A true challenge: Disseminated tuberculosis with tuberculous meningitis in a patient with underlying chronic liver disease.

Tuberculous meningitis (TBM) is a potentially life-threatening form of tuberculosis (TB) that affects the central nervous system. Its management in patients with concomitant chronic liver disease (CLD) presents unique challenges due to altered drug metabolism with potentially impaired spinal fluid drug penetration and hepatotoxicity. The standard regimen for TBM includes isoniazid (INH) and rifampin (RIF), and Pyrazinamide (PZA) which are metabolized by the liver and may cause hepatotoxicity, which can exacerbate preexisting liver disease. Thus, careful consideration is required to balance therapeutic efficacy with potential drug-induced hepatotoxicity. Regular monitoring of liver function tests and clinical response is essential to minimize adverse effects and optimize treatment outcomes. Further research is needed to establish evidence-based guidelines for the tailored management of TBM in this vulnerable patient subset. Overall, the treatment of TBM in patients with severe liver disease should be individualized and closely monitored.

Personality dimensions, depression, and eating behavior in individuals seeking bariatric surgery: a cluster analysis.

Introduction: Psychiatric comorbidity is frequent in bariatric surgery candidates. This study aimed to classify bariatric surgery patients according to patterns of preoperative measures of the severity of the eating disorder (ED), depression, and personality traits. Methods: In the present cross-sectional study, 115 adult candidates for bariatric surgery (75 females, 65.22% of sample; mean age 37) were considered for analysis. Patients' sociodemographic and psychopathological variables were collected. K-Means clustering analysis was adopted to classify bariatric surgery candidates according to their preoperative Eating Disorder Inventory-2 (EDI-2) scores. In addition, we assessed depression and personality traits using the Beck Depression Inventory-2 (BDI-2) and the Minnesota Multiphasic Personality Inventory-2 (MMPI-2). Results: Cluster analysis based on EDI-2 revealed two preoperative patterns: higher severity (n = 39), and low severity (n = 76). The more severe EDI-2 group had higher scores on the BDI-2 and presented higher scores on several MMPI-2 dimensions, particularly those related to anxiety (Psychasthenia, Anxiety, Fears, Obsessiveness), depression (Depression, including both content and clinical MMPI-2 subscales), externalizing symptoms (Anger, Cynicism, Type A Behavior), and social functioning (Social Introversion, Family Problems, Work Interference). Discussion: Eating disorders symptoms in candidates for bariatric surgery are closely related to depression and different psychological conditions assessed with MMPI-2. These psychological variables should be evaluated preoperatively and targeted with more specific psychological interventions.

School Absenteeism Among Racially and Ethnically Minoritized Transgender High School Students and Their Peers: A Cross-Sectional Study.

PURPOSE: To explore absenteeism among racially and ethnically minoritized transgender youth (trans REMY) compared to their White transgender (trans WY) and racially and ethnically minoritized cisgender (cis REMY) peers and identify associated psychosocial factors. METHODS: Biennial California Healthy Kids Survey 2017-2019 data was analyzed with a weighted sample of California's secondary school population. Students reported past 30-day absences due to mental health and harassment, depressive symptoms, suicidal ideation, cyberbullying, victimization, and school connectedness. Poisson and linear regression compared absenteeism and psychosocial factors among peer groups. For trans REMY, Poisson regression assessed associations between absenteeism and psychosocial factors. Analyses were adjusted for grade, sex, and socioeconomic status. RESULTS: The analytical sample (n = 25,085) included 206 trans REMY, 64 trans WY, and 24,815 cis REMY. Trans REMY had higher relative risk of absenteeism due to mental health concerns and harassment compared to cis REMY (adjusted relative risk 2.9, 95% confidence interval 2.1-4.0 and adjusted relative risk 8.1, 95% confidence interval 4.0-16.6, respectively) but similar risk when compared to trans WY. For trans REMY, depressive symptoms, suicidal ideation, and victimization were associated with higher relative risk of absenteeism due to mental health concerns. Cyberbullying was associated with a higher risk of absenteeism due to harassment. Higher school connectedness was associated with lower risk of absenteeism due to mental health concerns. DISCUSSION: Trans REMY reported higher rates of school absenteeism due to mental health concerns and harassment compared to some of their peers. Mental health symptoms, victimization, cyberbullying, and school connectedness were associated with absenteeism among trans REMY.

Community-Derived Recommendations for Improving Gender Affirmation of Black and Latine Transgender/Nonbinary Youth.

