Search Results (781)

Background/Objectives: Total neoadjuvant therapy (TNT), integrating systemic chemotherapy and radiotherapy before surgery or surveillance, has become a standard approach for locally advanced rectal cancer (LARC). However, optimal sequencing strategies and long-term outcomes of watch-and-wait (W&W) following sandwich TNT remain insufficiently characterized. We evaluated oncologic outcomes and treatment response in patients treated with an institutional sandwich TNT protocol. Methods: We conducted a retrospective cohort study of consecutive patients with LARC treated with sandwich TNT (induction chemotherapy followed by hypofractionated intensity-modulated radiotherapy with simultaneous integrated boost [IMRT-SIB] chemoradiotherapy and consolidation chemotherapy) at the Institute of Oncology Ljubljana between 2016 and 2023. The primary endpoint was an overall complete response (CR; pathological [pCR] and clinical [cCR]). Secondary endpoints included tumor regression grade (TRG), major pathological response (MPR), R0 resection rate, organ preservation, overall survival (OS), and disease-free survival (DFS). Results: Among 205 patients (median age 61 years), overall CR was 29.5% (pCR 19.3% and cCR 10.2%). Major pathological response (TRG 3–4) occurred in 37.6%. R0 resection was achieved in 94.5%. In the W&W cohort (n = 21), local regrowth occurred in 33.3% (95% CI, 14.6–57.0%) over a median follow-up of 4.96 years. Total mesorectal excision (TME)-free survival at 5 years was 73.1% (95% CI, 55.0–97.2%). Estimated 5-year OS was 81.1% (95% CI, 75.5–87.2%) and 5-year DFS was 75.2% (95% CI, 69.0–82.0). In multivariable analysis, non-R0 resection (HR 6.06, 95% CI, 1.99–18.42), MRI circumferential resection margin positivity (HR 3.11, 95% CI, 1.53–6.33), and MRI extramural vascular invasion positivity (HR 1.97, 95% CI, 1.05–3.91) remained independent predictors of DFS. Conclusions: Institutional sandwich TNT yields meaningful tumor response and durable survival in MRI-defined high-risk LARC. Structured W&W offers organ preservation with acceptable oncologic control under intensive surveillance. Full article

Background: Patients with pancreatic cancer (PC) commonly present with reduced aerobic fitness, sarcopenia, and malnutrition, which may increase perioperative risk and compromise access to chemotherapy treatments. Although exercise-based prehabilitation can improve physical fitness, its implementation is often limited by short diagnostic-to-surgery intervals and treatment-related toxicity. Methods: We conducted a pilot prospective pretest–posttest feasibility study in Torino, Italy. Patients with PC undergoing neoadjuvant chemotherapy prior to surgery were offered a 4-week, partially supervised, home-based bimodal exercise prehabilitation program (single-arm design) combining remotely monitored high-intensity interval training (HIIT) on a cycle ergometer with functional and resistance exercises. The primary outcome was adherence to prescribed exercise frequency, intensity, and duration, objectively assessed via remote monitoring. Secondary outcomes included cardiorespiratory fitness (CPET), muscle function, body composition, fatigue, quality of life, and circulating inflammatory markers. Results: From July 2022 to February 2024, 23 patients were screened; 15 were eligible and 10 enrolled. Four participants discontinued the intervention (two due to asthenia/fatigue, one due to chemotherapy-related adverse events, and one for organizational reasons), leaving six participants who completed the program. Among completers, fatigue and quality of life did not change meaningfully. Aerobic capacity and muscle function outcomes were generally stable, with few pre–post changes exceeding the minimum clinically important difference (MCID) thresholds used. Body composition markers and the assessed circulating cytokines/chemokines remained unchanged except for IL-6 levels, which decreased significantly (p < 0.05). Conclusions: A partially supervised, home-based HIIT-based prehabilitation program is feasible for a subset of PC patients undergoing neoadjuvant therapy, but a substantial attrition rate suggests the need for more flexible symptom-adapted prescriptions and enhanced supportive strategies. Full article

