The paradox of cancer genes in non-malignant conditions: implications for precision medicine.

Next-generation sequencing has enabled patient selection for targeted drugs, some of which have shown remarkable efficacy in cancers that have the cognate molecular signatures. Intriguingly, rapidly emerging data indicate that altered genes representing oncogenic drivers can also be found in sporadic non-malignant conditions, some of which have negligible and/or low potential for transformation to cancer. For instance, activating KRAS mutations are discerned in endometriosis and in brain arteriovenous malformations, inactivating TP53 tumor suppressor mutations in rheumatoid arthritis synovium, and AKT, MAPK, and AMPK pathway gene alterations in the brains of Alzheimer's disease patients. Furthermore, these types of alterations may also characterize hereditary conditions that result in diverse disabilities and that are associated with a range of lifetime susceptibility to the development of cancer, varying from near universal to no elevated risk. Very recently, the repurposing of targeted cancer drugs for non-malignant conditions that are associated with these genomic alterations has yielded therapeutic successes. For instance, the phenotypic manifestations of CLOVES syndrome, which is characterized by tissue overgrowth and complex vascular anomalies that result from the activation of PIK3CA mutations, can be ameliorated by the PIK3CA inhibitor alpelisib, which was developed and approved for breast cancer. In this review, we discuss the profound implications of finding molecular alterations in non-malignant conditions that are indistinguishable from those driving cancers, with respect to our understanding of the genomic basis of medicine, the potential confounding effects in early cancer detection that relies on sensitive blood tests for oncogenic mutations, and the possibility of reverse repurposing drugs that are used in oncology in order to ameliorate non-malignant illnesses and/or to prevent the emergence of cancer

Remembering the forgotten child: the role of immune checkpoint inhibition in patients with human immunod eficiency virus and cancer.

Patients with human immunodeficiency virus (HIV) infection have a high risk of developing virally-mediated cancers. These tumors have several features that could make them vulnerable to immune checkpoint inhibitors (ICIs) including, but not limited to, increased expression of the CTLA-4 and PD-1 checkpoints on their CD4+ T cells. Even so, HIV-positive patients are generally excluded from immunotherapy cancer clinical trials due to safety concerns. Hence, only case series have been published regarding HIV-positive patients with cancer who received ICIs, but these reports of individuals with a variety of malignancies demonstrate that ICIs have significant activity, exceeding a 65% objective response rate in Kaposi sarcoma. Furthermore, high-grade immune toxicities occurred in fewer than 10% of treated patients. The existing data suggest that the underlying biologic mechanisms that mediate development of cancer in HIV-infected patients should render them susceptible to ICI treatment. Preliminary, albeit limited, clinical experience indicates that checkpoint blockade is both safe and efficacious in this setting. Additional clinical trials that include HIV-positive patients with cancer are urgently needed

Delegated Agency Authority to Address Chemicals of Emerging Concern: EPA’s Strategic Use of Emergency Powers to Address PFAS Air Pollution

PFAS are a class of chemicals that pose some of the most serious and multifaceted health and environmental threats of the past century. Manufactured since the 1940s, used in everyday products from non-stick cookware, to fire-fighting foams, to makeup and shaving cream, and found in even the most remote parts of the world, PFAS are ubiquitous. The most thoroughly-studied PFAS have demonstrable serious health effects that include reproductive and developmental dysfunctions, interference with the body’s hormonal and immune systems, suppression of vaccine responsiveness, and links to various types of cancers. In response to scientists’ identification of the multitude of health threats posed by exposure to PFAS, EPA has prioritized regulatory action to address those threats, announcing a whole-of-agency approach that relies on the exercise of its authority under a host of federal environmental statutes.Despite the serious health and environmental threats posed by airborne emissions of PFAS, however, EPA has taken little to no action under the Clean Air Act (CAA). The only CAA program EPA has identified to address airborne PFAS is the one that authorizes regulation of national emission standards for hazardous air pollutants. Other regulatory mechanisms, such as the adoption of standards of performance for new sources, may also be useful.This Article focuses on a third option, which EPA to date seems to have ignored, despite its accelerating use in other contexts—EPA’s authority under § 303 of the CAA to tackle imminent and substantial endangerment to public health, welfare, or the environment through issuance of administrative orders or the initiation of a civil suit seeking abatement of activities contributing to the endangerment. We argued that this overlooked mechanism has great potential to minimize PFAS-related exposure risks pending completion of the often lengthy processes needed to implement other regulatory programs. The fact that EPA has never used § 303 to target PFAS raises the possibility that litigants will challenge any attempt to do so by relying on the major questions doctrine (MQD). We demonstrate that such a challenge should fail both because the doctrine is inapplicable and EPA’s statutory authority to abate PFAS emissions under § 303 is clear even if the MQD does apply. Our analysis provides a template for rebutting attacks on federal agency regulatory efforts in other contexts based on the MQD

