To determine the efficacy and safety of lenvatinib beyond first documented disease progression (LBP) and prognostic factors after progression in patients with radioiodine-refractory thyroid cancer. This retrospective study included adults with radioiodine-refractory thyroid cancer who received lenvatinib between January 2012 and November 2023 and continued treatment after initial RECIST 1.1 progression. Patients who subsequently received other multikinase inhibitors or selective targeted therapies were excluded. Time to second treatment failure (second TTF) was defined as time from initial progression to permanent lenvatinib discontinuation for any reason; second progression-free survival (second PFS) as time from initial progression to subsequent radiographic progression or death; and post-progression survival (PPS) as time from initial progression to death. Outcomes were estimated by Kaplan–Meier methods, and prognostic factors were explored by Cox regression. Safety was assessed. Twenty-four patients met the eligibility criteria for LBP. The objective response rate after progression was 0

e18133 Background: The morphological and genomic changes associated with relapse in young-onset tongue cancer remain unclear. Methods: Medical records of 107 patients aged <40 years with tongue squamous cell carcinoma were reviewed, and the patient characteristics, therapies, and clinical outcomes were analyzed. The pathological features of biopsied/resected specimens were characterized based on the tumor differentiation status, fibrosis, and immunostaining of p16. We performed next-generation sequencing on 16 paired primary and recurrent tumor samples from patients whose relapse was pathologically confirmed. Results: The age of the patients was 20–29 years in 33 patients and 30–39 years in 74 patients. The clinical stage was AJCC, stages 0–II in 68 patients (64%), and the well-differentiated pathological subtype was present in 74% of the cases. The 3-year overall survival (OS) rate in 107 young patients and the relapse-free survival (RFS) rate in 106 patients who underwent initial surgery were 80% and 71%, respectively. Patients with stages III to IV had worse OS and RFS than those with stages 0-II (3-year OS rate: 60% vs. 92%, P <0.001; 3-year RFS rate: 57% vs. 79%, P = 0.004). Thirty-three of the 106 patients (31%) experienced clinical relapse (with 25 with localized relapse and eight with metastatic relapse). Among the 33 patients with clinical relapse, 16 pairs were subjected to histopathological assessment and whole-exome sequencing. Twelve of the 16 paired specimens showed consistent tumor differentiation status between initial and relapsed samples (9 well-, 2 moderately-, and 1 poorly- differentiated tumors). Meanwhile, four pairs (25%) had altered differentiation status at relapse: two changed to differentiation, and two changed to dedifferentiation, including one case that relapsed as the scirrhous type. Immunostaining for p16, which suggests the involvement of human papillomavirus, was negative in all 16 pairs. Thirteen of the 16 pairs harbored mutations in either the initial or relapsed specimen. Concordant mutations were found in seven pairs (44%), including four with TP53 , one with concurrent TP53 and CDKN2A , one with CDKN2A , and one with PIK3CA . Discordant mutations were detected in five pairs (31%) as follows: two with TP53 , one with NOTCH1 , AJUBA and MAP4K3, one with PIK3CA and IPO7 , and one with FAT1 . At clinical relapse, out of eight discordant mutations, two mutations in TP53 and AJUB A emerged, while the other six mutations disappeared. No cases were found to harbor pathogenic germline variants associated with hereditary genetic syndromes. Conclusions: This analysis indicates that, in the context of clinical relapse, some cases exhibit unique morphological changes and clonal alterations in driver genes. TP53 -mutated clones were preserved in one-third of the cases. These findings provide insight into the molecular mechanisms underlying tumor relapse.

