Search

Background Accelerated tumor growth during immunotherapy in pre-existing measurable lesions, hyperprogressive disease (HPD), has been reported. However, progression of non-measurable lesions and new lesions are frequently observed in patients with advanced gastric cancer (AGC). Methods This retrospective study involved AGC patients at 24 Japanese institutions who had measurable lesions and received nivolumab after ≥ 2 lines of chemotherapy. HPD was defined as a ≥ two-fold increase in the tumor growth rate of measurable lesions. The pattern of disease progression was classified according to new lesions in different organs and ascites appeared/increase of ascites. Results Of 245 patients, 147 (60.0%) showed progressive disease (PD) as the best response and 41 (16.7%) showed HPD during nivolumab monotherapy. There was no significant difference in overall survival (OS) between patients with HPD and those with PD other than HPD (median OS 5.0 vs 4.8 months; hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.6–1.5; p = 1.0). Fifty-three patients developed new lesions in different organs and 58 had appearance/increase of ascites; these patients showed shorter OS than those without each of these features (median OS 3.3 vs 7.1 months, HR 1.8, 95% CI 1.2–2.7, p = 0.0031 for new lesions, and 3.0 vs 7.8 months, HR 2.6, 95% CI 1.8–3.8, p Conclusions New lesions in different organs and appearance/increase of ascites, rather than the original definition of HPD, are the patterns of disease progression associated with poor prognosis in AGC patients receiving nivolumab whose best response was PD.

Background: Immune-related adverse events (irAEs) in patients treated with immune check inhibitors are associated with favourable response rate and survivals in multiple cancers, including renal cell carcinoma (RCC). The aim of this study was to investigate how irAEs were associated with improved survivals in advanced RCC patients treated with nivolumab plus ipilimumab. Materials and methods: This retrospective study included patients who received nivolumab plus ipilimumab between September 2018 and February 2022 at six centres. We assessed associations of the development and the number of irAEs with overall survival (OS) and progression-free survival (PFS). To eliminate immortal time bias, landmark analysis and a Cox model with time-dependent variables were used. Results: This study included 129 patients with a median follow-up of 12.3 months. The 2-year OS and PFS rates were 55% and 42%, respectively. Ninety six patients experienced irAEs. The development of irAEs was positively associated with OS and PFS rates (hazard ratio [HR] 0.328, 95% confidence interval [CI] 0.165–0.648, p = 0.001; HR 0.334, 95% CI 0.151–0.737, p = 0.007). Patients who experienced multiple irAEs had longer OS (HR 0.507, 95% CI 0.235–1.097, p = 0.085 or HR 0.245, 95% CI 0.110–0.544, p < 0.001) and PFS (HR 0.572, 95% CI 0.316–1.036, p = 0.085 or HR 0.267, 95% CI 0.113–0.628, p = 0.002) compared with those who experienced single or zero irAE. Conclusions: Developing irAEs, particularly multiple irAEs, is associated with favourable survivals in advanced RCC patients treated with nivolumab plus ipilimumab.

Programmed death (PD)-1/PD-ligand 1 (PD-L1) antibodies have shown an intense clinical effect in some patients with PD-L1

Penile cancer is a rare cancer for which no medical guidelines have been established before in Japan. These guidelines aim to standardize, as much as possible, the therapeutic modality for penile cancer, for which empirical evidence is limited on a global scale, thereby bolstering therapeutic outcomes for patients with penile cancer. The new guidelines conform to the Minds Guide for Developing Clinical Practice Guidelines (2017) as much as possible. However, virtually no randomized comparative studies and meta-analyses based on such randomized studies have been conducted. Therefore, only the findings available at present were listed after conducting an exhaustive literature review of items with extremely low evidence levels and for which bodies of evidence and grades of recommendation were not evaluated. Clinical questions were set for items with a relatively large number of studies, including retrospective studies. However, since it is virtually impracticable to summarize bodies of evidence by systematic reviews, recommendation grades and evidence levels were discussed and determined by the consensus panel of the Preparatory Committee. The following were outlined: epidemiological, pathological, diagnostic, therapeutic, follow-up, and quality of life-related findings. Additionally, seven clinical questions were established to determine recommendation grades and evidence levels. We hope that these guidelines will prove to be useful to medical professionals engaged in clinical practice related to penile cancer in Japan and anticipate that critical reviews of the guidelines will lead to further refinement of the next edition.

