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J Randolph Hecht,1 Edith P Mitchell,2 Takayuki Yoshino,3 Manfred Welslau,4 Xun Lin,5 Edna Chow Maneval,6 Jolanda Paolini,7 Maria Jose Lechuga,7 Albrecht Kretzschmar8 1David Geffen School of Medicine at UCLA, Santa Monica, CA, 2Kimmel Cancer Center of Thomas Jefferson University, Philadelphia, PA, USA; 3National Cancer Center Hospital East, Chiba, Japan; 4Onkologische Praxis Klausmann/Welslau, Aschaffenburg, Germany; 5Pfizer Oncology, La Jolla, 6Seragon Pharmaceuticals, San Diego, CA, USA; 7Pfizer Oncology, Milan, Italy; 8Klinikum St Georg, Leipzig, Germany Background: Sunitinib is an oral inhibitor of tyrosine kinase receptors implicated in tumor proliferation, angiogenesis, and metastasis. In this randomized, multicenter, open-label Phase IIb study, sunitinib plus mFOLFOX6 (oxaliplatin plus leucovorin plus 5-fluorouracil) was compared with bevacizumab plus mFOLFOX6 as first-line therapy in patients with metastatic colorectal cancer. Methods: Patients were stratified by performance status, baseline lactate dehydrogenase level, and prior adjuvant treatment, and randomized 1:1 to receive sunitinib 37.5 mg/day for 4 weeks on and 2 weeks off plus mFOLFOX6 every 2 weeks or bevacizumab 5 mg/kg every 2 weeks plus mFOLFOX6 every 2 weeks. The primary endpoint was progression-free survival. Secondary endpoints included objective response rate, overall survival, safety, and quality of life. Results: Enrollment was closed early following accrual of 191 patients, based on an interim analysis showing an inferior trend in the primary progression-free survival efficacy endpoint for sunitinib. Ninety-six patients were randomized to sunitinib plus mFOLFOX6 and 95 to bevacizumab plus mFOLFOX6. Median progression-free survival was 9.3 months and 15.4 months, respectively, but the objective response rate was similar between the study arms. Median overall survival was 23.7 months and 34.1 months, respectively. Dose reductions and interruptions were more common with sunitinib. Hematologic toxicity was more common in the sunitinib arm. Conclusion: While the results of the sunitinib arm are comparable with those of previously reported FOLFOX combinations, the sunitinib-based combination was associated with more toxicity than that observed with bevacizumab and mFOLFOX6. The bevacizumab arm had an unexpectedly good outcome, and was much better than that seen in the Phase III trials. Combination therapy with sunitinib plus mFOLFOX6 is not recommended for patients with metastatic colorectal cancer. Keywords: antiangiogenesis, bevacizumab, combination therapy, metastatic colorectal cancer, oxaliplatin, sunitinib

Implicit and explicit self-esteem are assumed to be important factors in understanding the onset and maintenance of psychological problems. The current study aims to examine the association between implicit and explicit self-esteem and their interaction with depressive symptoms, suicidal ideation and loneliness. Specifically, the relationship between the size and the direction of the discrepancy between implicit and explicit self-esteem with depressive symptoms, suicidal ideation and loneliness were examined. Participants were 95 young female adults (M= 21.2 years, SD = 1.88) enrolled in higher education. We administered the IAT to assess implicit self-esteem, and the Rosenberg self-esteem scale to measure explicit self-esteem while psychological problems were assessed through self-reports. Results showed that discrepancies between implicit and explicit self-esteem were positively associated with depressive symptoms, suicidal ideation, and loneliness. In addition, the direction of the discrepancy was specifically relevant: damaged self-esteem (i.e., high implicit self-esteem and low explicit self-esteem) was consistently associated with increased levels of depressive symptoms, suicidal ideation, and loneliness. In contrast, defensive or fragile self-esteem (i.e., low implicit and high explicit self-esteem) was solely associated with loneliness. These findings provide further support that specifically damaged self-esteem is an important vulnerability marker for depressive symptoms, suicidal ideation, and loneliness.

Objective: Health disparities in lesbian, gay, bisexual, transgender, and queer/questioning (LGBTQ+), or sexual and gender minority (SGM) people are known. SGM people have higher cancer risk, but lower rates of screenings, resulting in a higher likelihood of late-stage disease. This study evaluates medical students' clinical cultural awareness in cancer care of SGM patients to identify gaps in education., Methods: This was a cross-sectional survey distributed to medical students at a academic center. There were 38 questions on demographics, attitudes, and knowledge of SGM topics. Descriptive statistics were used for demographic information and stratified analyses assessed responses by demographic subgroups., Results: There were 238 responses from 1145 students (response rate = 20.7 %). Of the responders, 91.2 % and 79 % were comfortable treating lesbian, gay, bisexual (LGB) and transgender patients respectively. Only 28.6 % and 21.8 % were confident treating LGB and transgender patients respectively after taking the survey. 91.2 % of students were interested receiving education regarding SGM health needs., Conclusion: While most medical students are comfortable treating LGBTQ+ patients, most are not confident in their knowledge. This difference is most profound in knowledge of transgender patients., Practice Implications: Schools must provide more education in SGM topics to improve student knowledge to produce competent providers., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

Background: Early studies showed promise of combined anti-epidermal growth factor receptor (EGFR) plus anti-vascular endothelial growth factor (VEGF) antibodies for advanced colorectal cancer (CRC), yet this was later rejected as toxic and ineffective in studies not selected for RAS status. We studied advanced KRAS wild-type CRC, as second-line treatment, using irinotecan-cetuximab with or without the anti-VEGF receptor antibody ramucirumab., Methods: Patients with 1 prior regimen including fluoropyrimidine, oxaliplatin, and bevacizumab, with KRAS wild-type tumors were stratified by Eastern Cooperative Oncology Group Performance Score, time since last chemotherapy, and progression on oxaliplatin to irinotecan-cetuximab (IC) (180 mg/m2 and 500 mg/m2 every 2 weeks) vs modified ICR (irinotecan-cetuximab with ramucirumab 150 mg/m2 and 400 mg/m2 plus 6 mg/kg, respectively). A total of 102 patients were compared for progression-free survival (PFS) as primary endpoint (85% power for 70% improvement in median PFS from 4.5 to 7.65 months)., Results: Of the 102 enrolled, 44 treated with irinotecan-cetuximab and 45 with modified ramucirumab were evaluable. Median PFS was 6.0 months vs 9.2 months, respectively (hazard ratio = 0.75, P = .07; statistically significant by study design for P < .128). Response rate was 23% vs 36% (P = .27), and disease-control rate was 52% vs 73% (P = .05). Grade 3 or higher toxicity was equivalent. Overall survival was not significantly different at approximately 19 months., Conclusion: Previous phase 3 trials without RAS genotyping rejected combining anti-epidermal growth factor receptor and anti-VEGF drugs. In this randomized multicenter phase 2 study for KRAS wild-type CRC (all previously bevacizumab treated), the addition of ramucirumab to irinotecan and cetuximab improved PFS and disease control rate, showing the combination is feasible and effective. Further, phase 3 trials with appropriate patient-selection are required. (NCT01079780)., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: Black women experience higher rates of taxane-induced peripheral neuropathy (TIPN) compared with White women when receiving adjuvant once weekly paclitaxel for early-stage breast cancer, leading to more dose reductions and higher recurrence rates. EAZ171 aimed to prospectively validate germline predictors of TIPN and compare rates of TIPN and dose reductions in Black women receiving (neo)adjuvant once weekly paclitaxel and once every 3 weeks docetaxel for early-stage breast cancer., Methods: Women with early-stage breast cancer who self-identified as Black and had intended to receive (neo)adjuvant once weekly paclitaxel or once every 3 weeks docetaxel were eligible, with planned accrual to 120 patients in each arm. Genotyping was performed to determine germline neuropathy risk. Grade 2-4 TIPN by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 was compared between high- versus low-risk genotypes and between once weekly paclitaxel versus once every 3 weeks docetaxel within 1 year. Patient-rated TIPN and patient-reported outcomes were compared using patient-reported outcome (PRO)-CTCAE and Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity., Results: Two hundred and forty of 249 enrolled patients had genotype data, and 91 of 117 (77.8%) receiving once weekly paclitaxel and 87 of 118 (73.7%) receiving once every 3 weeks docetaxel were classified as high-risk. Physician-reported grade 2-4 TIPN was not significantly different in high- versus low-risk genotype groups with once weekly paclitaxel (47% v 35%; P = .27) or with once every 3 weeks docetaxel (28% v 19%; P = .47). Grade 2-4 TIPN was significantly higher in the once weekly paclitaxel versus once every 3 weeks docetaxel arm by both physician-rated CTCAE (45% v 29%; P = .02) and PRO-CTCAE (40% v 24%; P = .03). Patients receiving once weekly paclitaxel required more dose reductions because of TIPN (28% v 9%; P < .001) or any cause (39% v 25%; P = .02)., Conclusion: Germline variation did not predict risk of TIPN in Black women receiving (neo)adjuvant once weekly paclitaxel or once every 3 weeks docetaxel. Once weekly paclitaxel was associated with significantly more grade 2-4 TIPN and required more dose reductions than once every 3 weeks docetaxel.

