Cancer of unknown primary (CUP) accounts for 1-3% of newly diagnosed cancers. For decades, management has relied on empirical platinum-based chemotherapy, which offers a poor prognosis with a median overall survival typically below one year. However, data from the ESMO 2025 Congress and the International Cancer of Unknown Primary Meeting (ICUPM) signal a transformative shift in the field. This review synthesises current and upcoming data on integrative genomic profiling, liquid biopsy-based tissue-of-origin prediction, functional imaging, and tumour-agnostic therapeutic strategies in CUP. Together, these advances support redefining CUP as a molecularly stratifiable disease requiring early comprehensive profiling and multidisciplinary interpretation to improve outcomes.

Carcinomas of the stomach and esophagogastric junction (EGJ) are the fifth leading cause of cancer-related deaths worldwide. In Germany, gastric cancer ranks tenth in incidence across both sexes. This summary of a German national guideline aims to provide the most relevant evidence-based recommendations on diagnosis and treatment of gastric and EGJ adenocarcinomas and has been comprehensively updated by an interdisciplinary panel of experts from national medical societies. New recommendations introduces preventive strategies, including management of familial risk due to microsatellite instability (MSI) and H. pylori eradication. The biomarkers HER2, PD-L1, MSI, and Claudin18.2 enable the use of targeted therapies that improve long-term outcomes in advanced disease. Combinations of chemotherapy with immunotherapy nivolumab, pembrolizumab, or tislelizumab significantly prolong survival compared with chemotherapy alone (e.g., nivolumab 14.4 vs. 11.1 months, HR 0.71; pembrolizumab 13.0 vs 11.4 months, HR 0.75; tislelizumab 17.2 vs. 12.6 months, HR 0.74) with 5-year survival rates up to 16%. In patients with high Claudin18.2 expression, zolbetuximab plus chemotherapy has improved median survival to 16.4 vs. 13.4 months (HR 0.77). For patients in good general condition, subsequent lines of therapy including biomarker-driven approaches (trastuzumab deruxtecan, pembrolizumab) or third-line therapies (e.g., trifluridine tipirazil) and advanced molecular diagnostics are recommended after treatment failure. The updated S3 guideline reflects the latest advances in diagnostics, improved palliative therapies, and supportive care. The objectives are to improve the quality of individual and broad care and to ensure consistent, evidence-based treatment strategies.

The effectiveness of conventional chemotherapy in treating metastatic triple-negative breast cancer (TNBC) is unsatisfactory. Apatinib, a small-molecule tyrosine kinase vascular inhibitor (TKI), is a multi-targeted anti-tumor angiogenesis agent that promotes apoptosis to inhibit tumors. Apatinib, when combined with chemotherapy, has demonstrated efficacy in treating advanced TNBC. Additionally, immune checkpoint inhibitors (ICIs) have emerged as a promising therapeutic option for metastatic TNBC; however, their efficacy still requires further improvement. One potential strategy to enhance the efficacy of ICIs in metastatic TNBC is through their combination with chemotherapy and anti-angiogenic agents. The combination of apatinib, chemotherapy, and ICIs has demonstrated favorable efficacy, with improved progression-free survival (PFS) compared with the conventional chemotherapy for advanced TNBC. This warrants further exploration of its clinical value. This triple therapy exhibits synergistic effects rather than representing a simple combination of agents. Apatinib can reverse chemoresistance and enhance the efficacy of programmed cell death protein 1 (PD-1) inhibitor therapy. Combining chemotherapeutic agents with ICIs is complementary, and apatinib, combined with chemotherapy, can modify the tumor microenvironment to improve the effectiveness of ICIs. This review examines the role of apatinib in treating TNBC and explores its potential mechanisms when combined with chemotherapeutic agents and ICIs for advanced TNBC in the era of immunotherapy.

Only limited data exist about immune status, secondary immunodeficiencies and vulnerability to infections in correlation to anti-CD20 antibody containing therapies (CD20CT) in non-Hodgkin's lymphoma (NHL) patients. Morbidity, mortality and hospitalisation rates in routine care are not known. Multicentre prospective observational study of 101 unselected NHL patients who were about to start CD20CT between 04/2021 and 12/2023 in nine haematology / oncology group practices in Germany. With the help of patient diaries, infections and hospitalisations over the course of one year were captured and compared to the 3-month period before receiving therapy. Additionally, demographics, treatment data, data on immune status and death rates were extracted from medical records retrospectively. Data was statistically analysed using IBM SPSS 29 Statistics. 101 patients with a median age of 68 years (28-90) at the time of enrolment could be analysed. 58% were male, 42% female. 30% suffered from diffuse large B-cell lymphoma (DLBCL), 24% from follicular lymphoma, 20% from chronic lymphocytic leukaemia (CLL) and 27% from other NHL. 8 patients died during the observation period. Cause of death was lymphoma in 4, infection/sepsis in 3 and not evaluable in 1 patient. The most frequently used treatment protocols were rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone (R-CHOP) in 35%, bendamustine/rituximab (BR) in 24%, rituximab in 10% and others in 31%. A quantitative determination of T helper cells (CD4 lymphocytes) was carried out in only 21 patients (21%). CD4 T-cell count was significantly different before and after initiation of CD20CT (1,048.9/µl vs. 459.7/µl) (p=.022). A quantitative determination of the IgG serum trough level was carried out in 22 patients (22%). The difference in mean IgG values before (875.4mg/dl) and after the start of therapy (738.8mg/dl) was statistically not significant (p=.068). Standardized to 1,000 days, the mean number of infections before treatment was 3.15 compared to 7.00 across all measurement points after the start of therapy (p<.001). Compared to the period before receiving CD20CT serum IgG levels and T-helper cells decreased and patients suffered from increased infection rates. Immune monitoring is only performed in a minority of patients.

KRAS mutations, particularly G12C, frequently cause non-small cell lung cancer (NSCLC). Due to the protective nature of the blood-brain barrier and the paucity of clinical data specifically about CNS involvement, brain metastases-which occur in up to 40% of patients with advanced KRAS-mutant NSCLC-present unique therapeutic challenges. The changing role of KRAS-targeted treatments in NSCLC with metastases to the central nervous system (CNS) is examined in this review. It highlights new clinical findings on KRAS G12C inhibitors, including sotorasib and adagrasib, and discusses the challenges in delivering medications across the blood-brain barrier. Along with outlining important resistance mechanisms, such as bypass signaling pathways, secondary KRAS mutations, and SHP2-mediated feedback, the review also examines new combination strategies that utilize SHP2 inhibitors, immunotherapy, and radiation. Even with recent progress in treatment, brain metastases continue to pose a significant challenge in managing KRAS-mutant non-small cell lung cancer. Among currently available agents, adagrasib has shown encouraging intracranial activity and CNS penetration, and rational combination strategies are being explored to overcome resistance. Ongoing research should prioritize CNS-specific endpoints and integrated treatment approaches tailored to patients with brain involvement. .