BACKGROUND: Gender affirmation is a process by which gender-diverse individuals are supported in their gender identity. Parents are critical in how gender-diverse youth, including Black and Latine transgender/nonbinary youth (BLTY), access various forms of gender affirmation-for example, social and medical transition. Culturally relevant supports are needed to bolster how BLTY and their parents navigate gender affirmation. PURPOSE: This study aimed to explore recommendations for aiding BLTY and parents in navigating the youth's gender journey. METHODS: Semi-structured interviews were conducted with parents of BLTY, BLTY, and BLT young adults (BLTYAs) recruited from clinics, community organizations, and social media. Interviews focused on gender affirmation and recommendations to promote BLTY's gender affirmation. Primary and secondary analysts coded transcripts using a priori and emergent codes. For this analysis, excerpts pertaining to recommended supports were analyzed to identify themes. RESULTS: Ten parents of BLTY, 10 BLTY (14-18 years), and 23 BLTYAs (18-30 years) participated. Participants provided recommendations at different socio-ecological levels. On the societal level, participants recommended improvements in media representation of racial and ethnic minority gender-diverse individuals. For organizations, participants recommended more clinicians who shared minoritized identities, clinicians knowledgeable in gender-affirming care, affordability of gender-affirming services, and school-based education regarding gender diversity. On interpersonal/individual levels, they suggested culturally informed peer support among BLTY and parents, including support groups, peer mentors, and camps with individuals who share their minoritized identities. CONCLUSIONS: Participants provided salient insights to supporting gender affirmation of BLTY, which can inform intervention development for BLTY and their families.

Black and Latine transgender/nonbinary youth (BLTY) have multiple minoritized identities as they are both racial/ethnic minorities and are gender diverse. These youth face unique challenges in being supported in their gender identity, and their parents face barriers to supporting their gender journey. Unfortunately, approaches to assisting BLTY and their parents in navigating this journey are poorly understood. We interviewed 10 BLTY, 10 related parents of the BLTY, and 23 Black and Latine transgender/nonbinary young adults (BLTYAs) recruited from clinics, community organizations, and social media. In this study, we explored their recommendations for better supporting and affirming BLTY. These recommendations targeted different areas of BLTY's lives. On a broader societal level, participants advocated media representation of gender-diverse individuals of color. For medical and mental health organizations, participants recommended more clinicians knowledgeable in supporting gender-diverse youth and more clinicians who share similar backgrounds with BLTY. For interpersonal and individual relationships, they recommended peer support groups and mentors for BLTY and parents of BLTY. These comprehensive recommendations from BLTY, parents, and BLTYAs can be implemented to better support BLTY in their gender identity through culturally based interventions in different domains.

Parental Gender Affirmation Model: A culturally informed framework.

Benefits of parental gender-affirming behaviors on the mental health and well-being of the broader gender-expansive youth population have been extensively documented. However, the nature and impact of these behaviors have not been explored by centering Black and Latine transgender/non-binary youth (BLTY). This article offers a new framework called the "Parental Gender Affirmation Model." This framework conceptualizes parental gender-affirming behaviors toward BLTY through the lenses of intersectional stigma and cultural gender norms and uses the Theory of Planned Behavior and Modified Gender Affirmation Model as foundational frameworks. We analyzed qualitative data from 43 interviews with BLTY, parents of BLTY, and Black and Latine transgender/non-binary young adults from California in the United States to develop the framework. The "Parental Gender Affirmation Model" starts with behavioral antecedents and ends with impacts of these behaviors on BLTY's well-being. This framework will inform the development of critically needed, culturally-informed interventions to support parental gender affirmation of BLTY.

Phase II Trial of Afatinib in Patients With EGFR-Mutated Solid Tumors Excluding Lung Cancer: Results From NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol A.