Background: Prostate cancer is one of the most heritable human cancers. Lynch syndrome is an autosomal dominant inheritance caused by germline mutations in DNA mismatch repair (MMR) genes, which are also associated with an increased incidence of prostate cancer. However, prostate cancer has not been defined as a Lynch syndrome-associated cancer. The proportion of Lynch syndrome patients in primary prostate cancers is unclear. In this study, we investigated MMR protein loss using universal immunohistochemical screening to determine the prevalence of Lynch syndrome in patients with localized prostate cancer who underwent radical prostatectomy. Methods: One hundred twenty-nine surgical specimens from radical prostatectomy performed at Toranomon Hospital between 2012 and 2015 were retrospectively tested using universal screening with immunohistochemistry staining for expression of the MMR proteins MLH1, PMS2, MSH2, and MSH6. For all suspected MMR-deficient patients, germline genetic tests focusing on MMR genes were performed. Results: MMR protein loss was found in only one patient (0.8%) who showed dual MSH2/MSH6 loss. This patient showed a single nucleotide germline mutation from c.1129 C to T (p.Glc377*) at exon 7 in the MSH2 gene. He was diagnosed with a primary prostate cancer at 66 years of age. He had a documented history of Lynch syndrome (Muir–Torre syndrome) with previous colon cancer, sebaceous tumor, and keratoacanthoma as well as subsequent bladder cancer, all of which also showed dual MSH2/MSH6 loss. He also had a strong family history of colorectal and other Lynch syndrome-associated cancers. The pathological stage was pT3aN0M0, and the pathological grade was Gleason 7(4+3) with tertiary pattern 5. Conclusions: In this study, immunohistochemical screening of MMR proteins for Lynch syndrome was performed in a series of prostate cancer cases. The prevalence of Lynch syndrome in localized prostate cancer was 0.8%, which is low compared with other Lynch syndrome-associated cancers.

Sleep stage scoring is important to determine sleep structure in preclinical and clinical research. The aim of this study was to develop an automatic sleep stage classification system for mice with a new deep neural network algorithm. For the purpose of base feature extraction, wake-sleep and rapid eye movement (REM) and non- rapid eye movement (NREM) models were developed by extracting defining features from mouse-derived electromyogram (EMG) and electroencephalogram (EEG) signals, respectively. The wake-sleep model and REM-NREM sleep model were integrated into three different algorithms including a rule-based integration approach, an ensemble stacking approach, and a multimodal with fine-tuning approach. The deep learning algorithm assessing sleep stages in animal experiments by the multimodal with fine-tuning approach showed high potential for increasing accuracy in sleep stage scoring in mice and promoting sleep research.

Comprehensive cancer genome profiling (CGP) has been nationally reimbursed in Japan since June 2019. Less than 10% of the patients have been reported to undergo recommended treatment. Todai OncoPanel (TOP) is a dual DNA-RNA panel as well as a paired tumor-normal matched test. Two hundred patients underwent Todai OncoPanel as part of Advanced Medical Care B with approval by the Ministry of Health, Labour and Welfare between September 2018 and December 2019. Tests were performed in patients with cancers without standard treatment or when patients had already undergone standard treatment. Data from DNA and RNA panels were analyzed in 198 and 191 patients, respectively. The percentage of patients who were given therapeutic or diagnostic recommendations was 61% (120/198). One hundred and four samples (53%) harbored gene alterations that were detected with the DNA panel and had potential treatment implications, and 14 samples (7%) had a high tumor mutational burden. Twenty-two samples (11.1%) harbored 30 fusion transcripts or MET exon 14 skipping that were detected by the RNA panel. Of those thirty transcripts, six had treatment implications and four had diagnostic implications. Thirteen patients (7%) were found to have pathogenic or likely pathogenic germline variants and genetic counseling was recommended. Overall, 12 patients (6%) received recommended treatment. In summary, patients benefited from both TOP DNA and RNA panels while following the same indication as the approved CGP tests. (UMIN000033647).