Purpose: Aromatase inhibitor (AI)-associated musculoskeletal symptoms (AIMSS) are common and frequently lead to AI discontinuation. SNPs in candidate genes have been associated with AIMSS and AI discontinuation. E1Z11 is a prospective cohort study designed to validate the association between 10 SNPs and AI discontinuation due to AIMSS., Patients and Methods: Postmenopausal women with stage I to III hormone receptor-positive breast cancer received anastrozole 1 mg daily and completed patient-reported outcome measures to assess AIMSS (Stanford Health Assessment Questionnaire) at baseline, 3, 6, 9, and 12 months. We estimated that 40% of participants would develop AIMSS and 25% would discontinue AI treatment within 12 months. Enrollment of 1,000 women with a fixed number per racial stratum provided 80% power to detect an effect size of 1.5 to 4. SNPs were found in ESR1 (rs2234693, rs2347868, and rs9340835), CYP19A1 (rs1062033 and rs4646), TCL1A (rs11849538, rs2369049, rs7158782, and rs7159713), and HTR2A (rs2296972)., Results: Of the 970 evaluable women, 43% developed AIMSS and 12% discontinued AI therapy within 12 months. Although more Black and Asian women developed AIMSS than White women (49% vs. 39%, P = 0.017; 50% vs. 39%, P = 0.004, respectively), the AI discontinuation rates were similar across groups. None of the SNPs were significantly associated with AIMSS or AI discontinuation in the overall population or in distinct cohorts. The OR for rs2296972 (HTR2A) approached significance for developing AIMSS., Conclusions: We were unable to prospectively validate candidate SNPs previously associated with AI discontinuation due to AIMSS. Future analyses will explore additional genetic markers, patient-reported outcome predictors of AIMSS, and differences by race., (©2024 American Association for Cancer Research.)

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., (©2024 American Association for Cancer Research.)

Pregnancy and lactation are special life stages that require regular nutritional and medical attention to help protect the health of the mother and promote the growth and development of the offspring. Despite an increased focus on maternal and fetal health over the last several decades, the rates of pregnancy-related morbidity and mortality are increasing in the United States (US). On average, Black women who are pregnant or lactating face greater health disparities and birth complications than other racial/ethnic groups in the US. The issues contributing to these disparities are multi-faceted and include sociocultural, economic, medical, and dietary factors. For example, Black women face greater rates of food insecurity, worse access to healthcare, and lower nutrient status when compared to White women. A growing body of research suggests that consuming a healthier dietary pattern is one of the most potent modifiable risk factors associated with improved fertility and reducing pregnancy-related complications. Recent publications have also shed light on the role of dairy foods in improving diet quality and nutrient status among Black women and for impacting maternal and fetal health outcomes, such as preeclampsia, spontaneous abortion, preterm birth, and fetal growth. To support healthy pregnancy and lactation, the current national dietary guidelines recommend the consumption of 3 servings of dairy foods per day. However, the vast majority of Black women in the US are falling short of these recommendations and are not meeting nutrient requirements for calcium and vitamin D. Therefore, strategies that target misconceptions surrounding lactose intolerance and focus on the health value of adequate dairy intake among Black women of child-bearing age may benefit both prenatal and postpartum health. This review presents the current evidence on health disparities faced by pregnant and lactating Black women in the US, and the role of dairy foods in supporting healthy pregnancy, fetal development, and lactation outcomes in this population., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Subprotocol K2 (EAY131-K2) of the NCI-MATCH platform trial was an open-label, single-arm, phase II study designed to evaluate the antitumor efficacy of the oral FGFR1-4 inhibitor, erdafitinib, in patients with tumors harboring FGFR1-4 mutations or fusions., Methods: Central confirmation of tumor FGFR1-4 mutations or fusions was required for outcome analysis. Patients with urothelial carcinoma were excluded. Enrolled subjects received oral erdafitinib at a starting dose of 8 mg daily continuously until intolerable toxicity or disease progression. The primary end point was objective response rate (ORR) with key secondary end points of safety, progression-free survival (PFS), and overall survival (OS)., Results: Thirty-five patients were enrolled, and 25 patients were included in the primary efficacy analysis as prespecified in the protocol. The median age was 61 years, and 52% of subjects had received ≥3 previous lines of therapy. The confirmed ORR was 16% (4 of 25 [90% CI, 5.7 to 33.0], P = .034 against the null rate of 5%). An additional seven patients experienced stable disease as best-confirmed response. Four patients had a prolonged PFS including two with recurrent WHO grade IV, IDH1-/2-wildtype glioblastoma. The median PFS and OS were 3.6 months and 11.0 months, respectively. Erdafitinib was manageable with no new safety signals., Conclusion: This study met its primary end point in patients with several pretreated solid tumor types harboring FGFR1-3 mutations or fusions. These findings support advancement of erdafitinib for patients with fibroblast growth factor receptor-altered tumors outside of currently approved indications in a potentially tumor-agnostic manner.

Purpose: The National Cancer Institute Molecular Analysis for Therapy Choice trial is a signal-finding genomically driven platform trial that assigns patients with any advanced refractory solid tumor, lymphoma, or myeloma to targeted therapies on the basis of next-generation sequencing results. Subprotocol E evaluated osimertinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in patients with EGFR mutations., Methods: Eligible patients had EGFR mutations (T790M or rare activating) and received osimertinib 80 mg once daily. Patients with lung cancer with EGFR T790M were excluded. The primary end point was objective response rate (ORR), and the secondary end points were 6-month progression-free survival (PFS), overall survival, and toxicity., Results: A total of 19 patients were enrolled: 17 were evaluable for toxicity and 13 for efficacy. The median age of the 13 included in the efficacy analysis was 63 years, 62% had Eastern Cooperative Oncology Group performance status 1, and 31% received >three previous systemic therapies. The most common tumor type was brain cancers (54%). The ORR was 15.4% (n = 2 of 13; 90% CI, 2.8 to 41.0) and 6-month PFS was 16.7% (90% CI, 0 to 34.4). The two confirmed RECIST responses were observed in a patient with neuroendocrine carcinoma not otherwise specified ( EGFR exon 20 S768T and exon 18 G719C mutation) and a patient with low-grade epithelial carcinoma of the paranasal sinus ( EGFR D770&#95;N771insSVD). The most common (>20%) treatment-related adverse events were diarrhea, thrombocytopenia, and maculopapular rash., Conclusion: In this pretreated cohort, osimertinib did not meet the prespecified end point threshold for efficacy, but responses were seen in a neuroendocrine carcinoma with an EGFR exon 20 S768T and exon 18 G719C mutation and an epithelial carcinoma with an EGFR D770&#95;N771insSVD mutation. Osimertinib was well tolerated and had a safety profile consistent with previous studies.

