Neoadjuvant PD-1/PD-L1 blockade yields robust efficacy in advanced cutaneous squamous cell carcinoma (cSCC), yet many patients fail to achieve a complete or major pathologic response. The reasons why some patients experience response but others do not are unclear.

We profiled cSCC specimens before, after 1 dose, and after 3-4 doses of PD-1/PD-L1 blockade to uncover resistance mechanisms and predict therapeutic response. In total, 27 patients across three cohorts, including two phase II trials, were studied. We created 1.7 mm tissue-core microarrays and performed single-cell spatial transcriptomics, including spatial clustering, gene-set enrichment, and spatial correlation analyses.

After profiling all samples, six distinct spatial niches emerged, each differentially enriched in responders versus non-responders. A high antigen presentation niche, B/plasma cell enriched niche, and inflammatory keratinocyte niche were more frequent in responders, whereas proliferative keratinocyte, low antigen presentation myeloid, and fibroblast-rich epithelial-mesenchymal transition niches prevailed in non-responders. Notably, spatial niche profiling on pretreatment samples outperformed PD-L1 status in predicting pathologic response. Each niche displayed unique gene coexpression modules, suggesting niche-specific resistance mechanisms. Individual tumor analyses revealed varied immune evasion strategies, including defective interferon-induced antigen presentation, immunosuppressive myeloid environments, and epithelial-mesenchymal transition.

Our single-cell spatial transcriptomic approach identifies six spatial niches that predict immunotherapy response better than PD-L1 status using only 1.7 mm tissue cores and may inform the development of biomarkers. Our results further underscore the heterogeneity of resistance mechanisms among cSCC patients, highlighting the need for tailored therapeutic strategies.

Although immunotherapy has revolutionized cancer treatment, its efficacy in castration-resistant prostate cancer (CRPC) remains limited, largely due to an immunologically "cold" tumor microenvironment with scarce T-cell infiltration. Unraveling the molecular mechanisms underlying immune evasion and developing novel strategies to activate innate antitumor immunity are therefore critical to overcoming immunotherapy resistance in CRPC.

Using bioinformatic approaches, we analyzed the protein kinase membrane-associated tyrosine/threonine 1 (PKMYT1) expression and its correlation with immune cell infiltration and response to immune checkpoint blockade (ICB) in public databases. PKMYT1 protein expression was further evaluated via immunohistochemistry in a clinical cohort of prostate cancer (PCa) specimens. Mechanistic investigations were conducted in PCa cell lines and mouse models. The immunological impact of PKMYT1 inhibition was delineated using single-cell RNA sequencing, and the therapeutic efficacy of RP-6306, either as monotherapy or in combination with programmed death-ligand 1 (PD-L1) blockade, was evaluated in syngeneic mouse models.

PKMYT1 expression was significantly overexpressed in CRPC compared with primary PCa. High PKMYT1 expression correlated with a suppressed antitumor immunity and poor clinical response to ICB. Mechanistically, PKMYT1 inhibition activated the cyclic guanosine monophosphate-adenosine monophosphate adenosine synthase (cGAS)-stimulator of interferon genes (STING) pathway, potentiated both type I and II interferon signaling, and upregulated chemokines, including CCL5 and CXCL10. The selective PKMYT1 inhibitor, RP-6306, enhanced the efficacy of ICB in the presence of CD8⁺ T cells. Treatment with a PKMYT1 inhibitor alone or in combination with PD-L1 blockade significantly increased the infiltration of activated CD8⁺ T cells and induced significant tumor suppression in vivo.

PKMYT1 is a pivotal dual regulator of tumor progression and immune evasion in CRPC. Our findings provide a compelling preclinical rationale for targeting PKMYT1 as a novel strategy to reprogram the tumor immune microenvironment and overcome resistance to immunotherapy.

Patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) often respond to cytotoxic therapy, but early disease progression is typical. Responses to immunotherapy alone are rare. Recent advances in chemoimmunotherapy combinations offer promise. We report results from cohorts A and B of REVOLUTION, an adaptive platform trial designed to evaluate the safety and antitumor activity of chemoimmunotherapy combinations in untreated mPDAC.

