Nivolumab-induced Thrombotic Thrombocytopenic Purpura in Patients with Gastric Tube Cancer.

Recently, immune checkpoint inhibitors (ICIs) have been used to treat several cancer types. ICIs have been reported to cause a wide variety of immune-related adverse events, including endocrine, neurologic, gastrointestinal, and cutaneous disorders. Thrombotic thrombocytopenic purpura (TTP) is an autoimmune hematologic disorder characterized by the presence of autoantibodies against a disintegrin and metalloprotease with thrombospondin-1, member 13. Several previous cases of TTP were thought to have been caused by ICI treatment. We herein report a rare case of TTP that developed after long-term treatment with an ICI (nivolumab) for gastric tube cancer.

Chylous Ascites Associated with Advanced Pancreatic Cancer That Improved with Appropriate Treatment: A Case Report.

Chylous ascites is a rare form of ascites with high triglyceride content arising from the thoracoabdominal lymph nodes in the peritoneal cavity due to various benign or malignant etiologies, including pancreatic cancer. During cancer chemotherapy, the accumulation of ascites can lead to the deterioration of the patient's general condition, making chemotherapy administration difficult, and resulting in a poor prognosis. We encountered a rare case of chylous ascites complicated by advanced pancreatic cancer. The patient presented with a discrepancy between the shrinkage of the pancreatic cancer and the accumulation of ascites. Therefore, we were able to promptly diagnose chylous ascites by performing biochemical tests. The patient was treated with octreotide, reportedly effective in treating chylous ascites, which rapidly improved the chylous ascites and general condition of the patient, allowing the patient to continue chemotherapy for pancreatic cancer. Therefore, physicians should consider the possibility of chylous ascites when clinically unexplained ascites are observed in patients with advanced cancer. The investigation and treatment of chylous ascites should be initiated as soon as possible.

Antibiotics May Interfere with Nivolumab Efficacy in Patients with Head and Neck Squamous Cell Carcinoma.

INTRODUCTION: Patients with the head and neck squamous cell carcinoma (SCC) are often treated with immune checkpoint inhibitors (ICIs). Recently, antibiotic intake was reported to lower the efficacy of ICIs in patients with several types of cancers. However, it is unclear if antibiotics affect the efficacy of ICIs in patients with head and neck SCC. We retrospectively assessed the influence of antibiotics on the treatment efficacy of nivolumab, an ICI, in patients with head and neck SCC. METHODS: We reviewed the medical records of patients with head and neck SCC treated with nivolumab at the Department of Medical Oncology, Tohoku University Hospital, between 2017 and 2021. Patients who received oral or intravenous antibiotics from a month before the day of nivolumab initiation to the day of the first imaging evaluation of ICI efficacy were assigned to the antibiotic-treated group. The remaining patients were assigned to the antibiotic-untreated group. The response rate (RR), progression-free survival (PFS), and overall survival time (OS) of both groups were compared. RESULTS: Forty-five patients were assigned to the antibiotic-treated group and 19 to the antibiotic-untreated group. The RR, median PFS, and median OS of the antibiotic-treated group were 23.7%, 3.2 months (95% confidential interval [CI]: 2.0-4.1), and 8.4 months (95% CI: 5.3-15.1) and those of the antibiotic-untreated group were 42.1%, 5.8 months (95% CI: 2.3-16.7), and 18.4 months (95% CI: 6.2-23.1), respectively. The PFS of the antibiotic-untreated group was significantly longer than that of the antibiotic-treated group. CONCLUSION: Our findings indicate that antibiotic treatment significantly shortens the PFS with nivolumab therapy in patients with head and neck SCC.

FOLFIRI Chemotherapy for Patients With Metastatic Urachal Carcinoma.