Purpose: Despite fibroblast growth factor receptor ( FGFR ) inhibitors being approved in tumor types with select FGFR rearrangements or gene mutations, amplifications of FGFR represent the most common FGFR alteration across malignancies. Subprotocol K1 (EAY131-K1) of the National Cancer Institute-MATCH platform trial was designed to evaluate the antitumor efficacy of the oral FGFR1-4 inhibitor, erdafitinib, in patients with tumors harboring FGFR1-4 amplification., Methods: EAY131-K1 was an open-label, single-arm, phase II study with central confirmation of presence of FGFR1-4 amplification in tumors. Patients with urothelial carcinoma were excluded. Enrolled patients received oral erdafitinib at a starting dose of 8 mg once daily continuously with escalation to 9 mg once daily continuously, on the basis of predefined time point assessments of phosphate levels, until disease progression or intolerable toxicity. The primary end point was centrally assessed objective response rate (ORR), with key secondary end points being 6-month progression-free survival (PFS6), PFS, overall survival (OS), and safety., Results: Thirty-five patients were enrolled into this study with 18 included in the prespecified primary efficacy analysis. The median age of the 18 patients was 60 years, and 78% had received ≥3 previous lines of therapy. There were no confirmed responses to erdafitinib; however, five patients experienced stable disease (SD) as best response. One patient with an FGFR1 -amplified breast cancer had a prolonged PFS >168 days (5.5 months). The median PFS was 1.7 months (90% CI, 1.1 to 1.8 months) and the median OS was 4.2 months (90% CI, 2.3 to 9.3 months). The estimated PFS6 rate was 13.8% (90% CI, 3.3 to 31.6). The majority of toxicities were grade 1 to 2 in nature, although there was one grade 5 treatment-related adverse event., Conclusion: Erdafitinib did not meet its primary end point of efficacy as determined by ORR in treatment-refractory solid tumors harboring FGFR1-4 amplifications. Our findings support that rearrangements and gene mutations, but not amplifications, of FGFR remain the established FGFR alterations with approved indications for FGFR inhibition.

This review describes the barriers and challenges faced by older adults of color with cancer and highlights methods to improve their overall care. In the next decade, cancer incidence rates are expected to increase in the United States for people aged ≥65 years. A large proportion will be older adults of color who often have worse outcomes than older White patients. Many issues contribute to racial disparities in older adults, including biological factors and social determinants of health (SDOH) related to healthcare access, socioeconomic concerns, systemic racism, mistrust, and the neighborhood where a person lives. These disparities are exacerbated by age-related challenges often experienced by older adults, such as decreased functional status, impaired cognition, high rates of comorbidities and polypharmacy, poor nutrition, and limited social support. Additionally, underrepresentation of both patients of color and older adults in cancer clinical research results in a lack of adequate data to guide the management of these patients. Use of geriatric assessments (GA) can aid providers in uncovering age-related concerns and personalizing interventions for older patients. Research demonstrates the ability of GA-directed care to result in fewer treatment-related toxicities and improved quality of life, thus supporting the routine incorporation of validated GA into these patients' care. GA can be enhanced by including evaluation of SDOH, which can help healthcare providers understand and address the needs of older adults of color with cancer who face disparities related to their age and race., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

This retrospective study documents the occurrence of single and multiple cutaneous apocrine gland tumours (CATs) on the dorsal midline of 16 captive African wild dogs (AWDs, Lycaon pictus) derived from 161 submissions to diagnostic laboratories in South Africa, France and Germany between 1997 and 2022. Animals included in the study came from zoological institutions in South Africa (n = 2), France (n = 5) and Germany (n = 1) and ranged from 5 to 14 years of age. Fifteen affected animals were female (94%) and one was male. CATs presented as raised, hairless, multilobular, grey firm masses, consistently located along the dorsal midline. Apart from a single cutaneous apocrine adenoma and a cystadenoma occurring concurrently with two non-cystic adenocarcinomas, neoplasms were consistent with malignant cutaneous apocrine adenocarcinomas with lymphatic spread and visceral metastases. Advanced age and female sex were identified as risk factors. A genetic component or association with the increasing use of GnRH agonist contraceptives was suspected but could not be established. This study highlights the need for close clinical monitoring of AWDs over the age of 5 years for the development of CATs along the dorsal midline and supports early surgical intervention. More research is needed to determine the role of inbreeding, endocrine changes and husbandry factors that may play a role in the development of CATs on the dorsal midline of AWDs., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Patients with advanced esophageal cancer carry poor prognoses; limited data exist to guide second-line therapy in the metastatic setting. Paclitaxel has been used yet is associated with limited efficacy. There is preclinical evidence of synergy between paclitaxel and cixutumumab, a monoclonal antibody targeting insulin-like growth factor-1 receptor. We conducted a randomized phase II trial of paclitaxel (arm A) versus paclitaxel plus cixutumumab (arm B) in the second-line for patients with metastatic esophageal or gastroesophageal junction (GEJ) cancers., Methods: The primary endpoint was progression-free survival (PFS); 87 patients (43 in arm A, 44 in arm B) were treated., Results: Median PFS was 2.6 months in arm A [90% CL 1.8-3.5] and 2.3 months in arm B [90% 2.0-3.5], P = .86. Stable disease was observed in 29 (33%) patients. Objective response rates for Arms A and B were 12% [90% CI, 5-23%] and 14% [90% CI, 6-25%]. Median overall survival was 6.7 months [90% CL 4.9-9.5] in arm A and 7.2 months [90% CL 4.9-8.1] in arm B, P = 56., Conclusion: The addition of cixutumumab to paclitaxel in second-line therapy of metastatic esophageal/GEJ cancer was well tolerated but did not improve clinical outcomes relative to standard of care (ClinicalTrials.gov Identifier: NCT01142388)., (© The Author(s) 2023. Published by Oxford University Press.)

Purpose: Colorectal cancer is the second leading cause of cancer mortality in the United States. Antiangiogenic therapy with bevacizumab combined with chemotherapy improves survival in previously untreated metastatic colorectal cancer. This study was conducted to determine the effect of bevacizumab (at 10 mg/kg) on survival duration for oxaliplatin-based chemotherapy in patients with previously treated metastatic colorectal cancer., Patients and Methods: Eight hundred twenty-nine metastatic colorectal cancer patients previously treated with a fluoropyrimidine and irinotecan were randomly assigned to one of three treatment groups: oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) with bevacizumab; FOLFOX4 without bevacizumab; or bevacizumab alone. The primary end point was overall survival, with additional determinations of progression-free survival, response, and toxicity., Results: The median duration of survival for the group treated with FOLFOX4 and bevacizumab was 12.9 months compared with 10.8 months for the group treated with FOLFOX4 alone (corresponding hazard ratio for death = 0.75; P = .0011), and 10.2 months for those treated with bevacizumab alone. The median progression-free survival for the group treated with FOLFOX4 in combination with bevacizumab was 7.3 months, compared with 4.7 months for the group treated with FOLFOX4 alone (corresponding hazard ratio for progression = 0.61; P < .0001), and 2.7 months for those treated with bevacizumab alone. The corresponding overall response rates were 22.7%, 8.6%, and 3.3%, respectively ( P < .0001 for FOLFOX4 with bevacizumab v FOLFOX4 comparison). Bevacizumab was associated with hypertension, bleeding, and vomiting., Conclusion: The addition of bevacizumab to oxaliplatin, fluorouracil, and leucovorin improves survival duration for patients with previously treated metastatic colorectal cancer.

The LGBTQ+ community experiences cancer disparities due to increased risk factors and lower screening rates, attributable to health literacy gaps and systemic barriers. We sought to understand the experiences, perceptions, and knowledge base of healthcare providers regarding cancer screening for LGBTQ+ patients. A 20-item IRB-approved survey was distributed to physicians through professional organizations. The survey assessed experiences and education regarding the LGBTQ+ community and perceptions of patient concerns with different cancer screenings on a 5-point Likert scale. Complete responses were collected from 355 providers. Only 100 (28%) reported past LGBTQ+-related training and were more likely to be female ( p = 0.020), have under ten years of practice ( p = 0.014), or practice family/internal medicine ( p < 0.001). Most (85%) recognized that LGBTQ+ subpopulations experience nuanced health issues, but only 46% confidently understood them, and 71% agreed their clinics would benefit from training. Family/internal medicine practitioners affirmed the clinical relevance of patients' sexual orientation (94%; 62% for medical/radiation oncology). Prior training affected belief in the importance of sexual orientation ( p < 0.001), confidence in understanding LGBTQ+ health concerns ( p < 0.001), and willingness to be listed as "LGBTQ+-friendly" ( p = 0.005). Our study suggests that despite a paucity of formal training, most providers acknowledge that LGBTQ+ patients have unique health needs. Respondents had a lack of consensus regarding cancer screenings for lesbian and transgender patients, indicating the need for clearer screening standards for LGBTQ+ subpopulations and educational programs for providers.