PURPOSE: National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH) was a multicohort phase 2 trial that assigned patients with advanced pretreated cancers to molecularly targeted therapies on the basis of tumor genomic testing. NCI-MATCH Arm A evaluated afatinib, an EGFR tyrosine kinase inhibitor (TKI) approved for advanced non-small cell lung cancer, in patients with tumors other than lung cancer harboring EGFR mutations. METHODS: Patients with advanced pretreated cancers other than lung cancer found to have selected actionable EGFR mutations were offered participation in Arm A. Previous therapy with an EGFR TKI was not allowed. Patients received afatinib 40 mg once daily continuously until disease progression or unacceptable toxicity. The primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), 6-month PFS, and overall survival (OS). RESULTS: Seventeen patients received protocol therapy. Tumor types included glioblastoma multiforme (GBM) (13), gliosarcoma (1), adenocarcinoma not otherwise specified (NOS) (2), and adenosquamous carcinoma of the breast (1). Fifty-nine percent of patients received ≥2 lines of previous therapy. The ORR was 11.8% (90% CI, 2.1 to 32.6), with one complete response lasting 16.4 months (GBM harboring a rare exon 18 EGFR-SEPT14 fusion) and one partial response lasting 12.8 months (adenocarcinoma NOS with the classic EGFR mutation, p.Glu746_Ala750del). Three patients had stable disease. The 6-month PFS was 15% (90% CI, 0 to 30.7); the median OS was 9 months (90% CI, 4.6 to 14.0). Rash and diarrhea were the most common toxicities. CONCLUSION: Afatinib had modest activity in a cohort of patients with heavily pretreated cancer with advanced nonlung, EGFR-mutated tumors, but the trial's primary end point was not met. Further evaluation of afatinib in GBM with EGFR exon 18 fusions may be of interest.

Surgical management of unilateral restrictive strabismus in an 8-month-old dog.

CASE HISTORY: An 8-month-old male, entire, mixed-breed dog was presented with a 1-month history of left exophthalmos and green mucopurulent ocular discharge. Subsequently, exophthalmos resolved but esotropia (medial strabismus) developed in the left eye, prompting referral to an ophthalmologist. CLINICAL FINDINGS: At the initial referral consultation, enophthalmos and esotropia of the left eye were identified. The patient showed mild improvement after a 3-week tapering course of oral prednisolone and doxycycline. MRI was performed and showed left medial rectus muscle atrophy with increased contrast enhancement which was consistent with chronic extraocular muscle myositis (EOM). A forced duction test was performed to confirm the diagnosis of fibrosing esotropia, which is likely a sequela of chronic EOM. DIAGNOSIS: Fibrosing esotropia presumably caused by untreated EOM. TREATMENT AND OUTCOME: One month later, esotropia progressed to a marked ventro-medial strabismus resulting in visual deprivation. Surgical release of the ventral oblique, medial and ventral recti muscles was performed, resulting in immediate resolution of the enophthalmos. Despite a tapering post-operative course of oral prednisolone, mild esotropia was present 4 weeks later. In an effort to stabilise the globe position, the low dose of prednisolone was increased to a higher anti-inflammatory dose before slowly tapering over 2 months. The vision in the left eye was improved after surgery and has been maintained since without further treatment. CLINICAL RELEVANCE: This is the first documented case of fibrosing esotropia in a young dog with prior signs of acute exophthalmos. Fibrosing esotropia has been documented in certain breeds or as a sequela to chronic EOM. In this patient, it was presumably caused by EOM, which was strongly supported by the case history, progression and MRI findings. Most historical reports of EOM described it as a bilateral condition that resolves with systemic corticosteroids at an anti-inflammatory dose. EOM has been shown to also present unilaterally and it can progress to strabismus if not promptly recognised and treated with systemic steroids. Surgical management can restore vision when severe strabismus results in visual deprivation.

EXPRESS: Landmark Publications in Analytical Atomic Spectrometry: Fundamentals and Instrumentation Development.

The almost-two-centuries history of spectrochemical analysis has generated a body of literature so vast that it has become nearly intractable for experts, much less for those wishing to enter the field. Authoritative, focused reviews help to address this problem but become so granular that the overall directions of the field are lost. This broader perspective can be provided partially by general overviews but then the thinking, experimental details, theoretical underpinnings and instrumental innovations of the original work must be sacrificed. In the present compilation, this dilemma is overcome by assembling the most impactful publications in the area of analytical atomic spectrometry. Each entry was proposed by at least one current expert in the field and supported by a narrative that justifies its inclusion. The entries were then assembled into a coherent sequence and returned to contributors for a round-robin review.

CARs derived from broadly neutralizing, human monoclonal antibodies identified by single B cell sorting target hepatitis B virus-positive cells.