The phase 3 CLEAR study demonstrated statistically significantly improved efficacy with lenvatinib plus pembrolizumab versus sunitinib, including progression-free survival and overall survival, in patients with previously untreated advanced renal cell carcinoma. This subset analysis investigated efficacy and safety in Japanese patients randomized to lenvatinib plus pembrolizumab or sunitinib in the CLEAR study.Progression-free survival, overall survival, tumor response, and safety were assessed in Japanese patients with previously untreated advanced renal cell carcinoma randomized to receive lenvatinib plus pembrolizumab (n = 42) or sunitinib (n = 31). Efficacy outcomes were analyzed by independent imaging review per Response Evaluation Criteria in Solid Tumors, version 1.1.Progression-free survival was longer with lenvatinib plus pembrolizumab than with sunitinib (median, 22.1 vs. 10.9 months; hazard ratio, 0.39; 95% CI, 0.20-0.74). Median overall survival was not estimable in the lenvatinib plus pembrolizumab arm and 30.6 months in the sunitinib arm (HR, 1.20; 95% CI, 0.39-3.66). Overall survival adjusted for the imbalance of Memorial Sloan-Kettering Cancer Center prognostic risk group favored lenvatinib plus pembrolizumab (hazard ratio, 0.67; 95% CI, 0.18-2.39). Objective response rate (69.0% vs. 45.2%; odds ratio, 2.71; 95% CI, 1.03-7.10) was higher and median duration of response (20.3 vs. 9.1 months) was longer with lenvatinib plus pembrolizumab versus sunitinib. Grade ≥ 3 treatment-emergent adverse events occurred in 95.2% versus 87.1% of patients in the lenvatinib plus pembrolizumab versus sunitinib arms.These findings support lenvatinib plus pembrolizumab as a potential first-line treatment for Japanese patients with advanced renal cell carcinoma.

Summary Background PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. Methods KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov , number NCT02853305 . Findings Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7–36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5–8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4–7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65–0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5–19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3–16·7) in the chemotherapy group (0·86, 0·72–1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1–17·9] with pembrolizumab vs 14·3 months [12·3–16·7] with chemotherapy; HR 0·92, 95% CI 0·77–1·11) and the population with CPS of at least 10 (16·1 months [13·6–19·9] with pembrolizumab vs 15·2 months [11·6–23·3] with chemotherapy; 1·01, 0·77–1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group. Interpretation The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. Funding Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.

Background Cabozantinib was established as the standard of care for the treatment of patients with renal cell carcinoma (RCC) whose disease had progressed after vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy in the global randomized trial METEOR. A phase 2 study was conducted to bridge the findings in METEOR to Japanese patients. Here, we report a biomarker analysis and update the efficacy and safety results of cabozantinib treatment. Methods Japanese patients with RCC who received at least one prior VEGFR-TKI were enrolled and received cabozantinib 60 mg orally once daily. The primary endpoint was objective response rate. Secondary endpoints included progression-free survival, overall survival, and safety. Exploratory analyses included the relationship between plasma protein hepatocyte growth factor (HGF) levels and treatment responses. Results In total, 35 patients were enrolled. The median treatment duration was 58.3 (range 5.1–131.4) weeks. The objective response rate was 25.7% (90% confidence interval [CI] 14.1–40.6). Kaplan–Meier estimate of median progression-free survival was 11.1 months (95% CI 7.4–18.4). The estimated progression-free survival proportion was 73.1% (95% CI 54.6–85.0) at 6 months. Median overall survival was not reached. Adverse events were consistent with those in METEOR and the safety profile was acceptable. Nonresponders to cabozantinib showed relatively higher HGF levels than responders at baseline. Conclusions Updated analyses demonstrate the long-term efficacy and safety of cabozantinib in Japanese patients with advanced RCC after at least one VEGFR-TKI therapy. Responders tended to show lower baseline HGF levels ClinicalTrials.gov Identifier: NCT03339219.

BackgroundRhabdomyolysis is a potentially fatal disease, and elevated serum creatine kinase (CK) is one of the key laboratory findings suggestive of this disease. It is important to distinguish rhabdomyolysis from other diseases because CK elevation can occur in a variety of etiologies. Cabozantinib is one of the standard treatments for patients with renal cell carcinoma, but the frequency of CK elevation with this drug is still unknown.MethodsTo investigate the frequency of serum CK elevation induced by cabozantinib, we retrospectively reviewed the electronic medical records of patients with advanced renal cell carcinoma who received cabozantinib at our institution from April 2020 to March 2021.ResultsSeven patients were included in the study; six experienced serum CK elevation, four were classified as grade 1, and the remaining two as grade 3 according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. In five patients, the time from cabozantinib administration to CK elevation was 14 days. Hypothyroidism can be one of the causes of CK elevation; however, two patients who had hypothyroidism caused by previous treatment were in the euthyroid condition due to hormone replacement. One patient with grade 1 CK elevation developed late-onset immune-related adverse event (irAE) myositis comorbid with suspected myasthenia gravis. One patient with grade 3 CK elevation developed muscle weakness and rhabdomyolysis.ConclusionsCK elevation is a common adverse event induced by cabozantinib. Most patients are asymptomatic and may not be clinically ill. However, physicians should be careful with the rare occurrence of symptomatic serum CK elevation, indicating rhabdomyolysis and neuromuscular irAEs, especially in patients who receive immune checkpoint inhibitors (ICIs).

