Immune-related adverse events (irAEs) have emerged as a potential surrogate marker for immunotherapy response across tumor types. We evaluated the association between irAEs and pathologic complete response (pCR) in a racially diverse cohort of patients with triple-negative breast cancer (TNBC) treated with neoadjuvant chemoimmunotherapy.

We conducted a retrospective analysis of 46 patients with early-stage TNBC treated with neoadjuvant chemoimmunotherapy between January 2021 and March 2023 at a single NCI-designated Comprehensive Cancer Center. irAEs, tumor-infiltrating lymphocytes (TILs), and clinicopathologic characteristics were abstracted from the medical record. Associations with pCR were analyzed using Fisher's exact and Wilcoxon rank-sum tests.

Among 46 patients, the median age was 60.5 years. Most identified as Black (n = 27, 58.7%) or Hispanic (n = 14, 30.4%). irAEs occurred in 13 patients (28.2%), most commonly hypothyroidism, rash, and arthritis. The pCR rate was 55.8% (24/43 evaluable patients). Patients who developed irAEs were more likely to achieve pCR (84.6% vs. 45.2%, p = 0.039). Higher TILs (median 29%) were associated with pCR both as a continuous variable (p = 0.004) and categorically (p = 0.002), but not with irAE development (p = 0.341). pCR was more common among Hispanic patients (p = 0.005), and inversely associated with Black race (p = 0.003) and older age (p = 0.028).

IrAEs may serve as a surrogate for treatment response to neoadjuvant chemoimmunotherapy in early TNBC. Additionally, racial and age-based differences in treatment response suggest underlying immunologic or biologic variation. These findings highlight the importance of diverse cohort representation in immunotherapy studies and warrant validation in prospective trials.

Hematopoietic stem cell transplantation (HSCT) is a curative option for children with high-risk acute lymphoblastic leukemia (ALL). This retrospective single-center study analyzed 236 pediatric ALL patients in complete remission who underwent allogeneic HSCT using ex-vivo T cell depletion between 2012 and 2021. The majority received haploidentical grafts (n = 202), while the remainder received matched unrelated donor (MUD) grafts (n = 34). At four years, event-free survival (EFS) and overall survival (OS) were 57% and 67%, respectively. Total body irradiation (TBI)-based conditioning was associated with significantly lower relapse rates and superior EFS compared to chemotherapy-based regimens. Non-relapse mortality (NRM) was low (9%), with no significant difference between donor types. Pre-transplant minimal residual disease (MRD) positivity and transplantation beyond first complete remission were independently associated with higher relapse and inferior survival. Chronic GVHD incidence was lower in patients receiving abatacept and tocilizumab instead of ATG. These findings confirm the safety and efficacy of ex-vivo T cell-depleted HSCT in pediatric ALL, with outcomes comparable between haploidentical and MUD donors. TBI-based conditioning and MRD negativity remain key prognostic factors for improved outcome.

Bone marrow-resident mesenchymal stem cells (BM-MSC) often play a role in acute myeloid leukemia (AML) progression and drug resistance by exerting immunomodulatory effects on cellular as well as soluble milieu. The current study aimed to understand the dynamic interplay between AML-BM-MSC and their soluble factors in determining the fate of AML blasts within the microenvironment.

AML-BM-MSC were cultured and characterized for expression of phenotyping markers, multilineage differentiation potential, and gene expression analysis by microarray. To understand cross talk, AML-BM-MSC were co-cultured with the AML cell line OCI-AML2 and assessed for changes in cell cycle phases, mitochondrial activity, and cytarabine-induced cell death. Differential regulation of AML blast fate was evaluated by conducting co-culture experiments with cell-free-conditioned media (PD-MSC-CM) and in the presence of cell-cell contact of AML-BM-MSC. Further, PD-MSC-CM was assessed in vivo for tumor reduction potential using a leukemia xenograft model.