The NCI-MATCH (Molecular Analysis for Therapy Choice) trial ( NCT02465060 ) was launched in 2015 as a genomically driven, signal-seeking precision medicine platform trial-largely for patients with treatment-refractory, malignant solid tumors. Having completed in 2023, it remains one of the largest tumor-agnostic, precision oncology trials undertaken to date. Nearly 6,000 patients underwent screening and molecular testing, with a total of 1,593 patients (inclusive of continued accrual from standard next-generation sequencing) being assigned to one of 38 substudies. Each substudy was a phase 2 trial of a therapy matched to a genomic alteration, with a primary endpoint of objective tumor response by RECIST criteria. In this Perspective, we summarize the outcomes of the initial 27 substudies in NCI-MATCH, which met its signal-seeking objective with 7/27 positive substudies (25.9%). We discuss key aspects of the design and operational conduct of the trial, highlighting important lessons for future precision medicine studies., (© 2023. Springer Nature America, Inc.)

Purpose: Cyclin D/CDK4/6 is critical in controlling the G1 to S checkpoint. CCND, the gene encoding cyclin D, is known to be amplified in a variety of solid tumors. Palbociclib is an oral CDK4/6 inhibitor, approved in advanced breast cancer in combination with endocrine therapy. We explored the efficacy of palbociclib in patients with nonbreast solid tumors containing an amplification in CCND1, 2, or 3., Patients and Methods: Patients with tumors containing a CCND1, 2, or 3 amplification and expression of the retinoblastoma protein were assigned to subprotocol Z1B and received palbociclib 125 mg once daily for 21 days of a 28-day cycle. Tumor response was assessed every two cycles., Results: Forty patients were assigned to subprotocol Z1B; 4 patients had outside assays identifying the CCND1, 2, or 3 amplification and were not confirmed centrally; 3 were ineligible and 2 were not treated (1 untreated patient was also ineligible), leaving 32 evaluable patients for this analysis. There were no partial responses; 12 patients (37.5%) had stable disease as best response. There were seven deaths on study, all during cycle 1 and attributable to disease progression. Median progression-free survival was 1.8 months. The most common toxicities were leukopenia (n = 21, 55%) and neutropenia (n = 19, 50%); neutropenia was the most common grade 3/4 event (n = 12, 32%)., Conclusions: Palbociclib was not effective at treating nonbreast solid tumors with a CCND1, 2, or 3 amplification in this cohort. These data do not support further investigation of single-agent palbociclib in tumors with CCND1, 2, or 3 amplification., (©2023 The Authors; Published by the American Association for Cancer Research.)

Purpose: NCI-MATCH is a precision medicine trial using genomic testing to allocate patients with advanced malignancies to targeted treatment subprotocols. This report combines two subprotocols evaluating trametinib, a MEK1/2 inhibitor, in patients with Neurofibromatosis 1 ( NF1 [S1] or GNA11/Q [S2]) altered tumors., Methods: Eligible patients had tumors with deleterious inactivating NF1 or GNA11/Q mutations by the customized Oncomine AmpliSeq panel. Prior MEK inhibitor treatment was excluded. Glioblastomas (GBMs) were permitted, including malignancies associated with germline NF1 mutations (S1 only). Trametinib was administered at 2 mg once daily over 28-day cycles until toxicity or disease progression. Primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS) at 6 months, PFS, and overall survival. Exploratory analyses included co-occurring genomic alterations and PTEN loss., Results: Fifty patients were eligible and started therapy: 46 with NF1 mutations (S1) and four with GNA11 mutations (S2). In the NF1 cohort, nonsense single-nucleotide variants were identified in 29 and frameshift deletions in 17 tumors. All in S2 had nonuveal melanoma and GNA11 Q209L variant. Two partial responses (PR) were noted in S1, one patient each with advanced lung cancer and GBM for an ORR of 4.3% (90% CI, 0.8 to 13.1). One patient with melanoma in S2 had a PR (ORR, 25%; 90% CI, 1.3 to 75.1). Prolonged stable disease (SD) was also noted in five patients (four in S1 and one in S2) with additional rare histologies. Adverse events were as previously described with trametinib. Comutations in TP53 and PIK3CA were common., Conclusion: Although these subprotocols did not meet the primary end point for ORR, significant responses or prolonged SD noted in some disease subtypes warrants further investigation.

Background: Alterations in fibroblast growth factor receptor 2 ( FGFR2 ) have emerged as promising drug targets for intrahepatic cholangiocarcinoma, a rare cancer with a poor prognosis. Futibatinib, a next-generation, covalently binding FGFR1-4 inhibitor, has been shown to have both antitumor activity in patients with FGFR -altered tumors and strong preclinical activity against acquired resistance mutations associated with ATP-competitive FGFR inhibitors., Methods: In this multinational, open-label, single-group, phase 2 study, we enrolled patients with unresectable or metastatic FGFR2 fusion-positive or FGFR2 rearrangement-positive intrahepatic cholangiocarcinoma and disease progression after one or more previous lines of systemic therapy (excluding FGFR inhibitors). The patients received oral futibatinib at a dose of 20 mg once daily in a continuous regimen. The primary end point was objective response (partial or complete response), as assessed by independent central review. Secondary end points included the response duration, progression-free and overall survival, safety, and patient-reported outcomes., Results: Between April 16, 2018, and November 29, 2019, a total of 103 patients were enrolled and received futibatinib. A total of 43 of 103 patients (42%; 95% confidence interval, 32 to 52) had a response, and the median duration of response was 9.7 months. Responses were consistent across patient subgroups, including patients with heavily pretreated disease, older adults, and patients who had co-occurring TP53 mutations. At a median follow-up of 17.1 months, the median progression-free survival was 9.0 months and overall survival was 21.7 months. Common treatment-related grade 3 adverse events were hyperphosphatemia (in 30% of the patients), an increased aspartate aminotransferase level (in 7%), stomatitis (in 6%), and fatigue (in 6%). Treatment-related adverse events led to permanent discontinuation of futibatinib in 2% of the patients. No treatment-related deaths occurred. Quality of life was maintained throughout treatment., Conclusions: In previously treated patients with FGFR2 fusion or rearrangement-positive intrahepatic cholangiocarcinoma, the use of futibatinib, a covalent FGFR inhibitor, led to measurable clinical benefit. (Funded by Taiho Oncology and Taiho Pharmaceutical; FOENIX-CCA2 ClinicalTrials.gov number, NCT02052778.)., (Copyright © 2023 Massachusetts Medical Society.)

Purpose: T-cell-mediated cytotoxicity is suppressed when programmed cell death-1 (PD-1) is bound by PD-1 ligand-1 (PD-L1) or PD-L2. Although PD-1 inhibitors have been approved for triple-negative breast cancer, the lower response rates of 25%-30% in estrogen receptor-positive (ER+) breast cancer will require markers to identify likely responders. The focus of this study was to evaluate whether PD-L2, which has higher affinity than PD-L1 for PD-1, is a predictor of early recurrence in ER+ breast cancer., Methods: PD-L2 protein levels in cancer cells and stromal cells of therapy-naive, localized or locoregional ER+ breast cancers were measured retrospectively by quantitative immunofluorescence histocytometry and correlated with progression-free survival (PFS) in the main study cohort (n = 684) and in an independent validation cohort (n = 273). All patients subsequently received standard-of-care adjuvant therapy without immune checkpoint inhibitors., Results: Univariate analysis of the main cohort revealed that high PD-L2 expression in cancer cells was associated with shorter PFS (hazard ratio [HR], 1.8; 95% CI, 1.3 to 2.6; P = .001), which was validated in an independent cohort (HR, 2.3; 95% CI, 1.1 to 4.8; P = .026) and remained independently predictive after multivariable adjustment for common clinicopathological variables (HR, 2.0; 95% CI, 1.4 to 2.9; P < .001). Subanalysis of the ER+ breast cancer patients treated with adjuvant chemotherapy (n = 197) revealed that high PD-L2 levels in cancer cells associated with short PFS in univariate (HR, 2.5; 95% CI, 1.4 to 4.4; P = .003) and multivariable analyses (HR, 3.4; 95% CI, 1.9 to 6.2; P < .001)., Conclusion: Up to one third of treatment-naive ER+ breast tumors expressed high PD-L2 levels, which independently predicted poor clinical outcome, with evidence of further elevated risk of progression in patients who received adjuvant chemotherapy. Collectively, these data warrant studies to gain a deeper understanding of PD-L2 in the progression of ER+ breast cancer and may provide rationale for immune checkpoint blockade for this patient group.