Clinical success of immune-checkpoint blockade (ICB) cancer immunotherapy is compromised by increased risk of immune-related adverse events (irAEs). However, mechanistic action(s) of immune responses underlying development of irAE remain not fully explored. Here, we found that in tumor-bearing aged, but not young, mice, antiprogrammed death receptor (PD)-1 therapy elicited irAE-like multiorgan dysfunctions with ectopic accumulation of T and B cells in damaged organs. In this preclinical model, the organ toxicities were mediated by immunoglobulin G (IgG) deposition because administration of IG from ICB-treated aged mice induced the pathogenicity specifically in naïve aged hosts. Mechanistically, CD4 T-cell–derived interleukin (IL)-21 upregulated B-cell–homing chemokine, CXCL13, preferentially in irAE organs from aged mice treated with anti–PD-1 therapy. The ICB-induced pathogenicity was alleviated by B-cell depletion or by blockade of IL-21 or CXCL13 activity. These results suggest that age-associated immune regulatory milieu contributes to the formation of tertiary lymphoid structure-like lymphocytic aggregates in irAE organs and irAE-related toxicity employing IL-21-CXCL13-auto-antibody axis. Supporting this, a systemic increase in CXCL13 and Il21 expression in CD4 T cells correlated with irAE incidence in ICB-treated patients. These findings provide rationale for therapeutic usefulness of CXCL13 in irAE management., がん免疫療法の副反応による臓器傷害の原因解明に新たな一歩 --がんに対する免疫応答と、有害事象に関わる免疫応答の違い--. 京都大学プレスリリース. 2022-07-13.

Background: Since the introduction of Immune checkpoint inhibitors (ICIs) combination therapy to renal cancer treatment, it has revolutionized the treatment of renal cancer, with many reports of excellent therapeutic effects. However, it is not known which patients will benefit the most. Materials and methods: PBMC(Peripheral Blood Mononuclear Cells)samples were collected prospectively from patients with advanced and metastatic renal cell carcinoma (RCC) prior to initiation of ICI treatment (baseline) and 2 or 3 weeks after the first cycle of ICI treatment (post-dose 1). We collected PBMCs from 24 patients with a cell count of more than 50,000 were analyzed using antibodies that distinguishCD4 and CD8 cells including Effector, Memory cells population, B cells, Monocyte, NK(Natural Killer) cells, MDSC(Myeloid-Derived Suppressor Cells ), DC(Dendritic cells), CD4 (Th1, Th2, Th17, Tfh), Immune checkpoint molecules including CD223 (LAG3), CD279 (PD1), TIM3, CD152 (CTLA4), CD278 (ICOS), FOXP3. Results: First, we compared the Fold Change (FC) before and after drug administration in the group that did not respond to treatment (SD: Stable Disease or PD: Progressive disease) and the group that did respond to treatment (PR: Partial Response, CR: Complete Response). The results showed that CD4 positive cells (non-responder Median 0.79 vs responder Median 1.64, p=0.0317, respectively), monocytes: CD56-HLADR+ (non-responder Median 0.87 vs responder Median 1.20, p=0.0159, respectively), but not in other cell populations.Next, we compared the groups that did and did not respond to treatment before and after treatment. We could not identify any biomarker cell population before treatment, the number of CD4 Effector cells (CD4+CD45RO-CD197-) was significantly higher in the post-treatment (PD1) group (PR or CR) than in the non-treatment group (SD or PD). (p=0.0303, respectively) Conclusion: Elevation of CD4 positive cells and monocytes (CD56-HLADR+) before and after treatment and the number of CD4 Effector cells (CD4+CD45RO-CD197-) after treatment may be biomarkers of treatment response. Citation Format: Takanobu Motoshima, Yuji Miura, Toshiki Amami, Shigeyasu Kitano, Masaya Baba, Tomomi Kamba. Predictive biomarkers of response to immune checkpoint inhibitors in metastatic renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3308.