With the introduction of total neoadjuvant therapy (TNT) in locally advanced rectal cancer treatment, multidisciplinary treatment options have become more diverse than before, and many challenges remain unresolved. A randomized clinical study in intermediate-risk locally advanced rectal cancer showed that neoadjuvant full-dose systemic chemotherapy with response-adapted omission of radiation therapy is non-inferior to concurrent chemoradiotherapy. Given that preoperative systemic chemotherapy provides an additional layer of local disease control, the traditional role and extent of neoadjuvant radiation therapy could be strategically re-evaluated within the TNT framework. In this context, a risk-adapted approach featuring selective reduction in elective nodal irradiation volume, particularly of the lateral pelvic lymph nodes, may offer a promising middle ground for treatment personalization. Drawing parallels from surgical practice—where total mesorectal excision is standard but lateral pelvic lymph node dissection is reserved for selected cases—this perspective advocates for similar selectivity in radiation therapy targeting, focusing on mesorectal and presacral regions while judiciously omitting lateral nodes in appropriately selected patients. This approach could maintain oncologic safety by focusing radiation therapy on limited but essential volumes. With modern intensity-modulated radiation therapy, reducing the target volume translates directly to enhanced organs-at-risk sparing, thereby mitigating radiation-induced toxicity. When combined with induction chemotherapy response assessment to refine patient selection, this approach can offer a biologically informed, personalized treatment paradigm that balances disease control with quality of life. Full article

Etoposide is a key component of many frontline and salvage chemotherapy regimens in pediatric oncology. However, its clinical use may be complicated by acute hypersensitivity reactions, which can disrupt treatment continuity and compromise therapeutic efficacy. Recent pediatric studies indicate that the incidence of etoposide-associated hypersensitivity is higher than historically reported and varies according to disease type and administration conditions. This narrative review provides a comprehensive overview of etoposide hypersensitivity in children, integrating clinical, immunological, and pharmaceutical perspectives. Current evidence suggests that true IgE-mediated type I hypersensitivity is uncommon in pediatric patients, whereas most reactions are consistent with non-IgE-mediated mechanisms, often related to formulation excipients such as polysorbate 80 and ethanol. We discuss the clinical features and differential diagnosis of acute reactions associated with etoposide administration, including hypersensitivity reactions and infusion-related reactions, such as ethanol-related toxicity. In addition, modifiable risk factors, preventive measures, and management strategies—such as infusion optimization, alternative formulations, and rapid desensitization protocols—are critically reviewed. A mechanism-based approach to etoposide hypersensitivity is essential to ensure patient safety while maintaining treatment intensity in pediatric cancer care. Full article

Recently, oral decitabine/cedazuridine has been approved for the treatment of AML patients who are not eligible for intensive chemotherapy. Although efficacy data on phenotypic features and the prognostic impact of molecular aberrations at diagnosis were reported in the registration study, serial determinations of the mutational landscape during therapy were not reported. In this study, we present data on a subset of five patients in whom molecular markers were monitored during treatment with oral decitabine/cedazuridine within the registration study. The following observations were made in individual patients. Regarding the changes in the molecular landscape during therapy in four/five patients, there was no major (>50%) reduction in mutated AML clones. There was only one patient with CRi and more than 50% reduction in the VAF of clones with molecular aberrations, including RAS pathway mutations. We observed a marked drop of blast cells (>50%) in two other patients without changes in the molecular profile. The overall survival was significantly longer in patients with CRi and PR, respectively, as compared to patients with no response. Finally, four/five (80%) of patients had druggable molecular aberrations at diagnosis, including mutations in IDH2 (2/5), NPM1 (2/5), and FLT3 (1/5). Our results show that in the majority of patients, changes in the genetic profiles are not seen despite decreases in blast cells in some patients. Disease-modifying activity with decreases in mutated clones is rare. Although the exact mechanism behind our findings remains undetermined, they are in line with the proposed effects of HMA on epigenetics in leukemia cells. Full article

