Severe hypersensitivity reactions to 2 immunotherapy agents in a patient with cutaneous squamous cell carcinoma.

Disclaimer: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.

miR-6883 downregulates HIF1α in colorectal and breast cancer cells.

Colorectal cancer (CRC) and breast cancer (BC) are deadly diseases that rank as the second and fourth leading causes of cancer-related deaths, respectively. We have previously shown that miR-6883 targets CDK4/6 and that palbociclib-mediated CDK4/6 inhibition destabilizes HIF1α. We hypothesize that miR-6883 downregulates HIF1α in CRC and BC cells.

Sexual Health in Women Affected by Gynecologic or Breast Cancer.

Sexual health problems are prevalent among women affected by gynecologic or breast cancer. It is important to understand the effects cancer treatment can have on sexual health and to have the tools necessary to identify and treat sexual health problems. This Clinical Expert Series discusses practical methods for routinely screening for sexual dysfunction and reviews sexual health treatment options for women affected by cancer.

Apoptotic cell death in disease-Current understanding of the NCCD 2023.

Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions.

GSK-3 inhibitor elraglusib enhances tumor-infiltrating immune cell activation in tumor biopsies and synergizes with anti-PD-L1 in a murine model of colorectal cancer.

Unlabelled: Inhibition of GSK-3 using small-molecule elraglusib has shown promising preclinical antitumor activity. Using in vitro systems, we found that elraglusib promotes immune cell-mediated tumor cell killing, enhances tumor cell pyroptosis, decreases tumor cell NF-κB-regulated survival protein expression, and increases immune cell effector molecule secretion. Using in vivo systems, we observed synergy between elraglusib and anti-PD-L1 in an immunocompetent murine model of colorectal cancer.

Temozolomide combined with ipilimumab plus nivolumab enhances T cell killing of MGMT-expressing, MSS colorectal cancer cells.

Colorectal cancer (CRC) is the third most frequently diagnosed cancer and third-deadliest cancer globally. Over 95% of patients with metastatic CRC have tumors that are microsatellite stable (MSS) and do not respond to immune checkpoint inhibitors (ICI). Results from the 2022 MAYA clinical trial suggest that the DNA-damaging agent temozolomide (TMZ), which is usually used to treat glioblastoma (GBM), sensitizes patients with MSS, MGMT-silenced CRC to ipilimumab + nivolumab ICI.

Immune Checkpoint Inhibitors for Gastrointestinal Malignancies: An Update.

Gastrointestinal (GI) malignancies are a heterogenous group of cancers with varying epidemiology, histology, disease course, prognosis and treatment options. Immune checkpoint inhibitors (ICIs) have changed the landscape of modern cancer treatment, though they have demonstrated survival benefit in other solid tumors more readily than in GI malignancies. This review article presents an overview of the landscape of ICI use in GI malignancies and highlights recent updates in this rapidly evolving field.

Clinical activity of 9-ING-41, a small molecule selective glycogen synthase kinase-3 beta (GSK-3β) inhibitor, in refractory adult T-Cell leukemia/lymphoma.

GSK-3β is a serine/threonine kinase implicated in tumorigenesis and chemotherapy resistance. GSK-3β blockade downregulates the NF-κB pathway, modulates immune cell PD-1 and tumor cell PD-L1 expression, and increases CD8 + T cell and NK cell function. We report a case of adult T-cell leukemia/lymphoma (ATLL) treated with 9-ING-41, a selective GSK-3β inhibitor in clinical development, who achieved a durable response.

miR-3132 upregulates surface TRAIL to induce apoptotic cell death in cancer cells.

TRAIL-based therapies are of significant clinical interest because of its unique ability to induce apoptosis in cancer cells while sparing normal and untransformed cells. This selective antitumor potential of the TRAIL pathway has been harnessed by development of therapeutics including recombinant (rh)TRAIL and TRAIL-receptor agonist antibodies such as mapatumumab and lexatumumab. While these TRAIL-based therapies have proven successful in preclinical studies and safe in early phase clinical trials, the limited serum half-life has been a hurdle for further clinical development.

Chemotherapy-induced cytokines and prognostic gene signatures vary across breast and colorectal cancer.

The mechanisms by which chemotherapeutic drugs mediate efficacy and toxicity in patients across cancers are not fully understood. A poorly understood aspect of the tumor cell response to chemotherapy is cytokine regulation. Some drug-induced cytokines promote the anti-cancer activity of the drugs, but others may promote proliferation, metastasis, and drug resistance.

Combination of ONC201 and TLY012 induces selective, synergistic apoptosis in vitro and significantly delays PDAC xenograft growth in vivo.

The five-year survival rate for pancreatic ductal adenocarcinoma (PDAC) has remained a dismal 9% for approximately 40 years with an urgent need for novel therapeutic interventions. ONC201 is the founding member of the imipridone class, comprised of orally bioavailable small molecules that have shown efficacy in multiple tumor types both in animal models and in Phase I/II clinical trials. ONC201 is a potent inducer of the tumor necrosis factor related apoptosis inducing ligand (TRAIL) pathway.

Antitumorigenic effect of combination treatment with ONC201 and TRAIL in endometrial cancer and .

ONC201 demonstrated promising activity in patients with advanced endometrial cancer in a Phase I clinical trial. ONC201 activates the integrated stress response (ISR) and upregulates TRAIL and its receptor DR5. We hypothesized ONC201 upregulation of DR5 could sensitize tumors to TRAIL and combination of ONC201 and TRAIL would lead to enhanced cell death in endometrial cancer models.

"Going Flat" After Mastectomy: Patient-Reported Outcomes by Online Survey.

Background: The Going Flat movement aims to increase awareness and acceptance of mastectomy alone as a viable option for patients. Little is known about motivations and satisfaction with surgical outcomes in this population.

Methods: An online survey was administered to 931 women who had a history of uni- or bilateral mastectomy for treatment of breast cancer or elevated breast cancer risk without current breast mound reconstruction.

TRAIL receptor agonists convert the response of breast cancer cells to ONC201 from anti-proliferative to apoptotic.

ONC201 was initially identified as an inducer of cell death through the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway. The compound is currently being tested in patients with hematological malignancies and solid tumors, including those of the breast. We investigated strategies to convert the response of breast cancers to ONC201 from anti-proliferative to apoptotic.

Digitizing clinical trials.

Clinical trials are a fundamental tool used to evaluate the efficacy and safety of new drugs and medical devices and other health system interventions. The traditional clinical trials system acts as a quality funnel for the development and implementation of new drugs, devices and health system interventions. The concept of a "digital clinical trial" involves leveraging digital technology to improve participant access, engagement, trial-related measurements, and/or interventions, enable concealed randomized intervention allocation, and has the potential to transform clinical trials and to lower their cost.

The current state of molecular testing in the treatment of patients with solid tumors, 2019.

The world of molecular profiling has undergone revolutionary changes over the last few years as knowledge, technology, and even standard clinical practice have evolved. Broad molecular profiling is now nearly essential for all patients with metastatic solid tumors. New agents have been approved based on molecular testing instead of tumor site of origin.