BACKGROUND/AIM: Urachal carcinoma is a rare cancer, with limited evidence regarding systemic chemotherapy for metastatic urachal carcinoma. This study aimed to evaluate the efficacy and safety of a combination therapy of 5-fluorouracil and irinotecan (FOLFIRI) in patients with metastatic urachal carcinoma. PATIENTS AND METHODS: Patients with metastatic urachal carcinoma treated with FOLFIRI between March 2008 and April 2023 at the Department of Medical Oncology, Tohoku University Hospital, were retrospectively analyzed using medical records. RESULTS: Six patients with urachal carcinoma received FOLFIRI. The histological type was adenocarcinoma in all patients. The metastatic or recurrent sites were the peritoneum, lungs, lymph nodes, and local relapse sites. Three patients received FOLFIRI as first-line chemotherapy, and the other three received FOLFIRI as second-line chemotherapy. Two patients had only non-measurable lesions as the targets of tumor response. The best response was the stable disease or non-complete response/non-progressive disease in four patients, with a disease control rate of 67%. The median progression-free survival was 7.5 months. In two patients with ascites only as the site of metastasis, the amount of ascites and serum tumor marker levels decreased after FOLFIRI was initiated. Grade 3/4 toxicities included grade 3 neutropenia in one patient and grade 3 diarrhea in one patient. CONCLUSION: FOLFIRI has modest efficacy and good tolerability for the treatment of metastatic urachal carcinoma.

Comparison of efficacy and safety between carboplatin-etoposide and cisplatin-etoposide combination therapy in patients with advanced neuroendocrine carcinoma, retrospective study.

INTRODUCTION: Neuroendocrine carcinoma (NEC) is characterized by a poor prognosis and is generally treated with platinum and etoposide combination therapy as first-line chemotherapy. However, it remains uncertain whether carboplatin and etoposide combination therapy (CE) and cisplatin and etoposide combination therapy (PE) have comparable treatment efficacy. In this retrospective analysis, we compared the efficacy and safety of CE and PE in patients with NEC. METHODS: We retrospectively reviewed the patient's clinical record from 2005 to 2022 at the Department of Medical Oncology, Tohoku University Hospital. Patients who received either CE or PE were included in the study. Statistical analyses were performed using JMP Pro 16.0 (SAS Institute Inc., Cary, N.C., USA). RESULTS: A total of 104 patients were enrolled, with 73 patients assigned to the CE group and 31 patients assigned to the PE group. Statistically, the response rate, progression-free survival (PFS) time and overall survival (OS) time were 42.6%, 5.1 months (95%CI: 3.5-6.3) and 13.6 months (95%CI: 8.9-17.4), respectively, in the CE groups and 44.4%, 5.6 months (95%CI: 3.1-7.0) and 12.5 months (95%CI: 11.2-14.6), respectively, in the PE groups. There was no significant difference in treatment efficacy between the CE and the PE groups. However, the number of patients with elevated creatinine (3.35 mg/dl and 3.88 mg/dl in two patients, respectively) was significantly higher in the PE group than in the CE group. CONCLUSION: The efficacy of CE and PE in patients with NEC is comparable. However, the incidence of renal dysfunction was found to be significantly higher in the PE group than in the CE group.

Depth of response may predict clinical outcome in patients with recurrent/metastatic head and neck cancer treated with pembrolizumab-containing regimens.

Background: Pembrolizumab-containing regimens are standards of care for recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC). The depth of response (DpR) predicts the survival of patients with several types of solid cancers; however, its association with the survival outcomes of patients with R/M HNSCC treated with pembrolizumab-containing regimens remains unclear. Methods: This study included 66 patients with R/M HNSCC who received a pemblolizumab-containing regimen as a first-line therapy at Tohoku University Hospital, Sendai, Japan. The patients' characteristics, combined positive score, baseline tumor size, tumor response, DpR, overall survival (OS), progression-free survival (PFS), PFS2, and adverse events were reviewed. The associations between DpR and survival outcomes were analyzed. Results: The 1 year-OS and 1 year-PFS rates of pembrolizumab-containing regimens were 69.4% and 24.4%, respectively. The response rate was 28.8%. The mean and median values of tumor change from baseline were 5.1% and -9.0%. In the correlation analysis, a significant negative correlation was observed between tumor change rate from baseline and survival outcomes (OS: r= -0.41, p=0.0017; PFS: r=-0.49, p<0.001). In the multivariate analysis, DpR with tumor change of ≤-45 was associated with better OS and PFS. Conclusion: DpR induced by pembrolizumab-containing regimens may be a predictive factor for OS and PFS in patients with R/M HNSCC.