How Students at the University of Colorado at Boulder Dispose of User-disposed Contraceptives and Potential Implications for the Environment

With intersex fish becoming more prominent and causing population collapse, and improper disposal causing contraceptives to wind up on beaches and killing aquatic animals, it is imperative to mitigate improper contraceptive disposal and its implications. With the intention of determining reasons for the improper disposal of contraceptives, I wrote and published a survey collecting quantitative and qualitative measurements of contraceptive use and disposal. These included questions of contraceptives used in the past year, disposal methods, and percent of the time disposed in that method compared to other methods, and the respondent’s reasoning. The survey also measured contraceptive disposal education and pertinent factors to respondents regarding contraceptive choice. A total of 138 people responded to the survey with 18% actually or claiming they would improperly dispose. Through correlation analysis, I determined that there was no statistically significant correlation between improper disposal and age, sex, or attendance at the University of Colorado, Boulder. In response to why respondents dispose in their chosen method(s), most of the people who improperly disposed cited ease or convenience as reasons, but there were others who reported they did not know what else to do. Contraceptives that were packaged with disposal instructions tended to be correctly disposed of; for example: two of the three users of the contraceptive ring properly disposed citing the instructions as their reasoning. There are typically no disposal instructions on both condom and oral contraceptive packaging. This leads me to recommend two actions to decrease improper contraceptive disposal: increased exposure to disposal education, and clearly indicating the proper disposal for contraceptives on their packaging

Incomplete Resolution of Deep Vein Thromboses during Rivaroxaban Therapy.

We present the case of a patient with a deep vein thrombosis (DVT) who failed rivaroxaban therapy. Our patient initially presented with left lower extremity edema, erythema, and pain. He was subsequently started on rivaroxaban therapy for a combined treatment period of 12 months, during and after which he persisted to have evidence of a DVT. The patient's prescribed drug regimen was changed from rivaroxaban to warfarin, which demonstrated a rapid resolution of the DVTs as determined by ultrasound assessment of our patient's lower extremity veins. Rivaroxaban, a factor Xa inhibitor, is a well-known oral anticoagulant that is used for a variety of indications and has become a mainstay in the treatment of deep vein thrombosis. With the introduction and emergence of this medication in the clinic, postmarketing reports of efficacy or lack thereof are important to review. In conclusion, we anticipate that it is likely that there are other patients with DVTs who may not respond to rivaroxaban and for whom alternative anticoagulation therapies should be explored

Hyperprogression and Immune Checkpoint Inhibitors: Hype or Progress?

There are currently seven approved immune checkpoint inhibitors (ICIs) for the treatment of various cancers. These drugs are associated with profound, durable responses in a subset of patients with advanced cancers. Unfortunately, in addition to individuals whose tumors show resistance, there is a minority subgroup treated with ICIs who demonstrate a paradoxical acceleration in the rate of growth or their tumors-hyperprogressive disease. Hyperprogressive disease is associated with significantly worse outcomes in these patients. This phenomenon, though still a matter of dispute, has been recognized by multiple groups of investigators across the globe and in diverse types of cancers. There are not yet consensus standardized criteria for defining hyperprogressive disease, but most commonly time to treatment failure less than 2 months and an increase in pace of progression of at least twofold between pre-immunotherapy and on-treatment imaging has been used. In some patients, the change in rate of progression can be especially dramatic-up to 35- to 40-fold. MDM2 amplification and EGFR mutations have been suggested as genomic correlates of increased risk of hyperprogression, but these correlates require validation. The underlying mechanism for hyperprogression is not known but warrants urgent investigation