Background: Immune checkpoint inhibitors (ICIs) have recently improved the prognosis of various cancers. In contrast, some immune-related adverse events (irAEs) caused by ICIs are fatal and have become problematic. The pathogenesis of irAEs remains unknown and must be elucidated to establish biomarkers. Materials and Methods: Plasma samples were collected prospectively from patients with advanced and metastatic renal cell carcinoma (RCC) prior to initiation of ICI treatment (baseline) and 2 or 3 weeks after the first cycle of ICI treatment (post-dose 1). Plasma cytokines and chemokines (GRO [CXCL1], IL-17A, IL-1β, IL-6, IL-8, IP-10 [CXCL10], MCP-1 [CCL2], TNFα) were measured by Luminex system, and plasma level of CXCL13 and anti-CD74 autoantibody levels were measured by ELISA. Their association with irAEs was analyzed. Results: In a discovery cohort of 13 patients, plasma levels of CXCL1, IL-17A, IL-1β, IL-6, IL-8, CXCL10, MCP-1, and TNFα were measured at baseline and post-dose 1. Only CXCL10, at post-dose 1 but not at baseline, was significantly associated with grade 2 or higher irAEs (p=0.0413). Plasma CXCL10 levels were then measured at baseline and post-dose 1 in a validation cohort of 43 RCC patients who received ICI-based treatment. Higher plasma CXCL10 levels both at baseline and post-dose1 were significantly associated with the occurrence of grade 2 or higher irAEs (p=0.0246 and 0.0137, respectively). We evaluated the relationship between plasma levels of CXCL10 and CXCL13, which we measured in a previous study, and the incidence of irAEs. At baseline, the plasma CXCL13 level was positively associated with the CXCL10 level (p=0.0007), but no significant association was observed post-dose 1 (p=0.2678). Plasma CXCL13 levels were significantly higher in patients with grade 2 or higher irAEs at baseline but not at post-dose 1 (p=0.0037 and 0.052, respectively). No significant association between plasma anti-CD74 autoantibody level and both irAE pneumonitis and any grade 2 or higher irAE was observed. Conclusion: Plasma CXCL10 is significantly associated with the occurrence of irAEs in patients with RCC treated with ICIs. CXCL10 is a potential predictive and on-treatment biomarker for irAEs. Citation Format: Yuji Miura, Takanobu Motoshima, Toshiki Anami, Hiromu Yano, Remi Mito, Shinji Urakami, Keiichi Kinowaki, Hirotake Tsukamoto, Ryoma Kurahashi, Yoji Murakami, Junji Yatsuda, Yukio Fujiwara, Tomomi Kamba, Yoshihiro Komohara. Predictive value of CXCL10 for the occurrence of immune related adverse events in patient with renal cell carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4326.

Background/aim Expression of human leukocyte antigen (HLA) class I and II and CD74, which functions as a chaperone of MHC class II, play essential roles in T-cell recognition. The aim of this study was to elucidate the association between the HLAs and CD74, and their correlation with the infiltrated immune cells in renal cell carcinoma (RCC). Materials and methods We retrospectively investigated the expression of HLA-A/B/C, HLA-DR, and CD74 in 38 patients with advanced RCC (T3/T4), and evaluated their correlations with CD4 and CD8-positive T-cell infiltration using immunohistochemistry. Results The expression of HLA-A/B/C, HLA-DR, and CD74 on cancer cells was observed in 37, 20, and 31 patients, respectively. The density of CD8- and CD4-positive T cells showed a positive correlation with HLA-DR expression. The density of CD4-positive lymphocytes was significantly associated with CD74 expression. Conclusion The expression of HLA-DR, rather than CD74, on cancer cells was potentially associated with the anti-cancer immune microenvironment.

The aim was to identify the characteristics and treatment patterns of early and advanced stage endometrial cancer patients using real-world data.Patients' data extracted from a Japanese health insurance claims database were analyzed.Of the 12,449 endometrial cancer patients, 74.4% were in stage I, 5.1% in stage II, 12.0% in stage III, and 8.4% in stage IV. Their median age was 60.5 years, higher in advanced stages (III/IV) than in early stages (I/II). Overall, 11,055 patients (88.8%) underwent surgery, and 4977 patients (40.0%) received post-surgery treatment, including chemotherapy (4441: 35.7%), chemoradiation therapy (379: 3.0%), and radiation therapy (157 patients: 1.3%); 1394 patients (11.2%) were not treated by surgery, and 742 patients (6.0%) received other treatment, with chemotherapy (548: 4.4%), radiation therapy (105: 0.8%), and chemoradiation therapy (89: 0.7%). The rate of patients undergoing surgery decreased, and that receiving chemotherapy increased significantly as cancer stage progressed. Paclitaxel/carboplatin was the most frequent first-line regimen (85.4% of patients), whereas various combination and monotherapy regimens were used as second- and third-line regimens. The most frequent second-line monotherapy was paclitaxel. The rate of monotherapy increased as the treatment line progressed (first-line 3.5%, second-line 22.0%, and third-line 36.4%).The characteristics and treatment patterns of endometrial cancer patients differed between early and advanced stages, as did the chemotherapy regimens among first-, second-, and third-lines. Since various regimens were used for second- and third-line chemotherapies, development of appropriate second- and third-line chemotherapy regimens is warranted. A real-world analysis of cancer patients using a nationwide claims database may be a valuable approach to identifying unmet medical needs.