Background: Fasting-based interventions are increasingly investigated as adjuncts to cancer treatment for the potential to reduce therapy-related toxicities, improve metabolic health, and enhance quality of life. However, clinical evidence regarding their efficacy, tolerability, and acceptability remains limited and fragmented. This scoping review aimed to systematically map the current evidence on fasting-based interventions in cancer patients and survivors. Methods: A literature search was conducted in PubMed, Scopus, Web of Science, and CINAHL up to 10 June 2025. Eligible interventional studies included cancer patients or survivors and evaluated fasting-based interventions, such as time-restricted eating, intermittent fasting, short-term fasting, or fasting-mimicking diets. Studies were categorized by fasting types and outcomes like fatigue, treatment toxicity, metabolic and hematologic parameters, weight, quality of life, adherence, acceptability, illness perception, and adverse events were assessed. Result: Twenty interventional studies of FMD, TRE, STF, IF, or fasting combined with altered dietary approaches conducted across 10 countries were included, comprising a total of 871 participants. Participant ages ranged from 28 to 75 years. Overall, 9 of 20 studies exclusively enrolled breast cancer patients or survivors, and chemotherapy was the most common treatment context in 11 studies. Five of six studies reported reductions in fatigue. Among the five studies assessing quality of life, one demonstrated improvement, three reported no change, and one yielded mixed results. Six of eight studies reported reductions in chemotherapy-related toxicity, and weight loss was observed in 10 of 12 studies. Reductions in IGF-1 and insulin levels were reported in six of seven and four of five studies, respectively. Hematologic changes were noted in six studies, and only one study assessed illness perceptions, reporting positive findings. Fasting-related adverse events, reported in nine studies, were generally mild and transient. High adherence and acceptability were observed across studies; however, findings were heterogeneous across intervention types and were largely derived from small or moderate-strength studies. A descriptive quality metric assessment indicated that most studies were of moderate methodological strength. More intensive fasting protocols, such as FMD and STF, appeared to demonstrate more consistent metabolic effects, whereas TRE showed higher adherence but more variable clinical outcomes. Conclusions: Fasting-based interventions have the potential to be feasible and well tolerated among cancer patients and survivors, with early evidence suggesting benefits in reducing fatigue, minimizing treatment-related toxicities, and favorable metabolic effects. Large, well-designed trials including diverse cancer populations are needed to confirm long-term outcomes and guide clinical integration. Full article

Background and Clinical Significance: Mixed-phenotype acute leukemia (MPAL) is a rare hematologic malignancy characterized by the co-expression of myeloid and lymphoid markers and is associated with poor prognosis. Myeloid sarcoma (MS), particularly in the mediastinum, is an uncommon extramedullary manifestation and is rarely reported in association with MPAL. Case Presentation: We report a rare case of mediastinal MS with biphenotypic features and pericardial extension occurring concurrently with MPAL, highlighting diagnostic challenges, therapeutic strategies, and long-term outcomes. We describe the clinical course, diagnostic workup, treatment, and follow-up of a 21-year-old woman who presented with cardiac tamponade secondary to a mediastinal mass. Histopathology and immunophenotyping established the diagnosis of mediastinal MS associated with MPAL (B/myeloid, NOS). Management included surgical cytoreduction, intensive induction chemotherapy, and consolidation with allogeneic hematopoietic stem cell transplantation (allo-HSCT) from an unrelated donor. Fertility preservation with oocyte retrieval, in vitro fertilization (IVF), and embryo cryopreservation was performed prior to conditioning. A focused literature review of MPAL cases with extramedullary involvement was conducted. The patient achieved complete remission following induction therapy and underwent allo-HSCT. Despite the historically poor prognosis of mediastinal MS and MPAL, she remains in sustained complete remission 13 years after diagnosis. A literature review identified only eight reported cases of MPAL with extramedullary disease, with mediastinal involvement described in a single case and allo-HSCT performed in only two patients. Conclusions: This case illustrates a rare presentation of MPAL with mediastinal myeloid sarcoma and cardiac tamponade, demonstrating that aggressive multimodal therapy including allo-HSCT may achieve durable remission even in high-risk presentations. Early multidisciplinary management and consideration of fertility preservation are essential in young patients. Full article

