The Warburg effect-induced lactate production in T-cell acute lymphoblastic leukemia (T-ALL) cell proliferation is well established, however, the role of lactate-mediated protein lactylation in this process remains poorly understood. In this study, we demonstrated that inhibiting lactate levels through the lactate dehydrogenase A (LDHA) inhibitor significantly reduced both cell proliferation and protein lactylation levels in T-ALL cells. Lactate deficiency led to a marked decrease in protein lactylation, accompanied by impaired cell proliferation. Meanwhile, lactate deficiency also induced the S‑phase cell cycle arrest and reduced DNA synthesis, which collectively impaired cell proliferation. Mechanistically, we observed that the decreased expression of lactylation in histone H3 at lysine 18 (H3K18lac) reduced the enrichment of this mark on the promoter region of neurotrophic receptor tyrosine kinase 3 (NTRK3), which supported the cell proliferation of T-ALL cells. Moreover, the overexpression of NTRK3 rescued the lactate deficiency-induced proliferation inhibition of T-ALL cells. Furthermore, exogenous lactate supplementation dramatically restored the decreased cell proliferation in T-ALL cells and restored H3K18lac levels. Our findings reveal a novel role of lactate-mediated protein lactylation in regulating T-ALL cell proliferation.

Colorectal cancer (CRC) develops and metastasizes within a microenvironment shaped by chronic inflammation, microbial exposure, stromal remodeling, and treatment pressure. Among the innate immune processes implicated in this setting, neutrophil extracellular traps (NETs) have attracted increasing attention. Initially described as antimicrobial structures, NETs have been implicated in several aspects of CRC biology, including inflammatory carcinogenesis, epithelial plasticity at the primary tumor site, gut-liver crosstalk, metastatic niche formation, and immune regulation. Experimental and translational studies suggest that they may influence tumor cell migration, extracellular matrix remodeling, hepatic colonization, and T-cell dysfunction, while also interacting with microbial and stromal signals in the liver. The available literature, however, does not support a uniformly deleterious role. Their biologic effect appears to vary with disease phase, anatomical site, neutrophil state, microbial context, and treatment exposure. In some settings, therapy-induced or early trap-associated responses may accompany tumor control rather than progression. In this review, we summarize current evidence on NETs in sporadic CRC, colitis-associated cancer (CAC), and colorectal cancer liver metastasis (CRLM), with particular attention to the gut-liver axis, immune microenvironment, biomarker development, and therapeutic intervention. We also discuss the major limitations of the field, including inconsistent detection strategies, overreliance on static or reductionist models, and limited spatially resolved human data. Overall, NETs may be better viewed as context-dependent effectors generated by distinct neutrophil states across different phases of disease.

Fetus-in-fetu (FIF) is a rare congenital anomaly in which a malformed monozygotic twin is incorporated within its host twin. FIF is usually retroperitoneal, whereas association with an intra-abdominal undescended testis is exceptionally uncommon. Because imaging may show a heterogeneous mass containing soft tissue, fat and calcified elements, FIF can be difficult to distinguish preoperatively from mature teratoma, especially when cryptorchidism is also present.

A 3-day-old male neonate was admitted because of jaundice and a palpable right abdominal mass. Physical examination revealed an underdeveloped right hemiscrotum without a palpable right testis; the left testis was palpable and a left hydrocele was suspected. Prenatal ultrasound demonstrated a mixed echogenic mass in the right lower abdomen and raised the possibility of FIF. Fetal magnetic resonance imaging (MRI) and postnatal contrast-enhanced computed tomography (CT) showed a well-circumscribed cystic-solid abdominal mass with fat-like signal/density and multiple calcified stripe-like components, leading to diagnostic uncertainty between FIF and teratoma. Serum alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) showed no abnormal elevation after interpretation according to neonatal age. Exploratory laparotomy revealed a 5.0 cm x 4.0 cm x 4.0 cm encapsulated cystic-solid mass arising from the right intra-abdominal undescended testis, without identifiable viable right testicular parenchyma. The mass and the atrophic right testicular/epididymal tissue were excised. Gross and histopathological examination demonstrated an organized axial skeleton/spinal structure and multiple differentiated tissues, including brain, intestine, liver, bone, skeletal muscle, skin, and epididymal duct tissue, fulfilling the Willis criterion for FIF.

This case highlights a very rare presentation of FIF associated with abdominal cryptorchidism. Recognition of calcified axial skeletal elements, fat components, organoid structures and the relationship to the spermatic cord/testicular structures may help pediatric surgeons and radiologists anticipate FIF rather than misdiagnosing the lesion as a testicular or abdominal teratoma. Complete surgical excision and long-term follow-up with ultrasonography and tumor markers are recommended.