Besides standard features, AML-BM-MSC exhibited increased vesicles, MSC bodies (exosomes), and mitochondria. Altered AML-BM-MSC demonstrated upregulation of inflammasome pathway markers in microarray, which was further validated by ELISA and quantitative real-time polymerase chain reaction. Co-culture experiments on AML-BM-MSC revealed protective effects on AML blasts in the presence of cytarabine. In contrast, PD-MSC-CM significantly inhibited AML cell growth alone and synergistically with cytarabine. Further, PD-MSC-CM significantly reduced tumor growth in the leukemia mouse model, and this effect was mediated by regulation of the NLRP3 inflammasome pathway.

Summarizing, the leukemic blasts and AML-MSC in the BM microenvironment interact differentially in cell-cell contact compared to only soluble factors. Further, our study has provided innovative leads that PD-MSC-CM effectively abrogates leukemia tumor growth, enhances chemosensitivity and can be developed further as an immunomodulatory novel "off-the-shelf" therapeutic agent for leukemia.

With modern risk stratification of multi-agent cytotoxic chemotherapy protocols, we now cure the majority of patients with pediatric acute lymphoblastic leukemia (ALL). However, patients with high-risk features or relapsed disease continue to have suboptimal outcomes. Conventional chemotherapy agents may increase long term organ toxicities even in more favorable patients. Improved understanding of the molecular characteristics of pediatric ALL has led to the preclinical and clinical development of more targeted and less systemically toxic therapeutic options for patients with ALL. Agents such as blinatumomab, inotuzumab ozogamicin, tisagenlecleucel and several others have revolutionized the treatment of relapsed or refractory ALL by either directing therapies locally to leukemic cells or by targeting specific leukemogenic pathways. Here we present current evidence for efficacy and toxicity profiles for these targeted therapies in pediatric patients with ALL. Many of these strategies have been more comprehensively studied in the adult population and we will highlight ongoing and needed clinical trials in pediatrics. We need to overcome our historically delayed approach to introducing new therapeutic options in pediatrics, as adults often benefit from innovations for years before they are evaluated in children. More proactively incorporating these emerging treatments into frontline therapy for the most vulnerable, high-risk pediatric ALL populations could meaningfully reshape our treatment paradigm. Earlier collaboration for development of clinical trials across pediatric and adult ALL may facilitate more rapid access to promising agents. We anticipate that successful upfront integration of more targeted approaches will improve response rates, reduce reliance on highly toxic chemotherapies and ultimately increase the likelihood of duration of remission. We expect the next generation of clinical trials will credential more targeted therapies for use in frontline therapy with the goal of improved outcomes with minimized toxicity for all patients with pediatric ALL, not just those with more favorable disease characteristics.

Autoimmune metaplastic gastritis (AMAG) is a form of autoimmune gastritis that is characterized by the immune system's attack on gastric parietal cells, leading to chronic inflammation. Gastric neuroendocrine tumors (GNETs) are rare neoplasms that can develop in the gastrointestinal tract in the presence of AMAG. This case presents a 69-year-old female who presented with dyspepsia, and on subsequent endoscopic evaluation, she was found to have AMAG in the context of elevated levels of serum chromogranin A (CgA) and gastrin, suggestive of a GNET. Despite an extensive diagnostic workup, including imaging, colonoscopy, small bowel follow-through, capsule study, and oncology workup, no GNET was identified. She was also found to have antibodies to parietal cells, suggestive of pernicious anemia. The elevated markers were attributed to enterochromaffin cell hyperplasia, secondary to hypergastrinemia from AMAG. This case invites a discussion about the need for more evidence-based guidelines in the workup and monitoring of spurious elevations of CgA and gastrin in the presence of AMAG. It also highlights the importance of careful and intentional clinical evaluation to avoid unnecessary tests and costs to the patient.