For decades, induction treatment of acute myeloid leukemia consisted of intensive chemotherapy for induction. High relapse rates and severe toxicity resulted in a five-year overall survival of ~30%. In patients ineligible for intensive treatment, hypomethylating agents (HMA) could be administered but generally failed to induce durable remissions. These limitations have driven the development of targeted drugs and less toxic therapeutic regimens. In the past decade, fourteen new agents have gained FDA and/or EMA approval, including small-molecule inhibitors targeting FLT3, IDH1, IDH2, BCL-2, menin, and the hedgehog pathway, as well as a CD33-directed antibody-drug conjugate. The combination of targeted drugs with intensive chemotherapy or HMA has resulted in improved remission rates and prolonged survival in certain patient subpopulations. However, many promising combinations are currently being evaluated in randomized trials and are not yet available in clinical routine. A combination that has become standard of care is HMA plus venetoclax for patients unfit for intensive chemotherapy, achieving high remission rates with relatively manageable toxicity. Moreover, targeted drugs directed against FLT3 and IDH1 have been approved in combination with intensive chemotherapy and HMA, respectively. Clinical decision-making requires rapid molecular diagnostic testing, assessment of a patient’s fitness for intensive chemotherapy, and management of toxicities and drug interactions. This narrative review, illustrated with patient vignettes, summarizes currently available therapies, guides through the latest trials on frontline combinations in AML, and provides a preview of how the therapeutic landscape may evolve in the near future. Full article

Glioblastoma multiforme is a devastating brain tumor that frequently progresses or recurs despite therapy. We used the glioblastoma-derived cell line, KNS-42, to study the response of the gap junction proteins, connexin46 and connexin43, to chemotherapeutic agents and to prolonged hypoxia to mimic conditions within the tumor microenvironment. Under standard culture conditions, KNS-42 cells have high levels of connexin43 and very low levels of connexin46. The cells that survived temozolomide treatment had increased connexin46 levels and decreased connexin43 levels. In contrast, prolonged hypoxia increased the levels of both connexins, the number of connexin immunopositive cells, and the intensity of the immunofluorescence signal per cell (which localized preferentially in the cytoplasm). Exposure to hypoxia for 12 days decreased the chymotrypsin-like proteasomal activity without altering connexin mRNA levels, suggesting that the changes in connexin levels result from reduced protein degradation. The increased connexin46 in temozolomide-resistant cells suggests that this connexin may have a role in chemotherapy resistance. The results also imply that changes in the microenvironment of glioblastomas (like hypoxia) can alter proteasomal activity and affect levels and subcellular distribution of connexin46 and connexin43. Finally, our data suggest that proteasomal inhibition may not be a good approach to glioblastoma therapy. Full article

Background/Objectives: Severe oral mucositis is widely viewed as a transient toxicity of antineoplastic therapy. Whether its long-term consequences differ between cancers that directly damage the upper aerodigestive tract (cancers of the lip, oral cavity, pharynx [CLOP]) and systemic hematologic malignancies is unknown. The aim of this study was to compare lifetime risks of mortality, dysphagia, malnutrition, respiratory disease, and cardiovascular disease in propensity-score-matched survivors of CLOP cancer versus leukemia with and without a history of ulcerative oral mucositis. Methods: Population-based retrospective cohort study using the TriNetX US Collaborative Network (90 healthcare organizations, >110 million patients). We identified 80,526 adults with a personal history of CLOP cancer (ICD-10-CM Z85.81) and 43,684 with leukemia (Z85.6) from 2005 to 2024. Cohorts were stratified by presence/absence of severe oral mucositis (K12.31 or K12.33 at any time). Separate 1:1 propensity-score matching was performed within each cancer type on age, sex, race/ethnicity, hypertension, diabetes, BMI, ECOG status, and external causes of morbidity. Exposures included documented severe (ulcerative) oral mucositis. Main outcomes and measures were all-cause mortality and incident dysphagia, malnutrition, respiratory disease (J00–J99), influenza/pneumonia (J09–J18), and circulatory disease (I00–I99) after the index date. Results: After 1:1 matching, 4181 CLOP patients with mucositis were compared with 4181 without, and 2508 leukemia patients with mucositis were compared with 2508 without. In CLOP survivors, mucositis was associated with markedly higher lifetime mortality (adjusted HR 1.94, 95% CI 1.87–2.01), dysphagia (HR 3.42, 95% CI 3.28–3.57), malnutrition (HR 2.81, 95% CI 2.66–2.97), any respiratory disease (HR 1.68, 95% CI 1.63–1.73), and influenza/pneumonia (HR 1.79, 95% CI 1.72–1.86). In leukemia survivors, mucositis conferred only modest or null excess risk (mortality HR 1.12, 95% CI 1.05–1.19; dysphagia HR 1.18, 95% CI 1.07–1.30; malnutrition HR 1.24, 95% CI 1.12–1.37; any respiratory disease HR 1.09, 95% CI 1.03–1.15). Conclusions and Relevance: Severe oral mucositis is a powerful, durable prognostic determinant in cancers of the upper aerodigestive tract, where it identifies patients associated with elevated lifelong risk of swallowing dysfunction, aspiration-related lung disease, malnutrition, and premature death. The markedly attenuated effect in leukemia survivors suggests that direct high-dose radiation-induced structural damage to the pharynx and oral cavity—rather than systemic immunosuppression or chemotherapy intensity alone—is the dominant mechanism. Full article