EWSR1::NFATC2 sarcoma is rare and its clinical features remain unclear. Given the similarity in presentation, it is possible that previously reported cases of Ewing-like adamantinoma may have been EWSR1::NFATC2 sarcoma. The present case report describes a tumor in a 55-year-old man that was originally thought to be a Ewing-like adamantinoma, but was recently found to be an EWSR1::NFATC2 sarcoma following direct sequencing. The patient experienced pain in their left lower leg at 38 years of age. The initial pathological diagnosis was 'epithelioid malignant tumor of the left tibia suggesting Ewing-like adamantinoma'. The patient underwent wide excision of the tumor in their left tibia with left total knee arthroplasty and a medial gastrocnemius muscle flap. Thereafter, the patient continued with no evidence of recurrent or metastatic disease; however, 14 years later, they developed multiple lesions in the left lung, left pleural dissemination, and enlargement of the mediastinal, left hilar and juxtaesophageal lymph nodes. Pathological diagnosis of transbronchial lung biopsy was consistent with 'Ewing-like adamantinoma'. The patient received doxorubicin-based systemic chemotherapy as first-line therapy, which resulted in stable disease. After disease progression, the patient received eribulin monotherapy, which resulted in stable disease for 15 months. Reverse transcription-polymerase chain reaction followed by direct sequencing revealed an in-frame EWSR1::NFATC2 fusion where exon 8 of EWSR1 (ENST00000397938.7) was fused to exon 3 of NFATC2 (ENST00000371564.8), and their diagnosis was changed to EWSR1::NFATC2 sarcoma. The disease progressed, left pleural dissemination progressed, left pleural effusion increased and peritoneal dissemination in the left paracolic gutter was suspected. Therefore, the patient was started on trabectedin monotherapy during 16 months of stable disease, and thereafter received pazopanib after they presented with progressive disease on prior trabectedin monotherapy. It is likely that there are more patients with undiagnosed EWSR1::NFATC2 sarcoma. To make a definitive diagnosis, a thorough investigation should be performed.

Introduction:The prognosis of unresectable metastatic adrenocortical carcinoma is very poor. We report a case of Lynch syndrome accompanying metastatic adrenocortical carcinoma treated with pembrolizumab. Case Presentation:A 73-year-old woman was diagnosed with left adrenocortical carcinoma and multiple lung, liver, and lymph node metastases. First-line mitotane therapy failed due to toxicity and progressive disease. Immunohistochemical analysis of mismatch repair proteins revealed an MSH6 deficiency. Pembrolizumab monotherapy was started for microsatellite instability-high/mismatch repair-deficient malignant disease. After the first administration, we experienced temporal clinical findings considered to reflect the collapse of tumors. She gained remarkable reductions in all lesions after four cycles. Genetic analysis disclosed the germline pathogenic variant of MSH6, so this case was diagnosed as Lynch syndrome. Conclusion:We report a patient with metastatic adrenocortical carcinoma in Lynch syndrome who demonstrated an excellent response to pembrolizumab. Genetic analyses can play a beneficial role in cases of adrenocortical carcinoma.

The upper gastrointestinal tract is a relatively rare site for immune-related adverse events (AEs) associated with immune checkpoint inhibitor treatment. A 79-year-old Japanese male with relapsed hypopharyngeal carcinoma after curative surgery with free-jejunum reconstruction and postoperative irradiation developed multiple lung metastases invading the mediastinum. Four months after the anti-PD-1 inhibitor pembrolizumab was initiated, repeated bleeding episodes occurred in the tracheostoma and mouth. Tumor progression, collapse, and bleeding were not observed on CT. Esophagogastroduodenoscopy identified erosion of the reconstructed free jejunum and esophageal mucosal injury (diagnosed as an immune-related AE) as the bleeding source. A corticosteroid (methylprednisolone) was introduced, resulting in a rapid response. Considering the risk of esophageal perforation/bleeding and the patient’s age, best supportive care and the termination of systemic chemotherapy were recommended. Acute esophagitis as irAE can be fatal, necessitating its early differentiation and corticosteroid treatment. Further clarification of the predilection and time course of this AE is warranted.

Medullary thyroid carcinoma is a rare thyroid malignancy derived from parafollicular C cells that is frequently driven by activating mutations in the REarranged during Transfection (RET) proto-oncogene. While most actionable RET mutations are located in the extracellular cysteine-rich or intracellular tyrosine kinase domains, mutations in the transmembrane domain are exceedingly rare and their oncogenic significance remains unclear. We report a case of a 59-year-old male with sporadic medullary thyroid carcinoma harboring a rare RET A641R mutation in the transmembrane domain. The patient experienced multiple locoregional recurrences after four surgical resections. While the companion diagnostic test did not identify RET mutations, comprehensive genomic profiling using a next-generation sequencing panel revealed the RET A641R mutation. Following administration of selpercatinib, a selective RET inhibitor, a rapid biochemical response with decreased serum carcinoembryonic antigen and calcitonin levels was observed, and radiological assessment showed partial response. This is the first report demonstrating the clinical efficacy of selpercatinib in a patient with medullary thyroid carcinoma harboring a RET A641R mutation, supporting the oncogenic potential of this rare variant. This case also emphasizes the importance of comprehensive genomic profiling in identifying rare but actionable RET alterations that are undetectable by targeted sequencing companion diagnostic tests. Selpercatinib may represent an effective therapeutic option for patients with medullary thyroid carcinoma driven by uncommon RET mutations, including mutations in the transmembrane domain.