BRAF and MEK Inhibitor Treatment for Metastatic Undifferentiated Sarcoma of the Spermatic Cord with BRAF V600E Mutation.

An 18-year-old Japanese man was diagnosed with an undifferentiated sarcoma of the spermatic cord, with multiple distant metastases to the lungs and bones. The patient received doxorubicin-based standard chemotherapy. Although the chemotherapy was effective, it induced severe adverse events, which led to treatment discontinuation. A comprehensive genomic profiling test using resected tumor tissue revealed the BRAF V600E mutation. Based on the result, the patient received combination therapy with dabrafenib and trametinib. The combination therapy achieved a good response with few adverse events. However, 6.5 months later, pleural metastases and meningeal dissemination had emerged. A liquid comprehensive genomic profiling test was performed after the progression to identify the resistance mechanism, which resulted in the detection of no actionable gene alterations other than BRAF V600E. This report shows that the BRAF V600E mutation may be a promising therapeutic target and that resistance to the targeted therapy could also occur in soft tissue sarcoma. The significance of BRAF mutations across different types of cancer should be validated, and it is necessary to apply targeted therapies and develop methods to overcome resistance based on the optimal use of comprehensive genomic profiling tests.

Antibiotic Treatment Improves the Efficacy of Oxaliplatin-Based Therapy as First-Line Chemotherapy for Patients with Advanced Gastric Cancer: A Retrospective Study.

Purpose: One of the first-line treatment for gastric cancer patients is oxaliplatin, and the efficacy of this chemotherapeutic can be attenuated by the microbiome. In this study, we retrospectively evaluated whether treatment with antibiotics improved the efficacy of oxaliplatin-based chemotherapy in patients with advanced gastric cancer. Patients and Methods: Fifty-four patients were assigned to the antibiotic-treated group and 35 to the antibiotic-untreated group. Results: The response rate of oxaliplatin-based chemotherapy in the antibiotic-treated and antibiotic-untreated groups was 66.7% and 41.4%, respectively (p = 0.038). The median progression-free survival after oxaliplatin-based chemotherapy in the antibiotic-treated and antibiotic-untreated groups was 8.8 and 5.2 months, respectively (hazard ratio = 0.456, 95% confidence interval = 0.254-0.819; p = 0.007, Log rank test). Univariate and multivariate analyses revealed that antibiotic treatment was the only clinical parameter that correlated with the response to oxaliplatin. Conclusion: Antibiotic treatment could be used therapeutically to enhance the efficacy of oxaliplatin-based chemotherapy in patients with advanced gastric cancer.

Erratum: lncRNA HAR1B has potential to be a predictive marker for pazopanib therapy in patients with sarcoma.

[This corrects the article DOI: 10.3892/ol.2021.12716.].

Inhibition of IRAK1/4 enhances the antitumor effect of lenvatinib in anaplastic thyroid cancer cells.

