Trastuzumab and Pertuzumab in Patients with Non-Breast/Gastroesophageal HER2-Amplified Tumors: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol J.

PURPOSE: NCI-MATCH assigned patients with advanced cancer and progression on prior treatment, based on genomic alterations in pretreatment tumor tissue. Arm J (EAY131-J) evaluated the combination of trastuzumab/pertuzumab (HP) across HER2-amplified tumors. PATIENTS AND METHODS: Eligible patients had high levels of HER2 amplification [copy number (CN) ≥7] detected by central next-generation sequencing (NGS) or through NCI-designated laboratories. Patients with breast/gastroesophageal adenocarcinoma and those who received prior HER2-directed therapy were excluded. Enrollment of patients with colorectal cancer was capped at 4 based on emerging data. Patients received HP IV Q3 weeks until progression or unacceptable toxicity. Primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS) and overall survival (OS). RESULTS: Thirty-five patients were enrolled, with 25 included in the primary efficacy analysis (CN ≥7 confirmed by a central lab, median CN = 28). Median age was 66 (range, 31-80), and half of all patients had ≥3 prior therapies (range, 1-11). The confirmed ORR was 12% [3/25 partial responses (colorectal, cholangiocarcinoma, urothelial cancers), 90% confidence interval (CI) 3.4%-28.2%]. There was one additional partial response (urothelial cancer) in a patient with an unconfirmed ERBB2 copy number. Median PFS was 3.3 months (90% CI 2.0-4.1), and median OS 9.4 months (90% CI 5.0-18.9). Treatment-emergent adverse events were consistent with prior studies. There was no association between HER2 CN and response. CONCLUSIONS: HP was active in a selection of HER2-amplified tumors (non-breast/gastroesophageal) but did not meet the predefined efficacy benchmark. Additional strategies targeting HER2 and potential resistance pathways are warranted, especially in rare tumors.

A propensity score-matched analysis of laparoscopic versus open pancreaticoduodenectomy: Is there value to a laparoscopic approach?

BACKGROUND: Laparoscopic pancreaticoduodenectomy has been found safe and associated with advantages over open pancreaticoduodenectomy in prior studies. We compared outcomes of laparoscopic pancreaticoduodenectomy versus open pancreaticoduodenectomy at a single institution after applying technical aspects and perioperative care learned from laparoscopic pancreaticoduodenectomy to the open pancreaticoduodenectomy practice. METHODS: From January 2010 to December 2020, all patients undergoing pancreaticoduodenectomy were identified, and information was collected in a prospective fashion. Open pancreaticoduodenectomy (n = 347) and laparoscopic pancreaticoduodenectomy (n = 242) were performed using the same selection criteria, operative technique, and recovery protocols at a single institution. Propensity score matching was performed, and then perioperative data and 90-day outcomes were compared, and statistical analysis was performed. RESULTS: A total of 589 patients underwent pancreaticoduodenectomy, including open pancreaticoduodenectomy (n = 347) and laparoscopic pancreaticoduodenectomy (n = 242). After excluding those undergoing total pancreatectomy or major vascular or concomitant organ resection, there were 497 patients (open pancreaticoduodenectomy = 301 and laparoscopic pancreaticoduodenectomy = 196). Propensity score matching was performed, and 187 open pancreaticoduodenectomy patients were matched to 187 laparoscopic pancreaticoduodenectomy patients. Operative time (475 vs 280 minutes) was longer, and estimated blood loss (150 vs 212 mL) was less for laparoscopic pancreaticoduodenectomy than open pancreaticoduodenectomy, respectively. Pancreatic fistula (18.8% vs 5.4%) and delayed gastric emptying (18.8% vs 9.7%) were higher for laparoscopic pancreaticoduodenectomy than open pancreaticoduodenectomy, respectively. Postpancreatectomy hemorrhage, major morbidity, mortality, hospital stay, and readmissions were nonsignificantly higher for laparoscopic pancreaticoduodenectomy than open pancreaticoduodenectomy. Intensive care use and overall costs were significantly higher for laparoscopic pancreaticoduodenectomy than open pancreaticoduodenectomy. CONCLUSION: In our experience, open pancreaticoduodenectomy offers similar to improved outcomes over laparoscopic pancreaticoduodenectomy, with less use of perioperative resources, thereby offering better value to patients requiring pancreaticoduodenectomy.