Background: Treatment decisions for older adults with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC) often rely on heterogeneous observational evidence and clinical judgment regarding survival benefits, regimen intensity, and tolerability. Methods: We systematically searched Embase, PubMed, and Scopus from inception to 30 March 2025, for studies reporting overall survival (OS) and/or progression-free survival (PFS) in older adults with advanced PDAC receiving systemic chemotherapy, as well as age-stratified outcomes among chemotherapy-treated patients. Hazard ratios (HRs) with 95% confidence intervals (CIs) were primarily extracted from multivariable-adjusted analyses. In cases without reported HRs, estimates were derived from summary statistics or Kaplan–Meier curves. The review protocol was registered in PROSPERO (CRD420261292913). Results: A total of 40 predominantly retrospective studies were included. Chemotherapy was associated with improved OS compared to best supportive care in older adults (9 studies; HR 0.46, 95% CI 0.39–0.54; I² = 18%). Among chemotherapy-treated patients, OS (34 studies; HR 1.00, 95% CI 0.99–1.02; I² = 23%) and PFS (11 studies; HR 0.96, 95% CI 0.86–1.07; I² = 10%) did not differ by age. Combination chemotherapy demonstrated superior OS (13 studies; HR 0.66, 95% CI 0.54–0.80; I² = 86%) with substantial heterogeneity and PFS (7 studies; HR 0.63, 95% CI 0.53–0.74; I² = 30%) compared to monotherapy. FOLFIRINOX and gemcitabine plus nab-paclitaxel demonstrated comparable OS (8 studies; HR 0.98, 95% CI 0.90–1.05; I² = 60%) and PFS (2 studies; HR 0.97, 95% CI 0.92–1.02; I² = 0%). Conclusions: Among carefully selected older adults with advanced PDAC, chemotherapy was associated with improved survival compared to supportive care. Chronological age did not predict outcomes, highlighting the need for geriatric-informed prospective trials. Full article