Anaplastic thyroid cancer (ATC) is an extremely aggressive tumor associated with poor prognosis due to a lack of efficient therapies. In Japan, lenvatinib is the only drug approved for patients with ATC; however, its efficacy is limited. Therefore, novel therapeutic strategies are urgently required for patients with ATC. The present study aimed to identify compounds that enhance the antiproliferative effects of lenvatinib in ATC cells using a compound library. IRAK1/4 Inhibitor I was identified as a candidate compound. Combined treatment with lenvatinib and IRAK1/4 Inhibitor I showed synergistic antiproliferative effects via the induction of cell cycle arrest at G2/M phase in the ATC cell lines 8305C, HTC/C3, ACT-1, and 8505C. Furthermore, IRAK1/4 Inhibitor I enhanced the inhibition of ERK phosphorylation by lenvatinib in 8305C, HTC/C3, and 8505C cells. In an HTC/C3 xenograft mouse model, tumor volume was lower in the combined IRAK1/4 Inhibitor I and lenvatinib group compared with that in the vehicle control, IRAK1/4 Inhibitor I, and lenvatinib groups. IRAK1/4 Inhibitor I was identified as a promising compound that enhances the antiproliferative and antitumor effects of lenvatinib in ATC.

Factors related to specialized palliative care use and aggressive care at end of life in Japanese patients with advanced solid cancers: a cohort study.

PURPOSE: This study aimed to (1) describe characteristics of aggressive care at the end of life (EOL) and (2) identify factors associated with specialized palliative care use (SPC) and aggressive care at the EOL among Japanese patients with advanced cancer. METHODS: This single-center, follow-up cohort study involved patients with advanced cancer who received chemotherapy at Tohoku University Hospital. Patients were surveyed at enrollment, and we followed clinical events for 5 years from enrollment in the study. We performed multivariate logistic regression analysis to identify independent factors related to SPC use and chemotherapy in the last month before death. RESULTS: We analyzed a total of 135 patients enrolled between January 2015 and January 2016. No patients were admitted to the intensive care unit, and few received resuscitation or ventilation. We identified no factors significantly associated with SPC use. Meanwhile, younger age (20-59 years, odds ratio [OR] 4.10; 95% confidence interval [CI] 1.30-12.91; p = 0.02) and no receipt of SPC (OR 4.32; 95% CI 1.07-17.37; p = 0.04) were associated with chemotherapy in the last month before death. CONCLUSION: Younger age and a lack of SPC were associated with chemotherapy at the EOL in patients with advanced cancer in Japan. These findings suggest that Japanese patients with advanced cancer may benefit from access to SPC.

Phase II Study of the Reuse of Trastuzumab with Docetaxel beyond Progression after First-Line Treatment in Second-Line Treatment for Unresectable, Metastatic Gastric Cancer (T-CORE1203).

Whether trastuzumab use beyond disease progression is beneficial in second-line treatment for patients with unresectable human epidermal growth factor receptor 2 (HER2)-positive gastric cancer remains to be elucidated. We conducted this phase II study to assess whether trastuzumab plus docetaxel was effective for patients with previously treated advanced HER2-positive gastric cancer. This trial was a single-arm, open-label, multicenter, phase II study, conducted by Tohoku Clinical Oncology Research and Education Society (T-CORE). Patients aged 20 years or older who had advanced HER2-positive gastric cancer and were refractory to trastuzumab, fluoropyrimidine, and cisplatin were enrolled. Patients were treated with 6 mg/kg trastuzumab and 60 mg/m2 docetaxel every 3 weeks. The primary endpoint was the overall response rate. The threshold overall response rate was estimated to be at 15%. Secondary endpoints were progression-free survival, 6-month survival rate, overall survival, and toxicities. A total of 27 patients were enrolled from 7 hospitals. The median age was 67 years. Partial response was seen in 3 patients among the 26 evaluated patients. The overall response rate was at 11.5% (90% confidence interval 1.2%-21.8%). The median progression-free survival was 3.2 months, the 6-month survival rate was 85%, and the median overall survival was 11.6 months. Febrile neutropenia was observed in 14.8%. The most frequently observed grade 3 non-hematologic toxicity was anorexia (14.8%). The primary endpoint was not achieved. The results support a current consensus that the continuation of trastuzumab in second-line therapy for gastric cancer is not a recommended option.

lncRNA HAR1B has potential to be a predictive marker for pazopanib therapy in patients with sarcoma.