Metabolic dysfunction-associated steatotic liver disease (MASLD), including its progressive form metabolic dysfunction-associated steatohepatitis (MASH), represents the hepatic manifestation of metabolic syndrome and is increasingly recognized as a multi-organ disease. MASLD is now the most prevalent chronic liver disease worldwide and a rising indication for liver transplantation. MASLD incidence continues to increase, driven by sedentary lifestyles, the obesity epidemic and associated pathologies such as type 2 diabetes. MASH is a significant risk factor for fibrosis, cirrhosis and hepatocellular carcinoma (HCC)-a leading cause of cancer-related death. Over the past decade, substantial progress has been made in elucidating the molecular and cellular mechanisms driving MASLD initiation and progression. Key pathogenic processes include insulin resistance, genetic drivers, dysregulated hepatic lipid metabolism, lipotoxicity, adipose tissue dysfunction, immune-mediated inflammation, fibrogenesis and perturbations of the gut-liver axis. Increasingly, these mechanistic insights are informing clinical translation. Genetic risk variants and polygenic risk scores are beginning to enable improved risk stratification for disease progression and HCC. Furthermore, therapeutic strategies targeting defined metabolic pathways are emerging, including approaches that reduce hepatic lipogenesis or modulate mitochondrial metabolism. Here we highlight the state of the art of molecular and cellular mechanisms underlying MASH pathogenesis and its transition to HCC.

Gut dysbiosis drives therapeutic resistance, yet the relationships among typical tumor markers, gut microbiota, and treatment efficacy remain poorly defined. Here, elevated serum CYFRA 21-1 in advanced non-small cell lung cancer (NSCLC) correlates with gut dysbiosis, including Bifidobacterium animalis depletion and reduced immunomodulatory metabolites. Fecal supernatant from patients with high-CYFRA attenuated immunochemotherapy efficacy in tumor-bearing mice, linked to disrupted tryptophan and phenylalanine metabolism. Adjuvant B. animalis subsp. lactis V9 enhanced tumor control and antitumor immunity, coinciding with elevated quinaldic acid and catechol, metabolites associated with caspase-dependent apoptosis and ferroptosis. Cell-free fecal supernatant transferred antitumor effects, independent of bacterial colonization. In a randomized, double-blind, placebo-controlled pilot trial (n = 30), adjunctive B. lactis V9 associated with a higher objective response rate (47% versus 33%), disease control rate (87% versus 67%), and prolonged progression-free survival in responders, who exhibited enriched B. animalis and elevated quinaldic acid/catechol (area under the curve = 0.73/0.82). These findings suggest CYFRA 21-1 may identify a modifiable, microbiome-linked state of treatment resistance.

Patients with neurofibromatosis type 1 develop Schwann cell tumors called neurofibromas that arise within peripheral nerves, driven by loss of neurofibromin and consequent increased RAS/RAF/MEK signaling. MEK inhibitors achieve partial responses for benign neurofibromas but are limited by toxicity and incomplete efficacy, necessitating alternative approaches. Using the Dhh-Cre;Nf1^fl/fl neurofibroma mouse model, we found that genetic ablation of Kras, but not Hras, markedly reduced neurofibroma development, inhibited MAPK activation, and rescued disrupted Remak bundles that are a morphologic hallmark of neurofibromas. These findings reveal a RAS paralog-specific requirement for KRAS in NF1-deficient neurofibroma initiation. Pharmacological KRAS inhibition with BI6674, an orally bioavailable KRAS^multi inhibitor, reduced tumor volume and proliferation in established neurofibromas and remodeled the tumor immune microenvironment, decreasing macrophages and dendritic cells. Combining KRAS and MEK inhibition further enhanced tumor regression. These findings demonstrate that KRAS is essential for neurofibroma formation and represents a promising therapeutic target, supporting clinical evaluation of KRAS inhibition for neurofibromas in patients with neurofibromatosis type 1.

Drug-induced thrombotic microangiopathy (TMA) is an important cause of kidney injury in patients receiving anticancer therapy, although kidney-limited forms without systemic manifestations are often difficult to recognize. Pegylated liposomal doxorubicin (PLD)-associated TMA remains under-recognized, particularly in patients receiving concomitant vascular endothelial growth factor (VEGF) inhibitors. We report a case of biopsy-proven kidney-limited TMA associated with bevacizumab and PLD in a 52-year-old woman with metastatic ovarian serous adenocarcinoma, characterized by a biphasic clinical course. She developed progressive kidney dysfunction and proteinuria during treatment with bevacizumab followed by PLD. Despite discontinuation of bevacizumab, kidney dysfunction persisted. Kidney biopsy demonstrated findings consistent with TMA, including mesangiolysis, glomerular basement membrane duplication, and focal PAS-positive pseudothrombi suggestive of VEGF inhibitor-associated endothelial injury. Electron microscopy further revealed endothelial detachment, accompanied by a substance containing liposome-like particles, suggestive of the characteristic ultrastructural findings previously reported in PLD-associated TMA. The patient had no evidence of microangiopathic hemolytic anemia or thrombocytopenia, and no alternative cause of TMA was identified. Following discontinuation of PLD, kidney function improved markedly with complete resolution of proteinuria. This case highlights the importance of kidney biopsy and careful clinicopathological correlation in diagnosing drug-induced kidney-limited TMA.