Africa is the only habitable continent that is not yet host to a light source - an important tool across disciplines. Scientists from the Executive Committee of the African Light Source Foundation discuss work towards building an advanced light source in Africa, and what remains to be done., Competing Interests: Competing interestsThe authors declare no competing interests., (© Springer Nature Limited 2022.)

Cases of Theileria -associated mortality are rarely reported in African wild artiodactyls. Descriptions of lesions are limited, particularly in endangered hippotraginids. Here, we analyzed retrospectively the gross and histologic findings in 55 roan antelope ( Hippotragus equinus ) with fatal natural theileriosis. The most frequently recorded gross findings in 40 cases were widespread petechiae and ecchymoses (72.5%), probable anemia (67.5%), icterus (60%), splenomegaly (60%), hepatomegaly (52.5%), and pulmonary edema (50%). Histologic lesions in 34 cases were characterized by multi-organ infiltrates of parasitized and nonparasitized mononuclear leukocytes (MLs), and fewer multinucleate giant cells (MNGCs). Liver, lung, kidney, adrenal gland, and heart were most consistently infiltrated, followed by spleen and lymph nodes. Leukocytes were phenotyped in lung, liver, kidney, and heart specimens from 16 cases, using immunohistochemistry to detect CD20, CD3, myeloid/histiocyte antigen (MAC387), IBA-1, and CD204 surface receptors. A roan polyclonal anti- Theileria sp. (sable) antibody was applied to the same tissues to identify intraleukocytic parasite antigens. Similar proportions of intravascular and extravascular IBA-1-, CD204-, and MAC387-reactive putative monocyte-macrophages and fewer CD3-positive putative T-lymphocytes were identified in all organs, especially the lungs in infected roan. CD20-positive putative B-lymphocytes were significantly scarcer than in uninfected controls. Intraleukocytic Theileria parasites labeled consistently in affected tissues. Some parasitized and nonparasitized MLs and the MNGCs failed to label with selected leukocyte markers. Fatal theileriosis in roans may largely be the result of multi-organ monocyte-macrophage activation with associated tissue injury and overwhelming systemic inflammation. The identity of the parasitized leukocytes and characteristics of the lymphohistiocytic response require further clarification in roans.

Background: While societal acceptance for sexual and gender minority (SGM) individuals is increasing, this group continues to face barriers to quality healthcare. Little is known about clinicians' experiences with SGM patients in the oncology setting. To address this, a mixed method survey was administered to members of the ECOG-ACRIN Cancer Research Group., Materials and Methods: We report results from the open-ended portion of the survey. Four questions asked clinicians to describe experiences with SGM patients, reservations in caring for them, suggestions for improvement in SGM cancer care, and additional comments. Data were analyzed using content analysis and the constant comparison method., Results: The majority of respondents noted they had no or little familiarity with SGM patients. A minority of respondents noted experience with gay and lesbian patients, but not transgender patients; many who reported experience with transgender patients also noted difficulty navigating the correct use of pronouns. Many respondents also highlighted positive experiences with SGM patients. Suggestions for improvement in SGM cancer care included providing widespread training, attending to unique end-of-life care issues among SGM patients, and engaging in efforts to build trust., Conclusion: Clinicians have minimal experiences with SGM patients with cancer but desire training. Training the entire workforce may improve trust with, outreach efforts to, and cancer care delivery to the SGM community., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tamargo, Mitchell, Wagner, Simon, Carlos, Giantonio, Schabath and Quinn.)

Purpose: National Cancer Institute-Molecular Analysis for Therapy Choice is a multicohort trial that assigns patients with advanced cancers to targeted therapies on the basis of central tumor genomic testing. Arm B evaluated afatinib, an ErbB family tyrosine kinase inhibitor, in patients with ERBB2 -activating mutations., Methods: Eligible patients had selected ERBB2 single-nucleotide variants or insertions/deletions detected by the National Cancer Institute-Molecular Analysis for Therapy Choice next-generation sequencing assay. Patients had performance status ≤ 1, left ventricular ejection fraction > 50%, grade ≤ 1 diarrhea, and no prior human epidermal growth factor receptor 2 (HER2) therapy. Patients received afatinib 40 mg once daily in 28-day cycles. The primary end point was objective response rate (ORR). Secondary end points were 6-month progression-free survival, overall survival, toxicity, and molecular correlates., Results: A total of 59 patients were assigned and 40 were enrolled. The median age was 62 years, 78% were female, 68% had performance status = 1, and 58% had received > 3 prior therapies. The confirmed ORR was 2.7% (n = 1 of 37; 90% CI, 0.14 to 12.2), and 6-month progression-free survival was 12.0% (90% CI, 5.6 to 25.8). A confirmed partial response occurred in a patient with adenocarcinoma of extra-mammary Paget disease of skin who progressed after cycle 6. Two unconfirmed partial responses were observed (low-grade serous gynecological tract and estrogen receptor-positive/HER2-negative immunohistochemistry breast ductal carcinoma). Of 12 patients with breast cancer, 1 additional patient with lobular carcinoma (estrogen receptor-positive/HER2 fluorescent in situ hybridization) had a 51% reduction in target lesions but progressed because of a new lesion at cycle 6. The most common (> 20%) treatment-related adverse events were diarrhea (68%), mucositis (43%), fatigue (40%), acneiform rash (30%), dehydration (27%), vomiting (27%), nausea (27%), anemia (27%), and anorexia (22%). Four patients (11%) discontinued because of adverse events., Conclusion: Although afatinib did not meet the prespecified threshold for antitumor activity in this heavily pretreated cohort, the response in a rare tumor type is notable. The safety profile of afatinib was consistent with prior studies.

Objective: Real-world data characterizing differences between African American (AA) and White women with metastatic triple-negative breast cancer (mTNBC) are limited. Using 9 years of data collected from community practices throughout the United States, we assessed racial differences in the proportion of patients with mTNBC, and their characteristics, treatment, and overall survival (OS)., Methods: This retrospective study analyzed de-identified data from 2,116 patients with mTNBC in the Flatiron Health database (January 2011 to March 2020). Characteristics and treatment patterns between AA and White patients with mTNBC were compared using descriptive statistics. OS was examined using Kaplan-Meier analysis and a multivariate Cox proportional hazards regression model., Results: Among patients with metastatic breast cancer, more AA patients (23%) had mTNBC than White patients (12%). This difference was particularly pronounced in patients who lived in the Northeast, were aged 45-65, had commercial insurance, and had initial diagnosis at stage II. AA patients were younger and more likely to have Medicaid. Clinical characteristics and first-line treatments were similar between AA and White patients. Unadjusted median OS (months) was shorter in AA (10.3; 95% confidence interval [CI]: 9.1, 11.7) vs. White patients (11.9; 95% CI: 10.9, 12.8) but not significantly different. After adjusting for potential confounders, the hazard ratio for OS was 1.09 (95% CI: 0.95, 1.25) for AA vs. White patients., Conclusions: The proportion of patients with mTNBC was higher in AA than White mBC patients treated in community practices. Race did not show an association with OS. Both AA and White patients with mTNBC received similar treatments. OS was similarly poor in both groups, particularly in patients who had not received any documented anti-cancer treatment. Effective treatment remains a substantial unmet need for all patients with mTNBC., Competing Interests: RT, LC, YY, VS, and B-mD are employed by Genentech, Inc. and hold stock in F. Hoffmann-La Roche, Ltd. The remaining author declares that aside from the medical editing support she received, the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tan, Cassoli, Yan, Shen, Day and Mitchell.)