To design new CARs targeting hepatitis B virus (HBV), we isolated human monoclonal antibodies recognizing the HBV envelope proteins from single B cells of a patient with a resolved infection. HBV-specific memory B cells were isolated by incubating peripheral blood mononuclear cells with biotinylated hepatitis B surface antigen (HBsAg), followed by single-cell flow cytometry-based sorting of live, CD19+ IgG+ HBsAg+ cells. Amplification and sequencing of immunoglobulin genes from single memory B cells identified variable heavy and light chain sequences. Corresponding immunoglobulin chains were cloned into IgG1 expression vectors and expressed in mammalian cells. Two antibodies named 4D06 and 4D08 were found to be highly specific for HBsAg, recognized a conformational and a linear epitope, respectively, and showed broad reactivity and neutralization capacity against all major HBV genotypes. 4D06 and 4D08 variable chain fragments were cloned into a 2nd generation CAR format with CD28 and CD3zeta intracellular signaling domains. The new CAR constructs displayed a high functional avidity when expressed on primary human T cells. CAR-grafted T cells proved to be polyfunctional regarding cytokine secretion and killed HBV-positive target cells. Interestingly, background activation of the 4D08-CAR recognizing a linear instead of a conformational epitope was consistently low. In a preclinical model of chronic HBV infection, murine T cells grafted with the 4D06 and the 4D08 CAR showed on target activity indicated by a transient increase in serum transaminases, and a lower number of HBV-positive hepatocytes in the mice treated. This study demonstrates an efficient and fast approach to identifying pathogen-specific monoclonal human antibodies from small donor cell numbers for the subsequent generation of new CARs.

Sensitive bispecific chimeric T cell receptors for cancer therapy.

The expression of a synthetic chimeric antigen receptor (CAR) to redirect antigen specificity of T cells is transforming the treatment of hematological malignancies and autoimmune diseases [1-7]. In cancer, durable efficacy is frequently limited by the escape of tumors that express low levels or lack the target antigen [8-12]. These clinical results emphasize the need for immune receptors that combine high sensitivity and multispecificity to improve outcomes. Current mono- and bispecific CARs do not faithfully recapitulate T cell receptor (TCR) function and require high antigen levels on tumor cells for recognition [13-17]. Here, we describe a novel synthetic chimeric TCR (ChTCR) that exhibits superior antigen sensitivity and is readily adapted for bispecific targeting. Bispecific ChTCRs mimic TCR structure, form classical immune synapses, and exhibit TCR-like proximal signaling. T cells expressing Bi-ChTCRs more effectively eliminated tumors with heterogeneous antigen expression in vivo compared to T cells expressing optimized bispecific CARs. The Bi-ChTCR architecture is resilient and can be designed to target multiple B cell lineage and multiple myeloma antigens. Our findings identify a broadly applicable approach for engineering T cells to target hematologic malignancies with heterogeneous antigen expression, thereby overcoming the most frequent mechanism of relapse after current CAR T therapies.

HA-1-targeted T-cell receptor T-cell therapy for recurrent leukemia after hematopoietic stem cell transplantation.

ABSTRACT: Relapse is the leading cause of death after allogeneic hematopoietic stem cell transplantation (HCT) for leukemia. T cells engineered by gene transfer to express T cell receptors (TCR; TCR-T) specific for hematopoietic-restricted minor histocompatibility (H) antigens may provide a potent selective antileukemic effect post-HCT. We conducted a phase 1 clinical trial using a novel TCR-T product targeting the minor H antigen, HA-1, to treat or consolidate treatment of persistent or recurrent leukemia and myeloid neoplasms. The primary objective was to evaluate the feasibility and safety of administration of HA-1 TCR-T after HCT. CD8+ and CD4+ T cells expressing the HA-1 TCR and a CD8 coreceptor were successfully manufactured from HA-1-disparate HCT donors. One or more infusions of HA-1 TCR-T following lymphodepleting chemotherapy were administered to 9 HCT recipients who had developed disease recurrence after HCT. TCR-T cells expanded and persisted in vivo after adoptive transfer. No dose-limiting toxicities occurred. Although the study was not designed to assess efficacy, 4 patients achieved or maintained complete remissions following lymphodepletion and HA-1 TCR-T, with 1 patient still in remission at >2 years. Single-cell RNA sequencing of relapsing/progressive leukemia after TCR-T therapy identified upregulated molecules associated with T-cell dysfunction or cancer cell survival. HA-1 TCR-T therapy appears feasible and safe and shows preliminary signals of efficacy. This clinical trial was registered at ClinicalTrials.gov as #NCT03326921.

Phase II Study of Osimertinib in Patients With Epidermal Growth Factor Receptor Mutations: Results From the NCI-MATCH ECOG-ACRIN (EAY131) Trial Subprotocol E.

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_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_N771insSVD mutation. Osimertinib was well tolerated and had a safety profile consistent with previous studies.

TIM-3+ CD8 T cells with a terminally exhausted phenotype retain functional capacity in hematological malignancies.