INTRODUCTION:The management of metastatic renal cell carcinoma (mRCC) has advanced with recent therapies, yet optimizing treatment remains challenging due to disease heterogeneity and the growing number of options. Integrating systemic and local treatments requires a multidisciplinary approach to improve outcomes. AREA COVERED:This review summarizes recent developments in treatment for mRCC. Upfront immuno-oncology (IO)-based combinations have improved survival, though concerns about overtreatment and toxicity persist. While the role of cytoreductive nephrectomy (CN) has declined to some extent, it may still benefit well-selected patients. Metastasis-directed therapies, including metastasectomy and stereotactic radiotherapy, provide prognostic value, particularly for oligometastatic lesions or brain metastases. Comprehensive genomic profiling (CGP) holds promise for personalized treatment but is currently limited by the lack of actionable mutations and predictive biomarkers. EXPERT OPINION:A personalized, multimodal approach is essential for optimizing mRCC management. Careful patient selection is key to balancing the benefits of treatment with the risks of toxicity. While CN and metastasis-directed therapies remain useful in select cases, advancing individualized care requires the development of validated biomarkers and broader application of CGP.

Targeted therapy for NTRK fusion gene-positive solid tumors has been approved as tumor-agnostic, but the frequency of such tumors is extremely low ( 1

Soft-tissue sarcoma (STS) is a rare malignancy that accounts for less than 1

Proteinuria has been described as a major on-target adverse event of lenvatinib, although its long-term impact on renal function and clinical outcomes remains unclear. We conducted a retrospective observational study to assess renal function and prognosis in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC) receiving lenvatinib. Overall, 70 patients with RR-DTC treated with lenvatinib were enrolled. When proteinuria was observed, the dose and schedule of lenvatinib were adjusted to achieve a urine protein-to-creatinine ratio (UPCR) of less than 3.5 g/gCre according to the study protocols of recent pivotal trials. In total, 50 (71%) and 25 (36%) patients presented with any-grade and grade 3 proteinuria, respectively. Multivariate analysis revealed that age [>65; odds ratio (OR) 8.24, 95% confidence interval (CI) 1.74-39.00, p < 0.01], history of diabetes mellitus (OR 7.79, 95% CI 1.31-46.20, p = 0.02), and hypertension (OR 4.07, 95% CI 1.22-13.60, p = 0.02) were significantly associated with the development of grade 3 proteinuria. Overall, the median estimating glomerular filtration rate (eGFR) gradually decreased every 3 months during treatment. However, no significant deterioration in eGFR was observed in patients with grade 3 proteinuria compared with patients with grades 0-2 proteinuria until 48 months. Patients who developed proteinuria had better survival outcomes than those without proteinuria. In conclusion, the proteinuria grade was not significantly associated with decreased eGFR under UPCR monitoring in our study. Therefore, lenvatinib can carefully be continued targeting UPCR of less than 3.5 g/gCre.

The phase 3 CheckMate 274 trial demonstrated superiority of adjuvant nivolumab over placebo after radical surgery in patients with high-risk urothelial carcinoma (UC). However, real-world data on the efficacy and safety profile of adjuvant nivolumab in Japan have not been reported. This retrospective study enrolled patients with high-risk UC who received adjuvant nivolumab therapy following radical surgery between 2022 and 2024 at our institution. We evaluated immune-related adverse events (irAEs) according to the Common Terminology Criteria for Adverse Events, version 5.0. Kaplan–Meier curves were used to assess disease-free survival (DFS) and overall survival (OS). Thirty-three patients with high-risk UC receiving adjuvant nivolumab therapy following radical surgery were identified, and median follow-up was 11 months. Three patients experienced grade 3 irAEs, and 8 discontinued adjuvant nivolumab therapy due to irAEs. No grade 4 or 5 irAEs were observed. Eight patients have completed 1 year of treatment, and nine are currently on treatment. Nine patients had recurrences and one died of cancer. Of the nine patients with recurrences, six relapsed while on adjuvant nivolumab therapy, two relapsed after completing 1 year of treatment, and one relapsed after discontinuation of irAE. The 1- and 2-year OS rates were 100

Introduction:Li-Fraumeni syndrome, an autosomal dominant cancer predisposition syndrome caused by a pathogenic variant of TP53, a tumor suppressor gene, leads to a high risk from early childhood of developing various types of cancers. Here, we report a case of advanced ureteral cancer in Li-Fraumeni syndrome.Case presentation:A 73 years-old female patient, who had been diagnosed genetically as Li-Fraumeni syndrome; suffered from chondrosarcoma in the left pelvic joint, bilateral breast cancer, endometrial cancer, gastric cancer, and colon cancer in her history. She was diagnosed as unresectable advanced urothelial cancer during continuous magnetic resonance imaging surveillance, underwent avelumab maintenance therapy after the combination of gemcitabine and cisplatin chemotherapy. The efficacies of gemcitabine and cisplatin chemotherapy and avelumab maintenance therapy were good.Conclusion:We report an advanced urothelial cancer in a patient with Li-Fraumeni syndrome who demonstrated good efficacies to sequential medical therapy.