REVOLUTION (NCT04787991) is an open-label, exploratory platform trial. Patients were assigned to enrolling cohorts in a non-randomized fashion. All patients received gemcitabine (1,000 mg/m²), nab-paclitaxel (125 mg/m²), and two doses of ipilimumab (1 mg/kg), administered intravenously. In addition, cohort A received nivolumab (360 mg intravenously every 3 weeks) and cohort B received hydroxychloroquine (600 mg orally two times a day). The primary endpoint was safety. Secondary endpoints included objective response rate (ORR), disease control rate, duration of response, progression-free survival, and overall survival (OS). Exploratory endpoints included pharmacodynamic changes and associations between biomarkers and clinical outcomes.

Both cohorts enrolled 15 patients. Grade 3-4 treatment-related adverse events occurred in 60% and 53% of patients in cohorts A and B, respectively. One grade 5 event occurred in cohort B, which exhibited more frequent dose modifications and non-compliance. Cohort A demonstrated an ORR of 33% (5/15) and a 12-month OS rate of 65.5% (95% CI 35.7% to 84.0%), with higher baseline levels of programmed cell death protein-1 (PD-1)⁺CD39⁺ central memory CD4⁺ T cells associated with prolonged survival. Cohort B demonstrated an ORR of 40% (6/15) and a 12-month OS rate of 53.9% (95% CI 24.3% to 76.3%). Cohort A showed increases in activated and proliferating CD4⁺ and CD8⁺ T cells, regulatory T cells, and circulating soluble PD-1 and Th1-associated cytokines. Cohort B exhibited delayed but sustained increases in activated CD4⁺ T cells and pharmacodynamic evidence of autophagy inhibition.

REVOLUTION cohorts A and B demonstrated encouraging antitumor activity in patients with mPDAC. In cohort B, hydroxychloroquine-related tolerability issues contributed to early discontinuations and reduced drug exposure. These findings highlight the potential and limitations of current chemoimmunotherapy approaches. Although neither cohort will be expanded, the results reinforce the continued promise of chemoimmunotherapy in mPDAC and the importance of refining these strategies.

Necrotising soft tissue infection (NSTI), or necrotising fasciitis (NF), is a life-threatening, rapidly spreading bacterial infection affecting soft tissues. Mortality rates can be up to 70%, emphasising the need for early diagnosis and intervention. However, timely identification remains challenging, particularly in immunocompromised patients, due to nonspecific early signs. This case involves a patient who developed NF 12 days after R-CHOP (Rituximab, Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisolone) chemotherapy. Despite clinical and radiological evidence of NF and a high Laboratory Risk Indicator for Necrotising Fasciitis score, blood tests revealed leucopenia, neutropenia and lymphopenia, with no fever and a low National Early Warning Score of one. This atypical presentation underscores the difficulty in diagnosing NF in immunosuppressed individuals. The case highlights the complexity of managing NSTI in such populations, stressing the importance of rapid recognition and treatment to improve outcomes in these high-risk scenarios.

Pheochromocytoma is a rare catecholamine-secreting tumour that can cause transient cardiomyopathy resembling Takotsubo syndrome due to catecholamine excess. Its diagnosis is often challenging because of the tumour's rarity and the non-specific, often paroxysmal nature of symptoms. We present the case of a previously healthy woman in her 30s who developed non-specific symptoms, including nausea, vomiting and palpitations, progressing to cardiogenic shock with severely impaired biventricular function requiring mechanical circulatory support. Further investigations revealed a pheochromocytoma-induced Takotsubo syndrome, which was successfully treated with adrenalectomy. This case report supports current evidence that early recognition and aggressive supportive care, including mechanical circulatory support as a bridge to surgery, can lead to full recovery from severe catecholamine-induced cardiac dysfunction.

High-grade serous ovarian cancer (HGSOC) presents significant therapeutic challenges, particularly due to acquired resistance to poly (ADP-ribose) polymerase inhibitors (PARPi) such as olaparib. This study examines the potential of apigenin (API), a naturally occurring flavonoid, to modulate survival pathways and restore olaparib sensitivity in HGSOC cell lines.