Health Insurance Coverage-Is Broader Always Better?

This Viewpoint discusses the traditional goals of health insurance and contrasts those with the current needs of insurance beneficiaries.

Magnetic resonance imaging-derived relative cerebral blood volume characteristics in a case of pathologically confirmed neurocysticercosis: illustrative case.

BACKGROUND: Neurocysticercosis (NCC) is a parasitic infection of the brain caused by ingesting water or food contaminated with tapeworm eggs. When it presents as a solitary mass, differentiation from a primary brain tumor on imaging can be difficult. Magnetic resonance imaging (MRI)-derived relative cerebral blood volume (rCBV) is a newer imaging technique used to identify areas of neovascularization in tumors, which may advance the differential diagnosis. OBSERVATIONS: A 25-year-old male presented after a seizure. Computed tomography (CT) and MRI demonstrated a partially enhancing lesion with microcalcifications and vasogenic edema. Follow-up rCBV assessment demonstrated mild hyperperfusion and/or small vessels at the lesional margins consistent with either an intermediate grade glioma or infection. Given the radiological equipoise, surgical accessibility, and differential diagnosis including primary neoplasm, metastatic disease, NCC, and abscess, resection was pursued. The calcified mass was excised en bloc and was confirmed as larval-stage NCC. LESSONS: CT or MRI may not always provide sufficient information to distinguish NCC from brain tumors. Although reports have suggested that rCBV may aid in identifying NCC, here the authors describe a case of pathologically confirmed NCC in which preoperative, qualitative, standardized rCBV findings raised concern for a primary neoplasm. This case documents the first standardized rCBV values reported in a pathologically confirmed case of NCC in the United States.

Pharmacy Benefit Managers: History, Business Practices, Economics, and Policy.

Importance: Pharmacy benefit managers (PBMs) play a major role in the provision of pharmacy services by acting as intermediaries between pharmacies, plan sponsors (insurance companies and employers), pharmaceutical manufacturers, and drug wholesalers. As their role and visibility have increased, PBMs have come under increased scrutiny from policymakers. However, no prior literature has systematically described the history, business practices, and policymaking of PBMs. Objective: To provide an overview of the PBM industry, including its history, the evolution of services provided by PBMs, an assessment of the current policy landscape, and analysis of how proposed policies could affect PBM practices and patient care. Evidence: This work reviews historical events; previous and current industry practices and publications; prior academic literature, existing statutes, regulations, and court cases; and recent legislative reforms and agency actions regarding PBMs. Findings: Pharmacy benefit managers evolved in parallel with the pharmaceutical manufacturing and health insurance industries. The evolution of the PBM industry has been characterized by horizontal and vertical integration and market concentration. The PBM provides 5 key functions: formulary design, utilization management, price negotiation, pharmacy network formation, and mail order pharmacy services. Criticism of the PBM industry centers around the lack of competition, pricing, agency problems, and lack of transparency. Legislation to address these concerns has been introduced at the state and federal levels, but the potential for these policies to address concerns about PBMs is unknown and may be eclipsed by private sector responses. Conclusions and Relevance: Pharmacy benefit managers are intermediaries in the pharmaceutical supply chain and perform multiple roles in the management and distribution of pharmaceuticals to patients. When regulating PBMs, it is important to adopt policies that address market failure problems by improving PBM competition as opposed to policies designed to serve the narrow financial interests of other market participants (eg, pharmacies, pharmaceutical manufacturers) without meeting the needs of consumers.

Association of Past and Future Paid Medical Malpractice Claims.