Bone and soft-tissue sarcomas are rare and are highly heterogeneous mesenchymal malignancies. It is therefore challenging to acquire the clinical data of patients with specific histological subtypes of sarcoma using large clinical trials, and there is a need to further establish the diagnosis and treatment of sarcomas. The results of the current study revealed that long non-coding RNA (lncRNA) highly accelerated region 1B (HAR1B) may serve as a predictive biomarker for pazopanib treatment in bone and soft-tissue sarcomas. Using multiplex reverse transcription-quantitative PCR and microarray analyses, the results demonstrated that HAR1B and HOX transcript antisense RNA (HOTAIR) were differentially expressed in pazopanib-sensitive cells and responders. It was further revealed that small interfering RNA-knockdown of HAR1B led to an increased resistance to pazopanib in sarcoma cell lines. Gene expression profiles associated with pazopanib sensitivity included cellular molecular pathways, such as genes involved in von-Willebrand factor-related signaling. The current study demonstrated that lncRNA HAR1B expression in sarcoma cell lines affected cellular sensitivity to pazopanib in patients with sarcoma.

LPIN1 downregulation enhances anticancer activity of the novel HDAC/PI3K dual inhibitor FK-A11.

Phosphatidylinositol-3 kinase (PI3K) inhibitor and histone deacetylase (HDAC) inhibitor have been developed as potential anticancer drugs. However, the cytotoxicity of PI3K inhibitor or HDAC inhibitor alone is relatively weak. We recently developed a novel HDAC/PI3K dual inhibitor FK-A11 and confirmed its enhanced cytotoxicity when compared to that of PI3K inhibitor or HDAC inhibitor alone on several cancer cell lines. However, the in vivo antitumor activity of FK-A11 was insufficient. We conducted high-throughput RNA interfering screening and identified gene LPIN1 which enhances the cytotoxicity of FK-A11. Downregulation of LPIN1 enhanced simultaneous inhibition of HDAC and PI3K by FK-A11 and enhanced the cytotoxicity of FK-A11. Propranolol, a beta-adrenoreceptor which is also a LPIN1 inhibitor, enhanced the in vitro and in vivo cytotoxicity and antitumor effect of FK-A11. These findings should help in the development of FK-A11 as a novel HDAC/PI3K dual inhibitor.

Antibiotics Improve the Treatment Efficacy of Oxaliplatin-Based but Not Irinotecan-Based Therapy in Advanced Colorectal Cancer Patients.

BACKGROUND: Oxaliplatin and irinotecan are generally used to treat advanced colorectal cancer (CRC) patients. Antibiotics improve the cytotoxicity of oxaliplatin but not irinotecan in a colon cancer cell line in vitro. This study retrospectively assessed whether antibiotics improve the treatment efficacy of oxaliplatin- but not irinotecan-based therapy in advanced CRC patients. Patients and Methods. The medical records of 220 advanced CRC patients who underwent oxaliplatin- or irinotecan-based therapy were retrospectively reviewed. The oxaliplatin and irinotecan groups were further divided into antibiotic-treated (group 1) and antibiotic-untreated (group 2) subgroups. RESULTS: In oxaliplatin groups 1 and 2, the response rate (RR) was 58.2% and 30.2%, while the disease control rate (DCR) was 92.5% and 64.2%, respectively; the median progression-free survival (PFS) was 10.5 months (95% confidence interval (CI) = 7.5-12.2) and 7.0 months (95% CI = 17.0-26.0), respectively, and the median overall survival (OS) was 23.8 months (95% CI = 5.1-9.1) and 17.4 months (95% CI = 13.1-24.9), respectively. In irinotecan groups 1 and 2, the RR was 17.8% and 20.0%, while the DCR was 75.6% and 69.1%, respectively; the median PFS was 8.2 months (95% CI = 6.2-12.7) and 7.9 months (95% CI = 12.0-23.0), respectively, and the median OS was 16.8 months (95% CI = 5.9-10.6) and 13.1 months (95% CI = 10.4-23.7), respectively. CONCLUSION: To improve the treatment efficacy of oxaliplatin-based therapy in advanced CRC patients, adding antibiotics is a potential therapeutic option.