Four human HGSOC cell lines (TYK-nu, Kuramochi, CAOV3, and OVCAR3) and their olaparib-resistant derivatives were used. Olaparib resistance was induced by gradually exposing cells to increasing concentrations of olaparib. Cells were treated with API, and cell viability, apoptosis, and cell cycle distribution were assessed using MTT assays and flow cytometry. Western blotting was performed to analyze STAT3 and AKT phosphorylation, apoptotic markers, and cell cycle regulators, while immunofluorescence was used to evaluate STAT3 subcellular localization.

API reduced cell viability in all HGSOC cell lines in a dose-dependent manner, exhibiting differential sensitivity. It induced cell death in TYK-nu and OVCAR3, while causing G2/M phase arrest in Kuramochi and CAOV3. API selectively inhibited pSTAT3 (Y705) and pAKT (S308) without altering total protein levels or STAT3 nuclear localization. Additionally, it downregulated key cell cycle regulators, including p53, p27, p21, and p16 across all lines. Cyclin B1 levels decreased universally, while CDC2 (CDK1) downregulation was specific to Kuramochi and CAOV3, correlating with G2/M arrest. Notably, API restored olaparib sensitivity in resistant Kuramochi and CAOV3 cells by reducing pSTAT3 (Y705) levels, indicating that STAT3 modulation may be a potential mechanism for overcoming resistance.

API suppresses HGSOC progression by inducing apoptosis, arresting the cell cycle, and modulating survival pathways. It also restores olaparib sensitivity in resistant cells, supporting its potential as an adjuvant therapy to enhance olaparib efficacy in combination treatments.

Epithelial ovarian cancer (OC) presents unique challenges in diagnosis and treatment, characterized by vague symptoms and signs, delayed diagnosis and frequent advanced stage (ad). Initial the standard of care (SOC) treatment includes intensive cytoreductive surgery (CRS) and platinum-paclitaxel chemotherapy with/without adding anti-angiogenetic agent and/or following poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) maintenance therapy based on biomarker-guided recommendation, such as BRCA mutation and/or homologous recombination deficiency (HRD significance). However, OC-associated high recurrence rates and development of chemoresistance to recurrent OC (rOC) result in the therapeutic failure and subsequent fatal outcomes. All suggest the current treatment for platinum-resistant rOC (PR-rOC) patients is clinically unmet. Therefore, better understandings of underlying mechanisms and molecular changes of cancer cells may offer hints to overcome the chemoresistance in OC. Chemoresistance may be derived from "naïve" (underlying or primary) hereditary or acquired adaption (secondary or induced), which are involved in an increasing ability to self-repairing DNA, dysregulated autophagy process and evasion of apoptosis and alternation in mitochondrial pathways as well as metabolic adaptions, changing signaling pathway for proliferation and survival, and modifying genetic and epigenetic resolution, contributing to sustaining proliferative signaling, resisting cell death, evading growth suppressor, inducing angiogenesis, activating invasion and metastases, deregulating cellular energetics, reaching cellular senescence and stemness, and epigenetic reprogramming of cancer cells. The first part is a brief review for PR-rOC, including mechanisms, and combating strategies but only limited to cytoreductive surgery for treating PR-rOC patients.

Enteric duplication cysts are a rare congenital malformation that consists of a cystic formation adjacent to the native gastrointestinal tract. A double wall appearance on fetal abdominal sonography is highly suggestive of its diagnosis. However, this sign also can be seen in an ovarian cyst, a mesenteric cyst, and a Meckel's diverticulum. To the best of our knowledge, this case is the first report of accurate prenatal diagnosis based upon the presence of a Y-configuration and peristalsis on prenatal sonography. We herein present prenatal and postnatal images including ultrasonogram and discuss the differential sonographic findings of an intra-abdominal cystic mass.