Importance: Many physicians believe that most medical malpractice claims are random events. This study assessed the association of prior paid claims (including a single prior claim) with future paid claims; whether public disclosure of prior paid claims affects future paid claims; and whether the association of prior and future paid claims decayed over time. Objective: To examine the association of 1 or more prior paid medical malpractice claims with future paid claims. Design, Setting, and Participants: This study assessed the association between prior paid claims (including a single prior claim) with future claims; whether public disclosure of prior claims affects future paid claims; and whether the association of prior and future paid claims decayed over time. This retrospective case-control study included all 881 876 licensed physicians in the US. All data analysis took place between July, 2018 and January, 2023. Exposure: Paid medical malpractice claims. Main Outcome and Measures: Association between a prior paid medical malpractice claim and likelihood of a paid claim in a future period, compared with simulated results expected if paid claims are random events. Using the same outcomes, we also assessed whether public disclosure of paid claims affects future paid claim rates. Results: This study included all 881 876 physicians licensed to practice in the US at the time of the study. Overall, 3.3% of the 841 961 physicians with 0 paid claims in the prior period had 1 or more claims in the future period vs 12.4% of the 34 512 physicians with 1 paid claim in the prior period; 22.4% of the 4189 physicians with 2 paid claims in the prior period; and 37% of the 1214 physicians with 3 paid claims in the prior period. The association between prior claims and future claims was similar for high-medical-malpractice-risk and lower-risk specialties; 1 prior-period claim was associated with a 3.1 times higher likelihood of a future-period claim for high-risk specialties (95% CI, 2.8-3.4) vs a 4.2 times higher likelihood for lower-risk specialties (95% CI, 3.8-4.6). The predictive power of a prior paid claim for future claims declined gradually as the time since the prior claim increased, for prior or future periods up to 10 years. Public disclosure did not affect the association between prior and future paid claims. Conclusions and Relevance: In this study of paid medical malpractice claims for all US physicians, a single prior paid claim was associated with substantial, long-lived higher future claim risk, independent of whether a physician was practicing in a high- or low-risk specialty, or whether a state publicly disclosed paid claims. Timely, noncoercive intervention, including education, has the potential to reduce future claims.

Pancreaticoduodenectomy After Liver Transplantation: A Single-Center Experience.

BACKGROUND: The aim of this study is to report the feasibility and short-term outcomes of pancreaticoduodenectomy (PD) in patients who have undergone orthotopic liver transplantation (OLT). METHODS: We performed a retrospective review of a prospectively maintained pancreatic surgical database for all patients undergoing pancreaticoduodenectomy (PD) after liver transplant from January 1995 until June 2022. Demographics, indications for pancreatic resection, liver transplant and time from liver transplant to PD were reported. Operative mortality and morbidity were recorded within 90 days of surgery. Continuous variables were recorded as mean and range, while categorical variables were summarized using frequency and percentage. Postoperative complications within 90 days from PD were graded based on Clavien-Dindo classification with major complication recorded as grade IIIa or higher. Additionally, a comprehensive literature review was performed. RESULTS: A total of 916 patients who underwent PD at our institution between January 1995 and June 2022 were identified, and 9 patients had previous OLT. Five patients were females and 4 males with a mean age of 65 years (range 51-78). Average body mass index (BMI) was 30.8. Two patients had major complications, and three patients had minor complications. No clinically relevant POPF, PPH or DGE were observed. One patient died within 90 days from PD due to ischemic biliary pancreatic limb causing intrabdominal sepsis. CONCLUSION: Although uncommon, PD after OLT is feasible with acceptable outcomes at high volume institutions and if performed by experienced surgeons.

The Impact of Caprini Guideline Indicated Venous Thromboembolism Prophylaxis in Colorectal Surgery Patients: Experience of a Single Health System.

