, particularly to neurology. In addition, the story of ICT reveals how a treatment never quite proven on paper was unquestionably efficacious in the local world in which it was performed. An institutionally-based treatment, ICT was administered in a specific area of the mental hospital deemed the insulin unit, a room with its own staff, practices, and attitudes toward mental illness. There, psychiatrists often experienced wondrous recoveries of individual, formerly intractable patients. These intense personal experiences allowed psychiatrists to feel truly efficacious, enabling them to reinvent themselves as medical doctors rather than behavioral and disciplinary supervisors. The confidence they derived from this capacity, along with the operating room-like setting of the insulin unit, the unit's specialized staffing and group bond, and the availability of both risk-assessment tests and a medley of treatments that countered side effects and complications, allowed ICT to be understood as an efficacious treatment for schizophrenia within the local world in which it was administered.