A 28-year-old pregnant woman, gravida 1, para 1, was referred to our hospital at 29 + 3 weeks' gestation for the evaluation of a fetal intra-abdominal cystic mass. On an ultrasound examination, a thick-walled, unilocular cystic mass, measuring 1.42 × 0.93 cm in diameter was detected. A double-layered wall was seen on the bottom line of the cystic mass. A serial ultrasound examination showed the enlargement of the cystic mass with advancing pregnancy. In addition to the multilayered wall, a Y-configuration was demonstrated in the sharing muscular wall, and real time peristaltic movements were visualized at 39 + 3 weeks' gestation. With all these findings taken together, we made a diagnosis of an enteric duplication cyst with confidence.

Prenatal sonography alone can be used for the accurate diagnosis of an ileal duplication cyst, allowing a laparoscopic-assisted surgical treatment following birth before the onset of symptoms or complications.

In recent years, polysaccharides with potential anticancer activity have attracted widespread attention. In this study, a homogeneous polysaccharide fraction, PEP-3 (102.35 kDa), was extracted and purified from the fruit of Phyllanthus emblica L. Structural analysis revealed that its backbone consists of methylated and unmethylated α-1,4-GalpA residues at the C-6 position. O-2 at α-2,4-Rhap-1→ participates in backbone extension, while O-4 serves as a branch point for the Galp and Araf side chains. Through machine learning-based target screening, HSP90 was identified as the core therapeutic target of PEP-3 for stomach adenocarcinoma (STAD) treatment and an important biomarker for diagnosis and prognosis. Mechanistic studies showed that PEP-3 inhibits HSP90 activity, leading to AKT degradation and activation of the Caspase cascade. In vitro experiments showed that the combination of PEP-3 and 5-fluorouracil (5-Fu) (PEP-3 concentration 400 μg/mL, 5-Fu concentration 3.13 μg/mL) exhibited a considerable synergistic effect, markedly enhancing apoptosis, inducing cell cycle arrest, promoting ROS and Ca²⁺ overload, and aggravating mitochondrial damage. These results indicate that PEP-3 enhances the chemosensitivity of 5-Fu by targeting HSP90 and inducing apoptosis through multiple pathways, while simultaneously reducing the toxic side effects of 5-Fu. This highlights its potential as a natural sensitizer for the treatment of STAD.

Pancreatic metastases are rare, accounting for approximately 2-5% of all pancreatic malignancies. Renal cell carcinoma (RCC) is the most common primary cancer that metastasizes to the pancreas and accounts for approximately 30-40% of all pancreatic metastatic lesions. Most reported cases involve clear cell RCC, while data regarding pancreatic metastases from non-clear cell RCC subtypes remain limited. Unlike metastases from other primary tumors, pancreatic metastases from RCC (PM-RCC) often follow a more indolent clinical course and are associated with a relatively favorable prognosis, suggesting distinct underlying biological behavior.

A comprehensive literature review was conducted using the MEDLINE/PubMed, Google Scholar, Cochrane Library, and Web of Science databases (January 1993-May 2025). Eligible studies included full-text articles, case reports, and original research describing renal cell carcinoma metastasis to the pancreas with an emphasis on mechanism, diagnosis, treatment, and outcomes.

The disproportionate tendency of kidney cancer to metastasize to the pancreas is best explained by the "seed and soil" hypothesis, reflecting a selective affinity between RCC cells and the pancreatic microenvironment. PM-RCC are usually metachronous, often occurring many years after nephrectomy, and are frequently asymptomatic and discovered incidentally on surveillance imaging. Characteristic imaging findings include hypervascular lesions on contrast-enhanced CT or MRI. Histopathological confirmation is critical, as PM-RCC has a markedly better prognosis than primary pancreatic neoplasms. Surgical resection remains the mainstay of treatment for isolated disease, with a 5-year survival exceeding 50%. In the era of targeted immunotherapy, systemic treatments further improve outcomes with the median overall survival surpassing that of patients with extra-pancreatic metastases.

PM-RCC is a unique clinical and biological entity characterized by indolent progression, favorable survival, and a strong response to surgical and targeted therapies. Understanding the molecular and microenvironmental mechanisms underlying this selective organotropism may refine therapeutic strategies and provide insights into the broader principles of metastatic disease.