BACKGROUND: Venous thromboembolism (VTE) is the most common cause of preventable mortality following colorectal surgery (CRS), occurring in about 2% of patients. As a result, prophylaxis including discharge chemoprophylaxis is recommended. While VTE risk assessment tools are available, the consistent adoption and utilization of these tools remains elusive. Our study objectives were to determine the utilization and impact of risk adjusted VTE prophylaxis in CRS patients. STUDY DESIGN: CRS cases performed between 1/1/2016 and 5/31/2021 were retrospectively analyzed. Caprini score and implemented VTE prophylaxis measures were determined. The primary outcome measure was receiving Caprini guideline indicated VTE prophylaxis. Secondary outcomes included VTE and bleeding. Categorical variables were compared by chi-square and Fisher's exact tests, and continuous variables by Kruskal-Wallis test. Logistic regression models were used to determine predictors of receiving appropriate VTE prophylaxis or experiencing postoperative VTE and bleeding. RESULTS: 10,422 CRS cases were analyzed and 90.6% were high risk for VTE. In-hospital appropriate prophylaxis rates in low, moderate, high, and very high-risk category patients were 91.2%, 56.1%, 61.0%, and 63.1%, respectively. Inpatient VTE was reduced by 75% in those receiving appropriate VTE prophylaxis. At discharge, 5.8% of patients received appropriate prophylaxis, in whom there were no VTE events at 30- and 90 days from discharge. Increasing Caprini score positively correlated with VTE risk in both the inpatient and discharge cohorts, but inversely correlated with the likelihood of receiving appropriate prophylaxis at discharge (OR .31, P <.0001). CONCLUSION: Caprini guideline indicated VTE prophylaxis in CRS patients reduced VTE events without increasing bleeding complications.

Criminal Records and Licensure in Five Allied Health Professions: Is There Evidence of a Disparate Impact on Historically Marginalized Groups?

CONTEXT: In health care, licensing is pervasive. Restrictions on applicants with criminal records may have a disparate impact on historically marginalized groups. There is bipartisan interest in evaluating whether occupational licensing requirements are too strict. METHODS: The authors analyze how 12 representative states (California, Colorado, Connecticut, Delaware, Florida, Illinois, Missouri, New York, Ohio, Pennsylvania, South Dakota, and Texas) respond when people with criminal records apply for a license for five entry-level allied health professions (dental hygienist, occupational therapy assistant, physical therapy assistant, radiologic technologist, and respiratory therapist). FINDINGS: With one exception for one allied health profession, all states require their licensing boards to consider past serious criminal convictions. A majority of states require the conviction to be substantially related to the scope of professional duties for it to provide a basis for disqualification. Most states make it difficult for applicants with criminal records to determine whether they may obtain a license. CONCLUSIONS: State licensing boards have considerable discretion in handling applicants with a criminal record. The trend is toward fewer restrictions, but more could be done to increase the transparency of state licensing board guidelines, practices, and procedures-particularly in the states that still rely on a "good moral character" test.

Comparing Post-Operative Outcomes of Pancreaticoduodenectomy for Pancreatic Ductal Adenocarcinoma: Neoadjuvant Therapy Versus Surgery First Approach.

OBJECTIVES: Optimal use of surgery first (SF) vs neoadjuvant therapy (NAT) for localized pancreatic ductal adenocarcinoma (PDAC) is still unclear. There is concern that NAT may result in worsened post-operative outcomes. Our study objectives were to show the impact of NAT on post-operative morbidity and mortality. METHODS: All patients undergoing resection for PDAC between 1/1/2010 and 12/31/2020 were reviewed and those who underwent pancreaticoduodenectomy (PD) were included. Demographics, perioperative details, and pathology details were gathered. Data pertaining to 90-day complications were obtained and graded according to international consensus guidelines. Those undergoing SF were compared to those who had NAT. Categorical variables were compared by Fisher's exact test and continuous variables by Student's t-test. RESULTS: Two hundred and forty-one subjects who underwent PD for PDAC were included in this review. There was no significant difference in the rate of major morbidity between subjects who received NAT vs SF (19.4 vs 20.3%, P = 1.0). Similarly, there were no significant differences in the rates of mortality (3.1 vs 4.2%, P = .742), post-operative pancreatic fistula (8.2 vs 10.5%, P = .658), or post-pancreatectomy hemorrhage (7.1 vs 7.7%, P = 1.0), respectively. CONCLUSION: Post-operative outcomes are not worsened by the use of the NAT approach prior to PD for PDAC. Further investigation is needed to reveal which patient subgroups may benefit from the use of NAT, especially regarding survival.