BACKGROUND/AIM:Immune-related adverse events (irAEs) develop in a subset of patients with metastatic renal cell carcinoma (mRCC) treated with immune-checkpoint-inhibitors (ICIs). Evidence regarding the prognostic impact of irAEs remains limited in these patients.PATIENTS AND METHODS:Ninety-one consecutive patients with mRCC treated with ICIs were retrospectively analyzed. Overall survival (OS) rates were estimated using the Kaplan-Meier method. In multivariate analysis, predictors of OS were analyzed using the Cox-proportional-hazards-model.RESULTS:Twenty-nine patients were treated with the combination of nivolumab plus ipilimumab. According to International Metastatic RCC Database Consortium risk classification, 27/47/17 patients were classified into favorable/intermediate/poor risk categories. The 1, 3, and 5-year OS-rates were 89, 70, and 57%, respectively. A total of 67 irAEs occurred in 44 patients (48%), including 15 patients with grade 3-4. OS was significantly longer in patients with irAEs (p=0.01). In multivariate analysis, Karnofsky performance status, prior nephrectomy, and irAEs were independent significant predictors of OS.CONCLUSION:In our study, irAEs were significantly associated with OS in mRCC patients treated with ICIs.

Introduction: Although systemic therapy, including multi-kinase inhibitors and cytotoxic chemotherapy, is an option for recurrent or metastatic adenoid cystic carcinoma of the head and neck (HNACC), it is not proven whether these therapies can prolong overall survival (OS). The present study investigated the impact of cytotoxic chemotherapy on survival outcomes compared with observation without chemotherapy. Methods: We retrospectively reviewed the medical records of the patients diagnosed with recurrent or metastatic HNACC. We compared the survival outcomes, including survival time from recurrence/metastasis (OS) patients who received systemic chemotherapy with paclitaxel (200 mg/m2) and carboplatin (area under the curve 6) (TC) on day 1 of a 3-week cycle and observation alone. Subgroup analysis was conducted to identify patients who can get benefit from TC. Results: Seventy-five patients (32 in TC and 43 in observation) were analyzed. There was no difference in median OS between TC and observation (52.2 months vs. 44.0 months, hazard ratio 0.76, 95% confidence interval 0.32–1.30, p = 0.21). Landmark analysis to reduce immortal bias also showed no difference between TC and observation in terms of OS. Subgroup analysis showed nonsignificant trends toward longer OS in asymptomatic patients with pulmonary metastasis and without bone metastasis. Conclusions: In our non-randomized comparison, patients who underwent TC did not show prolonged survival time from recurrence and/or metastasis diagnosis compared with observation alone in patients with recurrent or metastatic HNACC. Although systemic chemotherapy is a possible option for metastatic/recurrent HNACC, initial observation might be a valid strategy for asymptomatic patients without extrapulmonary diseases. Further research is warranted to identify the optimal patients and therapeutic regimens to prolong OS in HNACC.

Trabectedin is a therapeutic option for patients with advanced sarcoma. While a randomized trial demonstrated its prolonged progression-free survival (PFS), the reported PFS was <6 months. Some patients can achieve long-term disease control with this treatment. However, the reference information is insufficient. Herein, we retrospectively reviewed 51 sarcoma patients who received trabectedin. We analyzed the clinicopathological features, trabectedin dose, administration schedule, and clinical outcomes, including the overall response rate (ORR) and PFS. Among them, we assessed the detailed data of patients who achieved long-term disease control (PFS >1 year). The ORR in the 49 evaluable patients was 8%, and the median PFS in 51 patients was 7.5 months. Six patients (12%) achieved PFS of >1 year. Five of the six patients had metastatic lesions at trabectedin initiation. The pathological subtypes were myxoid liposarcoma (n = 2), leiomyosarcoma (n = 2), synovial sarcoma (n = 1), and Ewing sarcoma (n = 1). The final administration dose was the minimum dose (0.8 mg/m2) in two patients who continued the treatment over 20 cycles. The best radiological response was partial response (PR) in two myxoid liposarcoma patients and stable disease in four. The durations from trabectedin initiation to the first response in the two PR cases were 163 and 176 days, respectively. Our results support the validity of continuing trabectedin at a sustainable dose and interval in patients who can tolerate it. These results may be useful when considering the clinical application of trabectedin.