Although nivolumab plus ipilimumab has become a standard treatment regimen for metastatic clear cell renal cell carcinoma (ccRCC), its efficacy in non-clear cell carcinoma (nccRCC) has not been fully examined. In the current study, we evaluated the clinical outcomes of nivolumab plus ipilimumab in nccRCC compared with ccRCC.We retrospectively analyzed 22 patients with metastatic and/or locally advanced unresectable nccRCC who received nivolumab plus ipilimumab as a first-line therapy and compared them with 107 patients with ccRCC. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and toxicity were compared between the nccRCC and ccRCC groups.The histology of nccRCC included eight papillary, six unclassified, three chromophobe, two collecting duct carcinoma, and three other subtypes. Best objective response in nccRCC patients included three complete responses and five partial responses, resulting in an ORR of 36%, while that in ccRCC patients was 50% (p = 0.22). With a median follow-up of 11.9 months, OS was significantly shorter in patients with nccRCC than in those with ccRCC (median 20.8 months vs. not reached, p = 0.04), while there was no significant difference in PFS (median 6.3 vs. 10.8 months, p = 0.21). Treatment-related adverse events occurred in 14 (64%) nccRCC patients and 81 (76%) ccRCC patients.Combination treatment with nivolumab and ipilimumab demonstrated modest clinical efficacy in patients with nccRCC compared with patients with ccRCC, suggesting it could be a therapeutic option for metastatic nccRCC patients.

To clarify the status of insomnia and depression and the prescription of sleeping pills in hepatocellular carcinoma (HCC) patients before and after HCC diagnosis and treatment.Patients' data from a Japanese health insurance claims database were analyzed retrospectively to determine the incidence of insomnia and depression and their association with sleeping pill prescriptions during the 6 months before and after HCC diagnosis and treatment.A total of 9,109 HCC patients (median age at diagnosis = 71.5 years, 68.1% male) were analyzed. The incidences of insomnia and depression increased significantly after HCC diagnosis. Insomnia was reported in 15.0% of patients before diagnosis, and it increased to 27.6% after diagnosis. Similarly, depression was reported in 6.3% and 11.3% before and after diagnosis, respectively. The incidences of insomnia and depression before diagnosis were higher in patients with concomitant liver diseases including hepatitis, cirrhosis, and hepatic encephalopathy. However, the rate of sleeping pill prescription was significantly lower in patients with concomitant liver diseases after diagnosis. The incidence of fracture was higher in insomnia or depression patients than others and in patients treated with sleeping pills than without before and after diagnosis.HCC patients had increased risks of insomnia and depression after diagnosis. The high risk of fracture in HCC patients with insomnia and depression and treated with sleeping pills suggests that it is difficult to optimize the management of HCC patients, especially those with concomitant liver diseases.

Background: The first interim analysis of the KEYNOTE-564 study showed improved disease-free survival with adjuvant pembrolizumab compared with placebo after surgery in patients with clear cell renal cell carcinoma at an increased risk of recurrence. The analysis reported here, with an additional 6 months of follow-up, was designed to assess longer-term efficacy and safety of pembrolizumab versus placebo, as well as additional secondary and exploratory endpoints. Methods: In the multicentre, randomised, double-blind, placebo-controlled, phase 3 KEYNOTE-564 trial, adults aged 18 years or older with clear cell renal cell carcinoma with an increased risk of recurrence were enrolled at 213 hospitals and cancer centres in North America, South America, Europe, Asia, and Australia. Eligible participants had an Eastern Cooperative Oncology Group performance status of 0 or 1, had undergone nephrectomy 12 weeks or less before randomisation, and had not received previous systemic therapy for advanced renal cell carcinoma. Participants were randomly assigned (1:1) via central permuted block randomisation (block size of four) to receive pembrolizumab 200 mg or placebo intravenously every 3 weeks for up to 17 cycles. Randomisation was stratified by metastatic disease status (M0 vs M1), and the M0 group was further stratified by ECOG performance status and geographical region. All participants and investigators involved in study treatment administration were masked to the treatment group assignment. The primary endpoint was disease-free survival by investigator assessment in the intention-to-treat population (all participants randomly assigned to a treatment). Safety was assessed in the safety population, comprising all participants who received at least one dose of pembrolizumab or placebo. As the primary endpoint was met at the first interim analysis, updated data are reported without p values. This study is ongoing, but no longer recruiting, and is registered with ClinicalTrials.gov, NCT03142334. Findings: Between June 30, 2017, and Sept 20, 2019, 994 participants were assigned to receive pembrolizumab (n=496) or placebo (n=498). Median follow-up, defined as the time from randomisation to data cutoff (June 14, 2021), was 30·1 months (IQR 25·7–36·7). Disease-free survival was better with pembrolizumab compared with placebo (HR 0·63 [95% CI 0·50–0·80]). Median disease-free survival was not reached in either group. The most common all-cause grade 3–4 adverse events were hypertension (in 14 [3%] of 496 participants) and increased alanine aminotransferase (in 11 [2%]) in the pembrolizumab group, and hypertension (in 13 [3%] of 498 participants) in the placebo group. Serious adverse events attributed to study treatment occurred in 59 (12%) participants in the pembrolizumab group and one (