AKT mutant allele-specific activation dictates pharmacologic sensitivities.

AKT- a key molecular regulator of PI-3K signaling pathway, is somatically mutated in diverse solid cancer types, and aberrant AKT activation promotes altered cancer cell growth, survival, and metabolism1-8. The most common of AKT mutations (AKT1 E17K) sensitizes affected solid tumors to AKT inhibitor therapy7,8. However, the pathway dependence and inhibitor sensitivity of the long tail of potentially activating mutations in AKT is poorly understood, limiting our ability to act clinically in prospectively characterized cancer patients. Here we show, through population-scale driver mutation discovery combined with functional, biological, and therapeutic studies that some but not all missense mutations activate downstream AKT effector pathways in a growth factor-independent manner and sensitize tumor cells to diverse AKT inhibitors. A distinct class of small in-frame duplications paralogous across AKT isoforms induce structural changes different than those of activating missense mutations, leading to a greater degree of membrane affinity, AKT activation, and cell proliferation as well as pathway dependence and hyper-sensitivity to ATP-competitive, but not allosteric AKT inhibitors. Assessing these mutations clinically, we conducted a phase II clinical trial testing the AKT inhibitor capivasertib (AZD5363) in patients with solid tumors harboring AKT alterations (NCT03310541). Twelve patients were enrolled, out of which six harbored AKT1-3 non-E17K mutations. The median progression free survival (PFS) of capivasertib therapy was 84 days (95% CI 50-not reached) with an objective response rate of 25% (n = 3 of 12) and clinical benefit rate of 42% (n = 5 of 12). Collectively, our data indicate that the degree and mechanism of activation of oncogenic AKT mutants vary, thereby dictating allele-specific pharmacological sensitivities to AKT inhibition.

The evolution of RET inhibitor resistance in RET-driven lung and thyroid cancers.

The efficacy of the highly selective RET inhibitor selpercatinib is now established in RET-driven cancers, and we sought to characterize the molecular determinants of response and resistance. We find that the pre-treatment genomic landscape does not shape the variability of treatment response except for rare instances of RAS-mediated primary resistance. By contrast, acquired selpercatinib resistance is driven by MAPK pathway reactivation by one of two distinct routes. In some patients, on- and off-target pathway reactivation via secondary RET solvent front mutations or MET amplifications are evident. In other patients, rare RET-wildtype tumor cell populations driven by an alternative mitogenic driver are selected for by treatment. Multiple distinct mechanisms are often observed in the same patient, suggesting polyclonal resistance may be common. Consequently, sequential RET-directed therapy may require combination treatment with inhibitors targeting alternative MAPK effectors, emphasizing the need for prospective characterization of selpercatinib-treated tumors at the time of monotherapy progression.

Natural History and Characteristics of ERBB2-mutated Hormone Receptor-positive Metastatic Breast Cancer: A Multi-institutional Retrospective Case-control Study from AACR Project GENIE.

PURPOSE: We wanted to determine the prognosis and the phenotypic characteristics of hormone receptor-positive advanced breast cancer tumors harboring an ERBB2 mutation in the absence of a HER2 amplification. EXPERIMENTAL DESIGN: We retrospectively collected information from the American Association of Cancer Research-Genomics Evidence Neoplasia Information Exchange registry database from patients with hormone receptor-positive, HER2-negative, ERBB2-mutated advanced breast cancer. Phenotypic and co-mutational features, as well as response to treatment and outcome were compared with matched control cases ERBB2 wild type. RESULTS: A total of 45 ERBB2-mutant cases were identified for 90 matched controls. The presence of an ERBB2 mutation was not associated with worse outcome determined by overall survival (OS) from first metastatic relapse. No significant differences were observed in phenotypic characteristics apart from higher lobular infiltrating subtype in the ERBB2-mutated group. ERBB2 mutation did not seem to have an impact in response to treatment or time-to-progression (TTP) to endocrine therapy compared with ERBB2 wild type. In the co-mutational analyses, CDH1 mutation was more frequent in the ERBB2-mutated group (FDR < 1). Although not significant, fewer co-occurring ESR1 mutations and more KRAS mutations were identified in the ERBB2-mutated group. CONCLUSIONS: ERBB2-activating mutation was not associated with a worse OS from time of first metastatic relapse, or differences in TTP on treatment as compared with a series of matched controls. Although not significant, differences in coexisting mutations (CDH1, ESR1, and KRAS) were noted between the ERBB2-mutated and the control group.