Purpose: Activating mutations in PIK3CA are observed across multiple tumor types. The NCI-MATCH (EAY131) is a tumor-agnostic platform trial that enrolls patients to targeted therapies on the basis of matching genomic alterations. Arm Z1F evaluated copanlisib, an α and δ isoform-specific phosphoinositide 3-kinase (PI3K) inhibitor, in patients with PIK3CA mutations (with or without PTEN loss)., Patients and Methods: Patients received copanlisib (60 mg intravenous) once weekly on days 1, 8, and 15 in 28-day cycles until progression or toxicity. Patients with KRAS mutations, human epidermal growth factor receptor 2-positive breast cancers, and lymphomas were excluded. The primary end point was centrally assessed objective response rate (ORR); secondary end points included progression-free survival, 6-month progression-free survival, and overall survival., Results: Thirty-five patients were enrolled, and 25 patients were included in the primary efficacy analysis as prespecified in the Protocol. Multiple histologies were enrolled, with gynecologic (n = 6) and gastrointestinal (n = 6) being the most common. Sixty-eight percent of patients had ≥ 3 lines of prior therapy. The ORR was 16% (4 of 25, 90% CI, 6 to 33) with P = .0341 against a null rate of 5%. The most common reason for protocol discontinuation was disease progression (n = 17, 68%). Grade 3/4 toxicities observed were consistent with reported toxicities for PI3K pathway inhibition. Sixteen patients (53%) had grade 3 toxicities, and one patient (3%) had grade 4 toxicity (CTCAE v5.0). Most common toxicities include hyperglycemia (n = 19), fatigue (n = 12), diarrhea (n = 11), hypertension (n = 10), and nausea (n = 10)., Conclusion: The study met its primary end point with an ORR of 16% ( P = .0341) with copanlisib showing clinical activity in select tumors with PIK3CA mutation in the refractory setting., Competing Interests: Senthil DamodaranResearch Funding: EMD Serono (Inst), Guardant Health (Inst), Taiho Pharmaceutical (Inst), Novartis (Inst), Sermonix Pharmaceuticals (Inst) Fengmin ZhaoThis author is a member of the Journal of Clinical Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript. Dustin A. DemingConsulting or Advisory Role: Bayer, Promega, Array BioPharma, Lilly, PfizerResearch Funding: Merck (Inst), Bristol Myers Squibb (Inst), Genentech (Inst), Revolution Medicines (Inst), Millennium (Inst), Bayer Edith P. MitchellLeadership: Corvus PharmaceuticalsHonoraria: Sanofi, ExelixisConsulting or Advisory Role: Genentech, Novartis, Merck, Bristol Myers SquibSpeakers' Bureau: IpsenResearch Funding: Genentech (Inst), sanofi (Inst) Robert J. GrayResearch Funding: Agios, Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Genentech/Roche, Genomic Health, Genzyme, GlaxoSmithKline, Janssen-Ortho, Onyx, Pfizer, Sequenta, Syndax, Novartis, Takeda, AbbVie, Sanofi, Merck Sharp & Dohme Lisa M. McShaneThis author is a member of the Journal of Clinical Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript. Larry V. RubinsteinThis author is a member of the Journal of Clinical Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript. P. Mickey WilliamsResearch Funding: Illumina (Inst)Patents, Royalties, Other Intellectual Property: I was a coinventor of the DLBCL cell of origin patent recently filed by the NIH Stanley R. HamiltonResearch Funding: Minerva Biotechnologies, Intima Carlos L. ArteagaStock and Other Ownership Interests: Provista DiagnosticsConsulting or Advisory Role: Novartis, Lilly, Sanofi, Radius Health, Taiho Pharmaceutical, Puma Biotechnology, Merck, Origimed, Immunomedics, Daiichi Sankyo, Athenex, Astrazeneca, ArvinasResearch Funding: Pfizer, Lilly, TakedaOther Relationship: Susan G. Komen for the Cure Lyndsay N. HarrisPatents, Royalties, Other Intellectual Property: Philips Healthcare Peter J. O'DwyerConsulting or Advisory Role: GenentechResearch Funding: Bristol Myers Squibb (Inst), Pfizer (Inst), Novartis (Inst), Genentech (Inst), Mirati Therapeutics (Inst), Celgene (Inst), GlaxoSmithKline (Inst), BBI Healthcare (Inst), Pharmacyclics (Inst), Five Prime Therapeutics (Inst), Forty Seven (Inst), Amgen (Inst), H3 Biomedicine (Inst), Taiho Pharmaceutical (Inst), Array BioPharma (Inst), Lilly/ImClone (Inst), Syndax (Inst), Minneamrita Therapeutics (Inst)Expert Testimony: Lilly, Dai-ichi Sankyo Alice P. ChenUncompensated Relationships: Frontiers in Medicine Keith T. FlahertyStock and Other Ownership Interests: Clovis Oncology, Loxo, X4 Pharma, Strata Oncology, PIC Therapeutics, Shattuck Labs, Apricity Health, Oncoceutics, FOGPharma, Tvardi Therapeutics, Checkmate Pharmaceuticals, Kinnate Biopharma, Scorpion Therapeutics, ALX Oncology, xCures, Monopteros Therapeutics, Vibliome Therapeutics, Transcode Therapeutics, Soley TherapeuticsConsulting or Advisory Role: Novartis, Lilly, Oncoceutics, Tvardi Therapeutics, Takeda, Boston Biomedical, Debiopharm Group, FOGPharmaNo other potential conflicts of interest were reported.