Background: Neoadjuvant immunochemotherapy improves pathological response in resectable non-small cell lung cancer (NSCLC), but the need and intensity of postoperative adjuvant therapy across different pathological response rate (PRR) strata remain uncertain. Methods: In this single-center retrospective cohort, 105 patients with resectable NSCLC received neoadjuvant platinum-based chemotherapy with or without PD-1/PD-L1 inhibitors followed by R0 resection. PRR was defined as 1—residual viable tumor fraction and categorized as 0–60%, 60–90%, and ≥90% (major pathological response, MPR). Postoperative strategies included no further therapy, chemotherapy alone, or immunotherapy ± chemotherapy. Event-free survival (EFS) was analyzed using Kaplan–Meier estimates, multivariable Cox models, and restricted cubic spline-based treatment × PRR interaction. Results: Deeper PRR was associated with lower ypT/ypN stage and improved EFS. In the PRR 0–60% subgroup, immunotherapy-containing adjuvant regimens were associated with better EFS, whereas chemotherapy alone did not outperform observation. In the PRR 60–90% and MPR strata, EFS curves for different postoperative strategies largely overlapped, and in MPR patients, hazard ratios were close to 1. Interaction modeling suggested that the absolute 3-year EFS benefit of immunochemotherapy peaked at intermediate PRR (≈60–80%) and diminished as PRR approached ≥90%. Conclusions: The robustness of these findings was further confirmed through a sensitivity analysis focusing on a homogeneous cohort of clinical stage II-III patients receiving adjuvant therapy. Among NSCLC patients treated with neoadjuvant systemic therapy, PRR is a strong prognostic marker and modulates the benefit of postoperative immunotherapy. These data support a response-adapted strategy, with adjuvant immunotherapy intensification in low-PRR patients and potential de-escalation or surveillance alone in MPR patients, warranting validation in prospective PRR-stratified trials. Full article

Background and Objectives: Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers and remains a leading cause of cancer-related mortality worldwide. EGFR-targeted tyrosine kinase inhibitors (TKIs) have substantially improved outcomes in EGFR-mutant NSCLC; however, primary and acquired resistance continues to limit their long-term efficacy. HER3 (receptor tyrosine-protein kinase ErbB3), a member of the ErbB receptor family, has been implicated in TKI resistance through heterodimerization with EGFR and HER2, leading to downstream PI3K/AKT pathway activation. Despite its biological plausibility as a resistance mediator, the clinical significance of HER3 expression as a prognostic and predictive biomarker in EGFR-mutant NSCLC has not been thoroughly characterized in real-world cohorts. Materials and Methods: This retrospective, single-center study included 52 patients diagnosed with EGFR-mutant NSCLC who received TKI therapy at Afyonkarahisar Health Sciences University between January 2011 and September 2023. HER3 protein expression was evaluated by immunohistochemistry (IHC) on formalin-fixed, paraffin-embedded tumor tissue sections using the Huabio anti-HER3 antibody (clone PD00-44, 1:2000 dilution). Staining in more than 30% of tumor cells was considered HER3-positive; membranous staining intensity was scored on a 1–3 scale. Progression-free survival (PFS1, PFS2) and overall survival (OS) were analyzed using the Kaplan–Meier method and log-rank test. Statistical significance was set at p < 0.05. Results: Of 52 patients (55.8% female; mean age 64.5 years), 59.6% received chemotherapy and 40.4% received an EGFR TKI as first-line treatment; erlotinib constituted 71.2% of targeted therapies. In the first-line TKI group, HER3-negative patients had a numerically longer median PFS1 compared with HER3-positive patients (14.0 vs. 7.1 months; p = 0.285); however, this difference did not reach statistical significance and should be interpreted with caution given the small sample size. In contrast, among patients receiving first-line chemotherapy, HER3 staining status did not meaningfully affect PFS1 (4.1 vs. 2.5 months; p = 0.063). In second-line treatment, HER3-positive patients who received TKI after prior chemotherapy demonstrated a PFS2 comparable to or slightly exceeding that of HER3-negative patients (21.8 vs. 19.8 months; p = 0.49), suggesting that the sequencing of chemotherapy before TKI may attenuate the adverse effect of HER3 positivity. Median OS was 15.1 months in HER3-negative patients and 12.7 months in HER3-positive patients (p = 0.824); this numerical difference of approximately 3 months did not reach statistical significance and should therefore be interpreted cautiously. Among patients receiving TKI in the first line, HER3-positive patients had a shorter median OS than HER3-negative patients (9.6 vs. 14.2 months), whereas those receiving TKI in the second line showed a trend toward longer OS in HER3-positive patients (20.5 vs. 17.2 months). Conclusions: HER3 expression was associated with reduced first-line TKI efficacy in EGFR-mutant NSCLC, suggesting a possible role for HER3 in primary TKI resistance; however, these findings are exploratory and did not reach statistical significance. The observation that HER3-positive patients who received chemotherapy before TKI demonstrated outcomes comparable to HER3-negative patients raises the hypothesis that treatment sequencing may potentially influence the impact of HER3 positivity, though this requires prospective validation before any clinical conclusions can be drawn. These results suggest that HER3 expression may warrant further investigation as a candidate biomarker for treatment sequencing decisions and as a potential therapeutic target in EGFR-mutant NSCLC. Prospective studies evaluating chemotherapy–TKI sequencing and HER3-directed agents such as patritumab deruxtecan (HER3-DXd) in HER3-positive patients are needed to confirm these preliminary observations. Full article