503 Background: Pts presenting with NMIBC carcinoma in situ (CIS) have a high risk of progression. FGFR inhibition may benefit CIS pts with FGFRalt who are unresponsive to first-line BCG, for whom treatment (tx) options, other than radical cystectomy, are limited. Erdafitinib (erda), an oral selective pan-FGFR tyrosine kinase inhibitor, is approved for locally advanced or metastatic urothelial cancer in adults with FGFR3/2alt who have progressed during or after ≥1 line of platinum-containing chemotherapy. THOR-2 (NCT04172675) is a multicohort phase 2 study of erda in pts with HR-NMIBC. Here we report results from an exploratory cohort of pts with BCG-unresponsive CIS with FGFRalt with or without papillary disease (Cohort 2). Methods: Inclusion criteria: age ≥18 y, with histologically confirmed, BCG-unresponsive HR-NMIBC with FGFR3/2alt (by local/central testing) presenting as CIS, with or without a papillary tumor and who refused or were not eligible for cystectomy. In this cohort, pts received continuous oral erda 6 mg once daily without uptitration in 28-d cycles (dose selected to improve tolerability while maintaining activity to prevent disease recurrence, for this population). Erda was discontinued if no complete response (CR) was observed within 3 mos. Exploratory efficacy end points are CR rates at the Cycle 3 Day 1 (C3D1) disease evaluation and the Cycle 6 Day 1 (C6D1) disease evaluation; safety was a key secondary end point. Results: As of the data cutoff (Sep 2022) (median follow-up of 10 mos), 10 pts have received erda (enrolled population; median age 72 y [range 52-83]; 90% CIS [1 pt with Ta was mis-enrolled]). Pts received erda for a median duration 5.9 mos (range 1.1-17.0). Of 10 enrolled pts, the CR rates at first evaluation (C3D1) and second evaluation (C6D1) were 100% (9/9 evaluable pts) and 75% (6/8 evaluable pts), respectively. The median duration of response was 3.0 mos. The most common tx-emergent adverse events (TEAEs) were dry mouth (60%; n=6), hyperphosphatemia (50%; n=5), dysgeusia (50%; n=5), and diarrhea (50.0%; n=5). 1 pt (10%) had Gr 2 retinal detachment which led to tx discontinuation and 1 pt (10%) had Gr 1 subretinal fluid; both reported as resolved. Gr ≥3 tx-related TEAEs occurred in 3 pts (30%), and included dry mouth, stomatitis, nail disorder, onychomadesis, acute kidney injury, chronic kidney disease, sepsis, and hypotension in 1 pt each. 1 pt (10%) had serious tx-related TEAEs (dry mouth, hypotension, pneumonitis, acute kidney injury, and sepsis), and 1 pt (10%) discontinued tx due to a tx-related TEAE. No tx-related deaths were observed. Conclusions: Data from Cohort 2 of THOR-2 demonstrate efficacy at C3D1 and C6D1 evaluations in pts with HR-NMIBC with FGFRalt. Safety data were consistent with the known safety profile of erda. Clinical trial information: NCT04172675 .

Background To promote precision oncology in clinical practice, the Japanese Society of Medical Oncology, the Japanese Society of Clinical Oncology, and the Japanese Cancer Association, jointly published “Clinical practice guidance for next-generation sequencing in cancer diagnosis and treatment” in 2017. Since new information on cancer genomic medicine has emerged since the 1st edition of the guidance was released, including reimbursement for NGS-based multiplex gene panel tests in 2019, the guidance revision was made. Methods A working group was organized with 33 researchers from cancer genomic medicine designated core hospitals and other academic institutions. For an impartial evaluation of the draft version, eight committee members from each society conducted an external evaluation. Public comments were also made on the draft. The finalized Japanese version was published on the websites of the three societies in March 2020. Results The revised edition consists of two parts: an explanation of the cancer genomic profiling test (General Discussion) and clinical questions (CQs) that are of concern in clinical practice. Particularly, patient selection should be based on the expectation that the patient's post-test general condition and organ function will be able to tolerate drug therapy, and the optimal timing of test should be considered in consideration of subsequent treatment plans, not limited to treatment lines. Conclusion We expect that the revised version will be used by healthcare professionals and will also need to be continually reviewed in line with future developments in cancer genome medicine.