Systemic therapy for metastatic renal cell carcinoma (mRCC) has made significant strides over the past two decades. The combination of immuno-checkpoint inhibitors (ICIs) with VEGFR inhibitors, as well as ICI combinations, has become the standard first-line treatment for mRCC, with high response rates and a prolongation of progression-free survival (PFS) and overall survival (OS). However, these regimens have not demonstrated an overall survival advantage over sunitinib in the favorable prognosis subgroup of the IMDC risk stratification.

BackgroundThe Geriatric Nutritional Risk Index (GNRI) has been reported as a screening tool to assess the nutrition-related risk with mortality in older patients and those with the various diseases. However, the prognostic value of GNRI in metastatic renal cell carcinoma (mRCC) patients receiving nivolumab therapy remains unclear.MethodsFifty-six consecutive patients with mRCC receiving nivolumab between September 2013 and August 2020 at our institution were retrospectively analyzed. The survival outcomes and prognostic factors associated with overall survival (OS) were statistically analyzed.ResultsThirteen and forty-three patients were classified with low (GNRI < 92) and high (GNRI >= 92) GNRI, respectively. Patients with low GNRI demonstrated significantly shorter OS (P = 0.0002) than those with high GNRI. In multivariate analysis, GNRI at the time of nivolumab (P = 0.008) was extracted as the predictor for OS in addition to Karnofsky performance status (KPS) (P = 0.016). Integration of the GNRI into the International Metastatic Renal Cell Cancer Database Consortium (IMDC) risk classification improved the c-index from 0.761 to 0.833 (combination of GNRI with IMDC risk classification) and to 0.778 (substitution of GNRI with KPS in IMDC risk classification).ConclusionsGNRI was a significant prognostic biomarker in mRCC patients receiving nivolumab.

Breast tumors with neuroendocrine (NE) differentiation comprise an uncommon and heterogeneous group of tumors, including invasive breast cancer of no special type (IBC-NST) with NE features, neuroendocrine tumors (NETs), and neuroendocrine carcinoma (NEC). The most recent World Health Organization (WHO) classification in 2019 defined neuroendocrine neoplasms (NENs) of the breast (Br-NENs) as tumors in which >90% of cells show histological evidence of NE differentiation, including NETs (low-grade tumors) and NEC (high-grade). Due to the low prevalence of these tumors and successive changes in their diagnostic criteria over the years, only limited evidence of these tumors exists, derived mainly from case reports and retrospective case series. Breast tumors with NE differentiation are usually treated like the more commonly occurring IBC-NSTs. Immunohistochemistry (IHC) of breast tumors with NE differentiation usually shows a hormone receptor (HR)-positive and human epidermal growth factor type 2 (HER2)-negative profile, so that hormonal therapy with cyclin-dependent kinase (CDK)4/6 inhibitors or other targeted agents would be reasonable treatment options. Herein, we present a review of the literature on breast tumors with NE differentiation as defined in the latest WHO 2019 classification, and discuss the clinical management of these tumors.

The mainstay of medical treatment has been tyrosine kinase inhibitors (TKIs) for renal cell cancer (RCC), cytotoxic chemotherapy for urothelial cancer (UC), and androgen deprivation therapy for prostate cancer. These therapeutic modalities still play important roles in these malignancies. However, immune checkpoint inhibitors (ICIs) that target PD-1/PD-L1 or CTLA-4 are being rapidly introduced for the treatment of metastatic urological cancers, just as they have been for other malignancies. Currently, the paradigm of medical treatment for patients with metastatic urological cancer is dramatically changing. Accordingly, we need to organize and summarize the new therapeutic tools, which include immune checkpoint inhibitors, poly (ADP-ribose) polymerase (PARP) inhibitors, and antibody-drug conjugates (ADCs). This review provides an overview of agents and regimens that have just launched or will be launched in the near future in Japan. Based on the promising anti-tumor efficacy and manageable safety profiles being demonstrated in clinical trials, these new agents and therapies are expected to be rapidly introduced in Japanese clinical practice. Additionally, the newly designed ADC, enfortumab vedotin, which comprises a fully human monoclonal antibody conjugated to an anti-cancerous agent via a protease-cleavable linker, has just been launched in Japan. In order to provide the optimal treatment for our patients, we need to completely understand these new therapeutic tools.