Background and Aims: Management of patients with NASH who are at elevated risk of progressing to complications of cirrhosis (at-risk NASH) would be enhanced by an accurate, noninvasive diagnostic test. The new FAST™ score, a combination of FibroScan® parameters liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) and aspartate aminotransferase (AST), has shown good diagnostic accuracy for at-risk NASH (area-under-the-Receiver-Operating-Characteristic [AUROC] = 0.80) in European cohorts. We aimed to validate the FAST™ score in a North American cohort and show how its diagnostic accuracy might vary by patient mix. We also compared the diagnostic performance of FAST™ to other non-invasive algorithms for the diagnosis of at-risk NASH., Methods: We studied adults with biopsy-proven non-alcoholic fatty liver disease (NAFLD) from the multicenter NASH Clinical Research Network (CRN) Adult Database 2 (DB2) cohort study. At-risk-NASH was histologically defined as definite NASH with a NAFLD Activity Score (NAS) ≥ 4 with at least 1 point in each category and a fibrosis stage ≥ 2. We used the Echosens® formula for FAST™ from LSM (kPa), CAP (dB/m), and AST (U/L), and the FAST™-based Rule-Out (FAST™ ≤ 0.35, sensitivity = 90%) and Rule-In (FAST™ ≥ 0.67, specificity = 90%) zones. We determined the following diagnostic performance measures: AUROC, sensitivity (Se), specificity (Sp), positive predictive value (PPV), and negative predictive value (NPV); these were calculated for the total sample and by subgroups of patients and by FibroScan® exam features. We also compared the at-risk NASH diagnostic performance of FAST™ to other non-invasive algorithms: NAFLD fibrosis score (NFS), Fibrosis-4 (FIB-4) index, and AST to platelet ratio index (APRI)., Results: The NASH CRN population of 585 patients was 62% female, 79% white, 14% Hispanic, and 73% obese; the mean age was 51 years. The mean (SD) AST and ALT were 50 (37) U/L and 66 (45) U/L, respectively. 214 (37%) had at-risk NASH. The AUROC of FAST™ for at-risk NASH in the NASH CRN study population was 0.81 (95% CI: 0.77, 0.84. Using FAST™-based cut-offs, 35% of patients were ruled-out with corresponding NPV = 0.90 and 27% of patients were ruled-in with corresponding PPV = 0.69. The diagnostic accuracy of FAST™ was higher in non-whites vs. whites (AUROC: 0.91 vs 0.78; p = 0.001), and in patients with a normal BMI vs. BMI > 35 kg/m2 (AUROC: 0.94 vs 0.78, p = 0.008). No differences were observed by other patient characteristics or FibroScan® exam features. The FAST™ score had higher diagnostic accuracy than other non-invasive algorithms for the diagnosis of at-risk NASH (AUROC for NFS, FIB-4, and APRI 0.67, 0.73, 0.74, respectively)., Conclusion: We validated the FAST™ score for the diagnosis of at-risk NASH in a large, multi-racial population in North America, with a prevalence of at-risk NASH of 37%. Diagnostic performance varies by subgroups of NASH patients defined by race and obesity. FAST™ performed better than other non-invasive algorithms for the diagnosis of at-risk NASH., Competing Interests: Dr. Manal Abdelmalek: None for this project. Dr. Abdelmalek has served as a consultant to Merck, Bristol Myers Squibb, Novartis, Novo Nordisk, Hanmi, TaiwanJ, Madrigal and NGM Bio. Her institution has received grant support from Allergan, Intercept, Boehringer-Ingelheim, Bristol Myers Squibb, Madrigal, Novo Nordisk, NGM Bio, Novartis, Viking, Hanmi, TARGET NASH, Celgene, and Genentech. She receives royalties from Elsevier and Up-to-Date Dr. Cynthia Behling: Dr. Behling is a consultant for ICON, COVANCE, Eli Lilly, Hologic, and Leica outside the submitted work. Dr. Naga Chalasani: There are none for this paper. For full disclosure, Dr. Chalasani has ongoing consulting activities (or had in preceding 12 months) with Abbvie, Madrigal, Zydus, Galectin, Boehringer-Ingelheim, Altimmune, and Foresite. These consulting activities are generally in the areas of nonalcoholic fatty liver disease and drug hepatotoxicity. Dr. Chalasani has equity in RestUp, a home health care provider agency. Dr. Chalasani receives research grant support from DSM and Exact Sciences where his institution receives the funding. Dr. Anna Mae Diehl: Dr. Diehl has consulted for Allergan, Alderya Therapeutics, Boehringer-Ingelheim, Celgene, Filcitrine, IBM Watson Health, Lumena, Merk, Novartis, Pfizer, Pliant, Roche, Quest Diagnostics, and twoXAR. She has research collaborations with Allergan, Boehringer-Ingelheim, Bristol Myers Squibb, Conatus, Exalenze, Galactin, Galmed, Genfit, Gilead, Hanmi, Hi La, Immuron, Intercept, Madrigal Metabolomics, NGM Pharmaceuticals, Prometheus, and Shire. Dr. Samer Gawrieh: Dr. Gawrieh has consulted for TransMedics and Pfizer and received research grant support from Cirius, Galmed, Viking, Zydus and Sonic Incytes. Dr. Kris Kowdley: Dr. Kowdley has consulted for Akero, Calliditas, Corcept, CymaBay, Enanta, Genfit, Gilead, HighTide, Inipharm and Intercept. His institution has received grant and research support from Allergan, Enanta, Galectin, Gilead, Immuron, Intercept, Novartis, Prometheus, and Zydus. Dr. Kowdley is on the Advisory Board for Conatus and Gilead, and is on the Speaker Bureau for Abbvie, Gilead and Intercept. Dr. Rohit Loomba: There are none for this paper. Dr. Loomba serves as a consultant or advisory board member for 89bio, Alnylam, Arrowhead Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Bristol-Myer Squibb, Cirius, CohBar, DiCerna, Galmed, Gilead, Glympse bio, Intercept, Ionis, Metacrine, NGM Biopharmaceuticals, Novo Nordisk, Pfizer, Sagimet and Viking Therapeutics. In addition, his institution has received grant support from Allergan, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly and Company, Galmed Pharmaceuticals, Genfit, Gilead, Intercept, Inventiva, Janssen, Madrigal Pharmaceuticals, NGM Biopharmaceuticals, Novartis, Pfizer, pH Pharma, and Siemens. He is also co-founder of Liponexus, Inc. Dr. Loomba receives funding support from NIEHS (5P42ES010337), NCATS (5UL1TR001442), NIDDK (R01DK106419, 1R01DK121378, R01 DK124318, P30DK120515), and DOD PRCRP (CA170674P2). Dr. Brent Neuschwander-Tetri: None for the project. Consultant or advisor for Akero, Alimentiv, Allergan, Alnylam, Amgen, Arrowhead, Axcella, Boehringer Ingelheim, BMS, Durect, Enanta, Fortress, Gelesis, Genfit, Gilead, HepGene, High Tide, HistoIndex, Intercept, Ionis, LG Chem, Lipocine, Madrigal, Medimmune, Merck, Mirum, NGM, NovoNordisk, pH-Pharma, Sagimet, Siemens, Theratechnologies, 89Bio; Institutional research grants: Allergan, BMS, Cirius, Enanta, Genfit, Gilead, Intercept, Madrigal, NGM Dr. Arun Sanyal: None for this project. Dr. Sanyal is President of Sanyal Biotechnology and has stock options in Genfit, Akarna, Tiziana, Indalo, Durect Inversago and Galmed. He has served as a consultant to Astra Zeneca, Nitto Denko, Conatus, Nimbus, Salix, Tobira, Takeda, Jannsen, Gilead, Terns, Birdrock, Merck, Valeant, Boehringer-Ingelheim, Bristol Myers Squibb, Lilly, Hemoshear, Zafgen, Novartis, Novo Nordisk, Pfizer, Exhalenz and Genfit. He has been an unpaid consultant to Intercept, Echosens, Immuron, Galectin, Fractyl, Syntlogic, Affimune, Chemomab, Zydus, Nordic Bioscience, Albireo, Prosciento, Surrozen. His institution has received grant support from Gilead, Salix, Tobira, Bristol Myers, Shire, Intercept, Merck, Astra Zeneca, Malinckrodt, Cumberland and Novartis. He receives royalties from Elsevier and UptoDate. Dr. Mohammad Siddiqui: Dr. Siddiqui is a consultant for Pfizer and is on an advising board for AMRA. Dr. Norah Terrault: Dr. Terrault received institutional grant support from Gilead Sciences, Roche-Genentech and GSK, and consulting for Gilead Sciences, Saol Therapeutics and Moderna. Dr. Raj Vuppalanchi: Dr. Vuppalanchi received a one-time consultant fee from EchoSens on spleen stiffness measurement. No conflicts of interest: Jeanne Clark, Srinivasan Dasarathy, Mark Fishbein, Paula Hertel, David Kleiner, Arunkumar Krishnan, Mariana Lazo, Arthur McCullough, Laura Miriel, Emily Mitchell, James Tonascia, Mark Van Natta, Laura Wilson, Tinsay Woreta This does not alter our adherence to PLOS ONE policies on sharing data and materials.

The NCI-MATCH was designed to characterize the efficacy of targeted therapies in histology-agnostic driver mutation-positive malignancies. Sub-protocols F and G were developed to evaluate the role of crizotinib in rare tumors that harbored either ALK or ROS1 rearrangements. Patients with malignancies that progressed following at least one prior systemic therapy were accrued to the NCI-MATCH for molecular profiling, and those with actionable ALK or ROS1 rearrangements were offered participation in sub-protocols F or G, respectively. There were five patients who enrolled on Arm F (ALK) and four patients on Arm G (ROS1). Few grade 3 or 4 toxicities were noted, including liver test abnormalities, and acute kidney injury. For sub-protocol F (ALK), the response rate was 50% (90% CI 9.8-90.2%) with one complete response among the 4 eligible patients. The median PFS was 3.8 months, and median OS was 4.3 months. For sub-protocol G (ROS1) the response rate was 25% (90% CI 1.3-75.1%). The median PFS was 4.3 months, and median OS 6.2 months. Data from 3 commercial vendors showed that the prevalence of ALK and ROS1 rearrangements in histologies other than non-small cell lung cancer and lymphoma was rare (0.1% and 0.4% respectively). We observed responses to crizotinib which met the primary endpoint for ALK fusions, albeit in a small number of patients. Despite the limited accrual, some of the patients with these oncogenic fusions can respond to crizotinib which may have a therapeutic role in this setting., (© 2022. The Author(s).)

Polyphasic skeletal muscle degeneration, necrosis and mineralization of skeletal muscle was diagnosed in eight juvenile free-ranging lions ( Panthera leo ), from five different litters in the Greater Kruger National Park area that were unable to walk properly. A detailed investigation was not possible in free-ranging lions, so the cause could not be determined. The cases resembled hypokalemic polymyopathy in domestic cats with muscle weakness. A candidate-gene approach previously identified a nonsense mutation in the gene coding for the enzyme lysine-deficient 4 protein kinase (WNK4) associated with the disease in Burmese and Tonkinese cats. In this study, we sequenced all 19 exons of the gene in one case, and two control samples, to identify possible mutations that may be associated with polymyopathy in free-ranging lions. Here, no mutations were detected in any of the exons sequenced. Our findings indicate that the WNK4 gene is not a major contributor to the condition in these lions. Further studies into the pathogenesis of this condition are needed to inform conservation policies for this vulnerable, iconic African species.