A 78-year-old man had received interferon therapy and achieved sustained virologic response for chronic hepatitis C 10 years before. He came to our hospital due to liver damage. Abdominal ultrasonography showed a 90-mm mass lesion in the liver. The echoic level was high in the central part and low in the edge of the tumor. Moreover, there was an accumulation of low echoic irregular mass lesions around the hepatic portal region. Cervical ultrasonography also revealed several 15-mm mass lesions on the left clavicle, the imaging character of which was similar to the liver tumor. The liver tumor seemed to be hypovascular on dynamic computed tomography, but contrast-enhanced ultrasonography showed hyperenhancement at the early vascular phase and at maximum intensity projection showed a treelike branch vascular structure that derived from the central part to the margin of the mass. A needle biopsy of the liver tumor and a cervical lymph node resection were performed, which led to the definitive diagnosis of undifferentiated carcinoma of the liver with multiple lymph node metastasis, upon histological analysis. Undifferentiated carcinoma of the liver is extremely rare and contrast-enhanced ultrasonography was the most useful device for evaluating vascular characteristics in this case.

Immune checkpoint (IC) therapy provides substantial benefits to cancer patients but can also cause distinctive toxicities termed immune-related adverse events (irAEs). Biomarkers to predict toxicities will be necessary to improve management of patients receiving IC therapy. We relied on serological analysis of recombinant cDNA expression libraries to evaluate plasma samples from patients treated with IC therapy and identified autoantibodies, both in pretreatment and on-treatment samples prior to the development of irAEs, which correlate with the development of immune-related hypophysitis (anti-GNAL and anti-ITM2B autoantibodies) and pneumonitis (anti-CD74 autoantibody). We developed an enzyme-linked immunosorbent assay and tested additional patient samples to confirm our initial findings. Collectively, our data suggest that autoantibodies may correlate with irAEs related to IC therapy, and specific autoantibodies may be detected early for the management of irAEs.

Background A self-help workbook is expected to support cancer patients to cope with physical and psychosocial distress, to facilitate communication with medical staff, and to improve quality of life (QOL). We conducted a randomized controlled trial to evaluate the effectiveness of a self-help workbook intervention on QOL and survival. Methods From June 2014 to March 2015, patients with breast, colorectal, gastric, and lung cancer receiving outpatient chemotherapy were randomized into an intervention group (n = 100) or control group (n = 100). Intervention group participants received workbooks originally made for this study, read advice on how to cope with distress, and filled out questionnaires on the workbooks periodically. EORTC QLQ-C30 was evaluated at baseline, at 12 weeks, and at 24 weeks. The primary endpoint was Global Health Status / QOL scale (GQOL). Results No significant interaction was observed between the intervention and time in terms of GQOL or any of the functional scales. Among the 69 patients who continued cytotoxic chemotherapy at 24 weeks, the intervention was significantly associated with improved emotional functioning scores (P = 0.0007). Overall survival was not significantly different between the two groups. Conclusions Self-help workbook intervention was feasible in cancer patients receiving chemotherapy. Although the effect of the intervention was limited, a post-hoc subset analysis suggested that the intervention may improve emotional functioning among patients who receive long-term cytotoxic chemotherapy. Trial registration UMIN Clinical Trials Registry, UMIN000012842. Registered 14 January 2014.

Targeting the programmed cell death-1 signaling pathway has been approved for the anti-cancer therapy in several cancers including urothelial cancer. To determine predictive factors of the responsiveness to pembrolizumab in urothelial cancer patients, a retrospective study that used clinical information and paraffin-embedded samples obtained from patients diagnosed with urothelial cancer between 2015 and 2020 were performed. Seventeen patients who underwent total cystectomy or nephroureterectomy of the primary lesion and were treated with pembrolizumab for chemo-resistant disease were enrolled, and immunohistochemical analysis was performed. A key difference in the characteristics between the non-responder group and the responder group was the age of the patients (74 vs. 63 years, p = 0.0194). Although there was no statistically significant difference, the histological subtype with sarcomatoid and micropapillary components was only seen in the non-responder group, and squamous differentiation and lymph node metastasis were only seen in cases with a complete response. In the results of immunohistochemistry, the density of CD8-positive T-cells and Tregs was significantly increased in the responder group than in the non-responder group. In conclusion, younger age and a high number of tumor-infiltrating lymphocytes were predictive factors of a good response to immune checkpoint inhibitors, although further studies with more enrolled patients are necessary.