Adenoid cystic carcinoma (ACC) of the breast is an exceedingly rare subtype of triple-negative breast cancer, accounting for less than 0.1% of all breast malignancies. In contrast, invasive lobular carcinoma (ILC) is a more common special histologic type, comprising 5-15% of breast cancers and typically characterized by estrogen receptor positivity and complete loss of epithelial cadherin (E-cadherin) expression. The coexistence of these two biologically and morphologically distinct neoplasms within the same breast lesion is exceptionally rare and, to our knowledge, has not been previously documented.  A 62-year-old Caucasian female patient presented with nonspecific stinging discomfort in the right breast. Diagnostic imaging revealed a 1.8 cm irregular, spiculated mass. A core needle biopsy demonstrated invasive mammary carcinoma that was estrogen receptor-positive, progesterone receptor-positive, and human epidermal growth factor receptor 2 (HER2)-negative. Following right breast mastectomy and sentinel lymph node biopsy, final pathology revealed a biphasic neoplasm composed of both ACC and lobular carcinoma (LC) components. The ACC component exhibited classic cribriform and tubular architecture, a triple-negative immunophenotype, strong transformation-related protein 63 (p63) and cluster of differentiation 117 (CD117; c-Kit) positivity, and a low Ki-67 proliferation index (9.8%). The LC component lacked a classic single-file growth pattern but showed dyscohesive cell clusters with complete loss of E-cadherin expression, strong estrogen receptor positivity (94.18%), and a markedly elevated Ki-67 index (42.9%). All seven sentinel lymph nodes were negative for metastatic carcinoma.  This rare case of synchronous ACC and ILC underscores the diagnostic complexity of composite breast tumors. Accurate classification requires careful correlation of histomorphology with immunohistochemical findings, particularly when one or both components exhibit non-classical architectural patterns. Given the contrasting biological behavior of triple-negative ACC and hormone receptor-positive ILC, an individualized, multidisciplinary management strategy is essential. Increased awareness of such mixed neoplasms may enhance diagnostic precision and improve patient care.

Undifferentiated pleomorphic sarcoma (UPS) is a high-grade mesenchymal malignancy that can closely resemble benign giant-cell-rich lesions such as central giant cell granuloma (CGCG), especially on limited biopsies. We report a case of a female patient with an enlarging mandibular swelling and an expansile osteolytic lesion that was initially diagnosed as CGCG based on an incisional biopsy showing multinucleated giant cells in a fibroblastic stroma. However, extended immunohistochemistry and the aggressive radiologic features supported a revised diagnosis of giant-cell-rich variant UPS. This case highlights the potential for diagnostic confusion on insufficient samples and emphasizes the importance of adequate tissue sampling, correlation with imaging, and comprehensive ancillary testing when evaluating destructive mandibular lesions.

A Müllerian duct cyst is a rare epithelial-lined cyst originating from remnants of the Müllerian (paramesonephric) duct. While these cysts are typically found along the lateral or posterior vaginal wall in females or near the prostate in males, posterior mediastinal occurrence is exceedingly rare. Accurate preoperative diagnosis is challenging, as imaging findings often resemble those of more common posterior mediastinal lesions such as neurogenic tumors or bronchogenic cysts. Surgical resection is usually required for definitive diagnosis and treatment. Video-assisted thoracic surgery (VATS) via the confronting upside-down monitor setting is a novel approach that offers improved visualization and ergonomics, but has not previously been reported for resection of a posterior mediastinal Müllerian duct cyst. A 44-year-old woman was referred following the incidental detection of a right posterior mediastinal mass on chest radiography. She was asymptomatic, with normal laboratory results including tumor markers. Contrast-enhanced computed tomography (CECT) revealed a well-defined, non-enhancing mass adjacent to the right T5-T6 vertebral bodies, measuring 3.3 × 1.8 × 2.8 cm. Magnetic resonance imaging (MRI) showed a cystic lesion with high T2 signal intensity. A neurogenic tumor or bronchogenic cyst was suspected, and surgical resection was performed using a four-port VATS approach with the confronting upside-down monitor setting. Intraoperatively, a smooth-surfaced cyst originating from the T5 vertebral body was identified and resected en bloc with the adherent fifth intercostal vein. Histopathology revealed a cyst lined by cuboidal epithelium, positive for Claudin4, estrogen receptor, Wilms' Tumor 1 (WT1), and Paired box gene 8 (PAX8), and negative for Calretinin, findings consistent with a Müllerian duct cyst. The patient's postoperative course was uneventful, and she was discharged on postoperative day two. Posterior mediastinal Müllerian duct cysts, though rare, should be considered in the differential diagnosis of mediastinal cysts in perimenopausal women. Definitive diagnosis requires histopathological and immunohistochemical evaluation. VATS via the confronting upside-down monitor setting provides direct visualization, minimal instrument interference, and improved spatial orientation, making it a valuable surgical option, particularly for lesions in close proximity to the intercostal vessels or the vertebral column. This case represents the first reported resection of a posterior mediastinal Müllerian duct cyst using this approach. .

Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal neoplasm characterized by a unique dual differentiation toward smooth muscle and melanocytic lineages. While PEComas can arise in various gynecologic organs, primary malignant ovarian PEComa is exceptionally rare and shows a wide spectrum of clinical behaviors. We report a case of a rapidly progressive primary ovarian malignant PEComa with an extremely poor prognosis. A 73-year-old woman presented with fever and malaise. A CT scan incidentally revealed a left ovarian tumor, for which she was referred to our department. Tumor markers were within normal limits, but MRI and CT suggested a left ovarian malignancy. A total hysterectomy and bilateral salpingo-oophorectomy were performed. Pathological examination revealed a 9 cm solid mass with necrosis, cytologic atypia, high mitotic activity (14/HPF), and vascular invasion. Immunohistochemistry was positive for both melanocytic markers (MelanA, HMB45) and the myogenic marker desmin, leading to a diagnosis of malignant PEComa. Based on the presence of multiple worrisome features, the tumor was classified as malignant according to established criteria. Despite the absence of distant metastasis at initial imaging and surgery, the patient was offered adjuvant therapy but declined. She developed local recurrence and lung metastasis 72 days after surgery and died 169 days after surgery. This case highlights the clinical significance of a primary ovarian malignant PEComa and the importance of recognizing its potential for rapid and aggressive progression. The finding that multiple pathological risk factors predicted a poor clinical outcome reinforces the need for accurate diagnosis and prompt consideration of systemic therapy, such as mTOR inhibitors, in addition to surgical resection. This report contributes valuable insights into the clinical course of this rare tumor, underscoring the necessity of close follow-up and multidisciplinary management.

To evaluate the diagnostic performance and clinical utility of metagenomic next-generation sequencing (mNGS) in distinguishing immune checkpoint inhibitor-related pneumonitis (CIP) from infectious pneumonia in cancer patients undergoing immunotherapy.

A retrospective tertiary hospital cohort included 34 cancer patients (Feb 2022-Jan 2024) with prior ICI exposure, new/worsening respiratory symptoms, imaging infiltrates, and both mNGS and conventional microbiological testing (CMT). Final diagnoses were adjudicated by a multidisciplinary panel. We compared pathogen detection rates, sensitivity, specificity, and turnaround times (TAT) between mNGS and CMT.

In the infectious pneumonia group, mNGS detected pathogens in 17/18 cases (94%), whereas CMT detected only 6/18 (33%). In the CIP group, mNGS was negative in 14/16 cases (88%), compared with 11/16 negatives by CMT (69%). Using the adjudicated diagnosis as the reference, mNGS showed sensitivity 88%, and specificity 94%. In contrast, CMT's sensitivity was 69%, and specificity 33%. The median TAT for mNGS was 24 hours (IQR 22-31 h), versus 121.5 hours (IQR 80.5-156 h) for CMT (P < 0.001).

mNGS outperforms CMT in both diagnostic accuracy and timeliness for distinguishing CIP from infectious pneumonia among immunotherapy recipients. Incorporation of mNGS into the diagnostic workflow for suspected CIP may improve etiological discrimination and enable timely, individualized treatment. Further large-scale prospective studies are required to confirm these findings.