Efficacy of modified FOLFOX6 chemotherapy for patients with unresectable pseudomyxoma peritonei.

BACKGROUND: Pseudomyxoma peritonei (PMP) is a rare malignancy, and there is insufficient evidence about systemic chemotherapy for this disease. METHODS: We retrospectively evaluated the efficacy and safety of a chemotherapeutic regimen with 5-fluorouracil and oxaliplatin (modified FOLFOX6, mFOLFOX6) for patients with unresectable pseudomyxoma peritonei. Patients who received the therapy between April 2000 and February 2019 at the Department of Medical Oncology, Tohoku University Hospital, were enrolled in this study. RESULTS: Eight patients were treated with mFOLFOX6. The sites of primary tumor were appendix in six patients, ovary in a patient, and urachus in a patient. Six patients received surgery. Seven patients had histologically high-grade PMP, and one patient had low-grade PMP. The median follow-up duration was 27.2 months. All the patients had non-measurable regions as the targets of tumor response. Non-complete response or non-progressive disease was observed in seven patients, with a disease control rate of 87.5%. The median progression-free survival and overall survival were 13.0 months and 27.9 months, respectively. An obvious reduction in the symptoms was observed in two patients. Five patients experienced decline in the serum tumor markers, CEA or CA19-9. The grade 3/4 toxicity that was observed was grade 4 neutropenia in one patient and grade 3 neutropenia in two patients. CONCLUSIONS: mFOLFOX6 might be an effective and tolerable treatment option for patients with unresectable PMP. To our knowledge, this is the first case series of mFOLFOX6 in patients with unresectable PMP and the first case series of systemic chemotherapy for Asian patients with unresectable PMP.

Antibiotic therapy augments the efficacy of gemcitabine-containing regimens for advanced cancer: a retrospective study.

BACKGROUND: The addition of antibiotics reportedly augments the efficacy of gemcitabine (GEM) in tumor-bearing mice. However, whether this phenomenon is also observed in cancer patients remains unclear. In the present study, we aimed to assess whether antibiotics for treatment or prevention of infection augments treatment efficacies of GEM-containing regimens in patients with any type of cancer. METHODS: Medical records of patients diagnosed with cancer histopathologically and treated with GEM-containing regimens (n=169) were retrospectively reviewed. Patients were assigned into two groups: antibiotics-untreated group (patients who were treated with GEM-containing regimens but without antibiotics) and antibiotics-treated group (patients who were treated with GEM-containing regimens plus antibiotics). Response rates, progression-free survival (PFS) time, and overall survival (OS) time were analyzed for each group. RESULTS: The response rates of the antibiotics-untreated and antibiotics-treated groups with GEM-containing regimens were 15.1% and 27.6%, respectively. The median PFS times of the antibiotics-untreated and antibiotics-treated groups were 2.5 (95% CI: 1.86-3.73) and 4.9 (95% CI: 3.47-6.0) months, respectively. The median OS times of the antibiotics-untreated and antibiotics-treated groups were 7.53 (95% CI: 5.63-9.57) months and 13.83 (95% CI: 10.83-16.43) months, respectively. CONCLUSION: The addition of antibiotics augments the treatment efficacies of GEM-containing regimens, and it may be a potential therapeutic option to improve treatment efficacies of GEM-containing regimens in patients with advanced cancer.

[Successful Multidisciplinary Treatment Accomplished by Collaboration of Multiple Clinical Departments for Synchronous Quadruple Cancer].