Chronic antigen stimulation is thought to generate dysfunctional CD8 T cells. Here, we identify a CD8 T cell subset in the bone marrow tumor microenvironment that, despite an apparent terminally exhausted phenotype (TPHEX), expressed granzymes, perforin, and IFN-γ. Concurrent gene expression and DNA accessibility revealed that genes encoding these functional proteins correlated with BATF expression and motif accessibility. IFN-γ+ TPHEX effectively killed myeloma with comparable efficacy to transitory effectors, and disease progression correlated with numerical deficits in IFN-γ+ TPHEX. We also observed IFN-γ+ TPHEX within CD19-targeted chimeric antigen receptor T cells, which killed CD19+ leukemia cells. An IFN-γ+ TPHEX gene signature was recapitulated in TEX cells from human cancers, including myeloma and lymphoma. Here, we characterize a TEX subset in hematological malignancies that paradoxically retains function and is distinct from dysfunctional TEX found in chronic viral infections. Thus, IFN-γ+ TPHEX represent a potential target for immunotherapy of blood cancers.

Phase II Study of Erdafitinib in Patients With Tumors With Fibroblast Growth Factor Receptor Mutations or Fusions: Results From the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol K2.

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.

Phase II Study of Erdafitinib in Patients With Tumors With FGFR Amplifications: Results From the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol K1.

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.

A unique case of hypervirulent Klebsiella pneumoniae acute cholecystitis complicated by portal vein thrombophlebitis: A case report and literature review.

Hypervirulent Klebsiella pneumoniae remains a significant global public health concern, characterized by a unique syndrome involving monomicrobial primary pyogenic liver abscesses, often leading to metastatic complications such as endophthalmitis, meningitis, and other infections. These infections are frequently observed in immunocompetent hosts or diabetic patients, particularly those of Asian ethnicity. In this report, we present the case of a 66-year-old Burmese female, currently residing in the United States, who presented with severe swelling, pain, discharge, and vision loss in her left eye, along with abdominal pain. Subsequent investigation revealed monomicrobial Klebsiella pneumoniae acute cholecystitis with an adjacent liver abscess, complicated by bacteremia, endogenous endophthalmitis, and portal vein thrombosis. Treatment with ceftriaxone proved successful in addressing her intra-abdominal infections, while anticoagulation therapy was initiated following multidisciplinary discussions among all involved subspecialties. Early diagnosis and the timely administration of appropriate treatment are crucial in reducing mortality and preventing further complications.

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.

Systemically administered low-affinity HER2 CAR T cells mediate antitumor efficacy without toxicity.

BACKGROUND: The paucity of tumor-specific targets for chimeric antigen receptor (CAR) T-cell therapy of solid tumors necessitates careful preclinical evaluation of the therapeutic window for candidate antigens. Human epidermal growth factor receptor 2 (HER2) is an attractive candidate for CAR T-cell therapy in humans but has the potential for eliciting on-target off-tumor toxicity. We developed an immunocompetent tumor model of CAR T-cell therapy targeting murine HER2 (mHER2) and examined the effect of CAR affinity, T-cell dose, and lymphodepletion on safety and efficacy. METHODS: Antibodies specific for mHER2 were generated, screened for affinity and specificity, tested for immunohistochemical staining of HER2 on normal tissues, and used for HER2-targeted CAR design. CAR candidates were evaluated for T-cell surface expression and the ability to induce T-cell proliferation, cytokine production, and cytotoxicity when transduced T cells were co-cultured with mHER2+ tumor cells in vitro. Safety and efficacy of various HER2 CARs was evaluated in two tumor models and normal non-tumor-bearing mice. RESULTS: Mice express HER2 in the same epithelial tissues as humans, rendering these tissues vulnerable to recognition by systemically administered HER2 CAR T cells. CAR T cells designed with single-chain variable fragment (scFvs) that have high-affinity for HER2 infiltrated and caused toxicity to normal HER2-positive tissues but exhibited poor infiltration into tumors and antitumor activity. In contrast, CAR T cells designed with an scFv with low-affinity for HER2 infiltrated HER2-positive tumors and controlled tumor growth without toxicity. Toxicity mediated by high-affinity CAR T cells was independent of tumor burden and correlated with proliferation of CAR T cells post infusion. CONCLUSIONS: Our findings illustrate the disadvantage of high-affinity CARs for targets such as HER2 that are expressed on normal tissues. The use of low-affinity HER2 CARs can safely regress tumors identifying a potential path for therapy of solid tumors that exhibit high levels of HER2.