Mechanisms of Resistance to Noncovalent Bruton's Tyrosine Kinase Inhibitors.

BACKGROUND: Covalent (irreversible) Bruton's tyrosine kinase (BTK) inhibitors have transformed the treatment of multiple B-cell cancers, especially chronic lymphocytic leukemia (CLL). However, resistance can arise through multiple mechanisms, including acquired mutations in BTK at residue C481, the binding site of covalent BTK inhibitors. Noncovalent (reversible) BTK inhibitors overcome this mechanism and other sources of resistance, but the mechanisms of resistance to these therapies are currently not well understood. METHODS: We performed genomic analyses of pretreatment specimens as well as specimens obtained at the time of disease progression from patients with CLL who had been treated with the noncovalent BTK inhibitor pirtobrutinib. Structural modeling, BTK-binding assays, and cell-based assays were conducted to study mutations that confer resistance to noncovalent BTK inhibitors. RESULTS: Among 55 treated patients, we identified 9 patients with relapsed or refractory CLL and acquired mechanisms of genetic resistance to pirtobrutinib. We found mutations (V416L, A428D, M437R, T474I, and L528W) that were clustered in the kinase domain of BTK and that conferred resistance to both noncovalent BTK inhibitors and certain covalent BTK inhibitors. Mutations in BTK or phospholipase C gamma 2 (PLCγ2), a signaling molecule and downstream substrate of BTK, were found in all 9 patients. Transcriptional activation reflecting B-cell-receptor signaling persisted despite continued therapy with noncovalent BTK inhibitors. CONCLUSIONS: Resistance to noncovalent BTK inhibitors arose through on-target BTK mutations and downstream PLCγ2 mutations that allowed escape from BTK inhibition. A proportion of these mutations also conferred resistance across clinically approved covalent BTK inhibitors. These data suggested new mechanisms of genomic escape from established covalent and novel noncovalent BTK inhibitors. (Funded by the American Society of Hematology and others.).

Medication Adherence and Blood Pressure Control: A Scientific Statement From the American Heart Association.

The widespread treatment of hypertension and resultant improvement in blood pressure have been major contributors to the dramatic age-specific decline in heart disease and stroke. Despite this progress, a persistent gap remains between stated public health targets and achieved blood pressure control rates. Many factors may be important contributors to the gap between population hypertension control goals and currently observed control levels. Among them is the extent to which patients adhere to prescribed treatment. The goal of this scientific statement is to summarize the current state of knowledge of the contribution of medication nonadherence to the national prevalence of poor blood pressure control, methods for measuring medication adherence and their associated challenges, risk factors for antihypertensive medication nonadherence, and strategies for improving adherence to antihypertensive medications at both the individual and health system levels.

The context-specific role of germline pathogenicity in tumorigenesis.

Human cancers arise from environmental, heritable and somatic factors, but how these mechanisms interact in tumorigenesis is poorly understood. Studying 17,152 prospectively sequenced patients with cancer, we identified pathogenic germline variants in cancer predisposition genes, and assessed their zygosity and co-occurring somatic alterations in the concomitant tumors. Two major routes to tumorigenesis were apparent. In carriers of pathogenic germline variants in high-penetrance genes (5.1% overall), lineage-dependent patterns of biallelic inactivation led to tumors exhibiting mechanism-specific somatic phenotypes and fewer additional somatic oncogenic drivers. Nevertheless, 27% of cancers in these patients, and most tumors in patients with pathogenic germline variants in lower-penetrance genes, lacked particular hallmarks of tumorigenesis associated with the germline allele. The dependence of tumors on pathogenic germline variants is variable and often dictated by both penetrance and lineage, a finding with implications for clinical management.