Immune checkpoint inhibitors have improved cancer prognosis, but are associated with immune-related adverse events, including rare renal complications. Here, we report the case of a 68-year-old Japanese man with unresectable advanced non-small cell lung cancer who developed nephrotic syndrome and organizing pneumonia associated with durvalumab therapy. The patient developed significant proteinuria during glucocorticoid treatment for organizing pneumonia. Renal biopsy led to a diagnosis of durvalumab-associated nephrotic syndrome. Histological examination revealed complex features, characterized by lesions resembling focal segmental glomerulosclerosis, marked foot process effacement and detachment, and prominent tubulointerstitial nephritis. Notably, his proteinuria improved following discontinuation of durvalumab and treatment with losartan potassium, dapagliflozin, and finerenone, without a substantial increase in the glucocorticoid dose. The clinical course highlights the heterogeneity of durvalumab-associated nephrotic syndrome.

Food assistance interventions that are culturally tailored, minimize stigma, and promote self-efficacy are needed to promote uptake among low-income, racial, and ethnic minoritized people with cancer. We developed a culturally tailored food voucher intervention and tested its associations with food insecurity (primary outcome) and health-related quality of life (HRQOL), financial toxicity, and cancer treatment adherence (exploratory outcomes).

Between July 2023 and August 2023, we recruited low-income, racial, and ethnic minoritized adults > 18 years of age with cancer receiving treatment who screened positive for food insecurity using the 2-item Hunger Vital Sign in a community oncology clinic. All consented participants received $40 monthly gift cards redeemable at preferred, local retailers for 6 months along with usual care comprised of trained community health workers who screened for and assisted with addressing health-related social needs. We conducted validated surveys at baseline (time of enrollment) and 6-month follow-up (post-intervention) to assess patient-reported outcomes and assessed adherence to cancer treatment through chart review. We compared pre- and post-intervention food insecurity using McNemar's tests and mean HRQOL and financial toxicity using paired t-tests.

Of 30 people eligible, all (100%) participated; 27 (90%) identified as Latino/a/e/x; 24 (80%) spoke Spanish as their preferred language; and 16 (53%) had stage 3 or 4 cancer. At 6-month follow-up, as compared to baseline, food insecurity decreased from 100% to 16.7% (95% CI 0.48-0.84, p < 0.001); HRQOL improved (mean score ± standard deviation 71.9 ± 16.1 (p = 0.025) versus 78.9 ± 10.2); and 100% adhered to recommended treatment.

This culturally tailored food voucher intervention may be one approach to improve food insecurity and clinical outcomes among low-income Latino/a/e/x patients with cancer.

Use of adjuvant endocrine therapy (ET) for ductal carcinoma in situ (DCIS) varies widely in clinical practice. We investigated oestrogen receptor (ER) testing, the initiation of ET, and the effect of ET on outcomes for DCIS in New Zealand.

Women with DCIS (2000-2022) were identified from the New Zealand Breast Cancer Foundation National Register and linked to the national pharmaceutical data. Logistic regression identified factors associated with ER testing, and cumulative incidence of breast cancer events was estimated with death as a competing risk.

Among 5813 women with DCIS, 894 patients (15.4%) had ER testing, with the rate increasing from 11.1% in 2000 to 23.3% in 2006, before declining to 13.9% in 2022. The Waikato region contributed 65.6% of ER tests. In Waikato, testing was more likely among women who received adjuvant radiotherapy after breast-conserving surgery, likely reflecting a site-specific clinical practice. In other regions, testing was more frequent among older women, Māori ethnicity, those with symptomatic presentation, and those with DCIS size > 20 mm, potentially reflecting selective testing. Among 729 patients with ER-positive DCIS, only 183 (25.1%) commenced ET, of whom 80.3% were in Waikato. ET users had the lowest cumulative risk of breast cancer event, but differences were not statistically significant.

ER testing and initiation of ET for DCIS remained low, except in Waikato, where clinical centres participated in ET trials and ER testing became more common. Standardised ER testing and greater clinician participation in clinical trials may lead to improved evidence-based care.

Not applicable.