A 60-year-old man consulted a clinic complains of sore throat. Squamous cell carcinoma of the hypopharynx and adenocarcinoma of the stomach were pointed out and he was refered to our hospital. As a result of detailed systemic examination, squamous cell carcinoma of the esophagus and squamous cell carcinoma of the right lung were also pointed out, which led to a diagnosis of synchronous quadruple cancer. On the basis of discussions among multiple clinical departments, systemic chemotherapy with cisplatin(CDDP), fluorouracil (5-FU) and docetaxel(DTX) was preceded locolegional therapies. After that, complete thoracoscopic right lower lobectomy and then a laparoscopic distal gastrectomy was performed. Radiation therapy was applied for hypopharyngeal cancer. Finally, endoscopic submucosal dissection for esophageal cancer was performed. Twenty months have passed since the last treatment, the patient is alive with a relapse-free condition.

In Vitro and in Vivo antitumor activity and the mechanism of siphonodictyal B in human colon cancer cells.

Liphagal, isolated from the marine sponge Aka coralliphaga, exhibits phosphatidylinositol 3-kinase alpha (PI3Kα) inhibitory activity and cytotoxic effects in human cancer cells. Siphonodictyal B, the biogenetic precursor of liphagal, also has PI3K inhibitory activity. However, its cytotoxic or antitumor activities have not been evaluated. In this study, we demonstrated that siphonodictyal B inhibits several kinases such as CDK4/6, CDK7, and PIM2 in addition to PI3K in vitro and that siphonodictyal B exhibits more potent cytotoxic effects than liphagal against human colon cancer cell lines. Furthermore, treatment with siphonodictyal B resulted in increased PARP cleavage, a larger sub-G1 fraction, and a larger annexin V-positive cell population, all of which are indicative of apoptosis induction. As a mechanism of apoptosis induction, we found that siphonodictyal B activates the p38 MAPK pathway, leading the upregulation of proapoptotic factors. Moreover, siphonodictyal B increased ROS levels, thus promoting p38 MAPK pathway activation. NAC, an ROS scavenger, almost completely reversed both the cytotoxic and p38 MAPK pathway-activating effects of siphonodictyal B. These results indicate that the p38 MAPK pathway might be involved downstream of ROS signaling as part of the mechanism of siphonodictyal B-induced apoptosis. Finally, siphonodictyal B displayed antitumor effects in a human colon cancer xenograft mouse model and increased p38 phosphorylation in tumor tissue. These results suggest that siphonodictyal B could serve as the basis of a novel anticancer drug.

Therapeutic Benefits of Ipilimumab among Japanese Patients with Nivolumab-Refractory Mucosal Melanoma: A Case Series Study.

The antibodies targeting programmed death 1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) have provided survival benefits in patients with advanced malignant melanoma. The anti-PD-1 antibodies nivolumab and pembrolizumab are considered superior to the anti-CTLA-4 antibody ipilimumab as first-line therapy, suggesting that ipilimumab should be administered to patients with anti-PD-1 antibody-refractory melanoma in the second-line setting. However, there is limited evidence regarding the efficacy and safety of ipilimumab after disease progression on anti-PD-1 antibody therapy. Moreover, in patients with mucosal melanoma, a rare and aggressive subtype, evidence is extremely poor. This study aimed to clarify the efficacy and safety of ipilimumab among Japanese patients with nivolumab-refractory advanced mucosal melanoma. We retrospectively analyzed the seven patients with advanced mucosal melanoma who were treated with ipilimumab after disease progression on nivolumab at our hospital between September 2015 and December 2017. No patient achieved complete response or partial response to ipilimumab therapy. However, six patients achieved stable disease, and of these patients, three achieved a decline in the tumor size. All the three patients with a decline in tumor size developed grade 3 toxicity: two patients developed colitis and one patient experienced alanine aminotransferase elevation. The median progression-free survival (PFS) for prior nivolumab therapy was 148 days. The median PFS for ipilimumab therapy after disease progression with nivolumab was 193 days. The median overall survival was 661 days. In conclusion, although even partial response was undetectable with ipilimumab therapy, ipilimumab could produce additional PFS among nivolumab-refractory advanced mucosal melanoma patients.