Purpose: PIK3CA mutations frequently contribute to oncogenesis in solid tumors. Taselisib, a potent and selective inhibitor of phosphoinositide 3-kinase, has demonstrated clinical activity in PIK3CA -mutant breast cancer. Whether PIK3CA mutations predict sensitivity to taselisib in other cancer types is unknown. National Cancer Institute-Molecular Analysis for Therapy Choice Arm EAY131-I is a single-arm, phase II study of the safety and efficacy of taselisib in patients with advanced cancers., Methods: Eligible patients had tumors with an activating PIK3CA mutation. Patients with breast or squamous cell lung carcinoma, or whose cancer had KRAS or PTEN mutations, were excluded. Patients received taselisib 4 mg, orally once daily continuously, until disease progression or unacceptable toxicity. The primary end point was objective response rate. Secondary end points included progression-free survival (PFS), 6-month PFS, overall survival (OS), and identification of predictive biomarkers., Results: Seventy patients were enrolled, and 61 were eligible and initiated protocol therapy. Types of PIK3CA mutations included helical 41 of 61 (67%), kinase 11 of 61 (18%), and other 9 of 61 (15%). With a median follow-up of 35.7 months, there were no complete or partial responses. Six-month PFS was 19.9% (90% CI, 12.0 to 29.3) and median PFS was 3.1 months (90% CI, 1.8 to 3.7). Six-month OS was 60.7% (90% CI, 49.6 to 70.0) and median OS was 7.2 months (90% CI, 5.9 to 10.0). Individual comutations were too heterogeneous to correlate with clinical outcome. Fatigue, diarrhea, nausea, and hyperglycemia were the most common toxicities, and most were grade 1 and 2., Conclusion: In this study, taselisib monotherapy had very limited activity in a heterogeneous cohort of heavily pretreated cancer patients with PIK3CA -mutated tumors; the presence of a PIK3CA mutation alone does not appear to be a sufficient predictor of taselisib activity., Competing Interests: Ian E. KropEmployment: Freeline Therapeutics (I), PureTech (I), AMAG Pharmaceuticals (I)Leadership: AMAG Pharmaceuticals (I), Freeline Therapeutics (I), PureTech (I)Stock and Other Ownership Interests: AMAG Pharmaceuticals (I), Freeline Therapeutics (I), PureTech (I)Honoraria: Genentech/Roche, AstraZeneca, CelltrionConsulting or Advisory Role: Genentech/Roche, Seattle Genetics, Daiichi Sankyo, Macrogenics, Novartis, Merck, Bristol Myers Squibb, AstraZenecaResearch Funding: Genentech (Inst), Pfizer (Inst) Juneko E. Grilley-OlsonConsulting or Advisory Role: Bayer, Chimerix, Kura Oncology, SpringWorks TherapeuticsResearch Funding: NanoCarrier (Inst), Genentech (Inst), Seattle Genetics (Inst), Pfizer (Inst), Loxo (Inst), Astellas Pharma (Inst), Iovance Biotherapeutics (Inst) Josh D. LauringEmployment: Janssen Research & DevelopmentStock and Other Ownership Interests: Johnson & JohnsonConsulting or Advisory Role: Galderma (I), Regeneron (I), Novartis (I)Speakers' Bureau: Galderma (I), AbbVie (I), Pfizer (I)Patents, Royalties, Other Intellectual Property: I intermittently receive royalty payments for cell lines created in my laboratory, which are licensed for commercial sale to Horizon Discovery, Ltd by Johns Hopkins UniversityTravel, Accommodations, Expenses: Galderma (I), AbbVie (I) Edith P. MitchellLeadership: Corvus PharmaceuticalsHonoraria: Sanofi, ExelixisConsulting or Advisory Role: Genentech, Novartis, Merck, Bristol Myers SquibSpeakers' Bureau: IpsenResearch Funding: Genentech (Inst), sanofi (Inst) Robert J. GrayResearch Funding: Agios, Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Genentech/Roche, Genomic Health, Genzyme, GlaxoSmithKline, Janssen-Ortho, Onyx, Pfizer, Sequenta, Syndax, Novartis, Takeda, AbbVie, Sanofi, Merck Sharp & Dohme P. Mickey WilliamsResearch Funding: Illumina (Inst)Patents, Royalties, Other Intellectual Property: I was a coinventor of the DLBCL cell of origin patent recently filed by the NIH Stanley R. HamiltonResearch Funding: Minerva Biotechnologies, Intima James M. FordThis author is the Editor-in-Chief for JCO Precision Oncology. Journal policy recused the author from having any role in the peer review of this manuscript.Research Funding: Genentech (Inst), AstraZeneca (Inst), Puma Biotechnology (Inst), Pfizer (Inst), Merus (Inst), Bayer (Inst), Incyte (Inst) Agustin A. GarciaConsulting or Advisory Role: Biotheranostics, GlaxoSmithKlineResearch Funding: Advenchen Laboratories (Inst), Seattle Genetics (Inst), Merck (Inst), Iovance Pharm (Inst) Xingwei D. SuiConsulting or Advisory Role: Novartis Robert D. SiegelResearch Funding: Merck (Inst), Mirati Therapeutics (Inst), GRAIL (Inst), Altor BioScience (Inst), Galera Therapeutics (Inst), Apollomics (Inst), Strata Oncology (Inst), Arcus Biosciences (Inst), Bristol Myers Squibb (Inst), Cancer Insight (Inst), Puma Biotechnology (Inst), Conjupro Biotherapeutics (Inst), Razor Genomics (Inst), Sanofi (Inst), Seattle Genetics (Inst)Other Relationship: American Board of Internal Medicine (ABIM) Brian M. SlomovitzConsulting or Advisory Role: Clovis Oncology, AstraZeneca, Genentech, Incyte, Agenus, GlaxoSmithKline, GOG Foundation, Myriad Genetics, Merck, Eisai Carlos L. ArteagaStock and Other Ownership Interests: Provista DiagnosticsConsulting or Advisory Role: Novartis, Lilly, Sanofi, Radius Health, Taiho Pharmaceutical, Puma Biotechnology, Merck, Origimed, Immunomedics, Daiichi Sankyo, Athenex, Astrazeneca, ArvinasResearch Funding: Pfizer, Lilly, TakedaOther Relationship: Susan G. Komen for the Cure Lyndsay N. HarrisPatents, Royalties, Other Intellectual Property: Philips Healthcare Peter J. O'DwyerConsulting or Advisory Role: GenentechResearch Funding: Bristol Myers Squibb (Inst), Pfizer (Inst), Novartis (Inst), Genentech (Inst), Mirati Therapeutics (Inst), Celgene (Inst), GlaxoSmithKline (Inst), BBI Healthcare (Inst), Pharmacyclics (Inst), Five Prime Therapeutics (Inst), Forty Seven (Inst), Amgen (Inst), H3 Biomedicine (Inst), Taiho Pharmaceutical (Inst), Array BioPharma (Inst), Lilly/ImClone (Inst), Syndax (Inst), Syndax (Inst), Syndax (Inst), Syndax (Inst), syndax (Inst), Minneamrita Therapeutics (Inst)Expert Testimony: Lilly, Dai-ichi Sankyo Alice P. Chen(OPTIONAL) Uncompensated Relationships: Frontiers in Medicine Keith T. FlahertyStock and Other Ownership Interests: Clovis Oncology, Loxo, X4 Pharma, Strata Oncology, PIC Therapeutics, Shattuck Labs, Apricity Health, Oncoceutics, FOGPharma, Tvardi Therapeutics, Checkmate Pharmaceuticals, Kinnate Biopharma, Scorpion Therapeutics, ALX Oncology, xCures, Monopteros Therapeutics, Vibliome Therapeutics, Transcode Therapeutics, Soley TherapeuticsConsulting or Advisory Role: Novartis, Lilly, Oncoceutics, Tvardi Therapeutics, Takeda, Boston Biomedical, Debiopharm Group, FOGPharmaNo other potential conflicts of interest were reported.