Liver transplantation has emerged as a curative treatment option for selected patients with unresectable hepatic malignancies beyond hepatocellular carcinoma, marking a paradigm shift in transplant oncology. For colorectal cancer liver metastases (CRLM), prospective trials have demonstrated that highly selected patients achieve 5-year OS rates of 60–83%, with the Oslo score identifying optimal candidates for transplantation. Perihilar cholangiocarcinoma (pCCA) has been successfully treated using strict patient selection criteria combined with neoadjuvant therapy, achieving 5-year OS rates of 50–68%, though emerging data suggests chemotherapy-based approaches may be preferable to radiation in selected cases. Intrahepatic cholangiocarcinoma (iCCA), previously considered a contraindication to transplantation, can now achieve excellent long-term outcomes (79.5% 5-year OS) in patients demonstrating sustained response to neoadjuvant chemotherapy and radioembolization, with metabolic tumor volume < 70 cm³ serving as an objective prognostic marker. Across these three emerging indications, successful outcomes depend on strict patient selection based on tumor biology, intensive multimodal neoadjuvant therapy, multidisciplinary evaluation in high-volume centers, and careful observation during treatment to exclude patients with aggressive disease. This evolution in transplant practice offers curative intent therapy to patients that previously only had palliative therapeutic options, fundamentally transforming hepatobiliary and oncologic surgery. Full article

Background: Proton beam therapy (PBT) is a valuable alternative to photon radiotherapy of CNS tumors in children and adolescents. While most recent studies deal with the outcome or long-term side effects of PBT, the aim of this study was to investigate the feasibility of PBT with a particular focus on the acute toxicity of a simultaneous radiochemotherapy (sPBCT). Patients and methods: We enrolled 199 children [median age 7.4 years (range, 0.9–17.9)], who received altogether 200 courses of PBT/sPBCT at initial diagnosis (n = 121) or at relapse (n = 79) with sPBCT in 52 (26%) courses. Data collection to PBT/sPBCT was based on the medical records and the KiProReg (Registry study of Standard Proton Therapy in Children at West German Proton Therapy Center) with a primarily descriptive-statistical and logistic regression analysis. Results: During PBT/sPBCT a total of n = 704 adverse events (AEs, mean 3.4 per course) were observed. Eighty-seven of them were graded as high-grade adverse events (HGAEs, Common Terminology Criteria for Adverse Eventº ≥3 (CTCAE)) which occurred in 67 (33.5%) PBT/sPBCT courses. HGAEs were in particular hematotoxicity (n = 43; 64.1%) and infections (n = 18; 26.8%). A significantly higher rate of HGAEs was documented in patients treated with sPBCT (n = 33/52; 63.5%) compared to those with PBT only (n = 34/148; 23.0%) (p = 0.001). In children with sPBCT, 15 (28.8%) patients could not receive the recommended dose or schedule of the planned chemotherapy (CTx) due to HGAEs, with the rate of planned CTx courses performed being significantly lower in patients receiving intensive intravenous CTx (p < 0.001). Interruptions of PBT and of simultaneous CTx were both significantly associated with the occurrence of infections [Odds ratios 3.002 (95% CI 1.005–8.971, p = 0.049) and 3.905 (95% CI 1.005–15.174, p = 0.049)]. Total discontinuation of treatment did not occur. Conclusions: Concurrent CTx during proton therapy is associated with a significant increased risk for HGAE occurrence and therapy interruptions requiring individual dose and schedule adjustments dependent on CTx intensity, very experienced interdisciplinary teams as well as intensive care and in-/out-patient oncology facilities on site. Full article