Association between specific human leukocyte antigen alleles and development of thyroid immune-related adverse event.

Aim: Inherent variations in human leukocyte antigen (HLA) alleles have been revealed epidemiologically to influence the development of autoimmune diseases. HLA alleles may thus also be associated with the development of immune-related adverse events (irAEs), such as thyroid irAE. Materials & methods: In this case-control study, 71 cancer patients who received immune checkpoint inhibitors were enrolled and HLA-genotyped and the frequency of HLA alleles was compared. Results: A*26:01, DPA1*01:03 and DPB1*02:01 were significantly more frequent in patients with thyroid irAE than in patients without any irAEs (35.0 vs 3.2% [p = 0.004], 80.0 vs 45.2% [p = 0.020] and 55.0 vs 25.8% [p = 0.044], respectively). Conclusion: A*26:01, DPA1*01:03 and DPB1*02:01 appear to be associated with thyroid irAE.

Everyone has a unique combination of human leukocyte antigens (HLAs) in their body that help the immune system identify threats. HLAs were named from the fact that they were first identified on the surface of human leukocytes. Afterward, HLAs were also found on all human cells. HLAs present antigens to immune cells. These HLAs also influence how the immune system attacks cancer cells. Immune checkpoint inhibitors are drugs that can help the immune system fight cancer, but they sometimes cause severe adverse events. In this study, we investigated whether specific HLA genes are related to the development of an adverse event that affects the thyroid in cancer patients treated with immune checkpoint inhibitors. We found an association between three HLA genes (A*26:01, DPA1*01:03 and DPB1*02:01) and the development of the thyroid adverse event. However, larger studies are needed to confirm and generalize these initial exploratory findings.

E3 Ubiquitin Ligase NEDD4 Affects Estrogen Receptor α Expression and the Prognosis of Patients with Hormone Receptor-Positive Breast Cancer.

Neural precursor cell-expressed developmentally downregulated 4-1 (NEDD4) is an E3 ligase that leads to the degradation of proteins, including estrogen receptor α. We evaluated whether the expression level of NEDD4 affected the outcome of breast cancer patients. We performed a retrospective cohort study enrolling 143 patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer. Of the 66 patients with high NEDD4 mRNA levels (high NEDD4 group) and 77 patients with low NEDD4 mRNA levels (low NEDD4 group), 98.4% and 96.1%, respectively, of the patients had received neoadjuvant/adjuvant hormone therapy. Disease-free survival and overall survival were significantly longer in the low NEDD4 group than in the high NEDD4 group (p = 0.048 and p = 0.022, respectively). Western blotting revealed a high expression of estrogen receptor α in the NEDD4-knockdown culture cells. The proliferation of NEDD4-knockdown cells treated with tamoxifen or estradiol deprivation was suppressed, compared with that of NEDD4-expressing cells. Knockdown of NEDD4 in breast cancer cells induced the accumulation of estrogen receptor α and increased sensitivity to hormone therapy. In summary, this mechanism may lead to a better prognosis in hormone receptor-positive breast cancer patients with a low expression of NEDD4.

A rare case of recurrent ovarian cancer with TPM3-NTRK1 gene rearrangement: A case report.

NTRK gene fusion is rare in gynecological cancer. Entrectinib is a novel targeted drug, which is a potent inhibitor of TRK A, B and C. The present case report described a case of recurrent ovarian cancer with TPM3-NTRK1 rearrangement, which was detected by next-generation sequencing (NGS) and treated with entrectinib. A 56-year-old woman was diagnosed as having stage IV ovarian cancer with positive pleural fluid cytology. Neoadjuvant chemotherapy and interval debulking surgery, followed by chemotherapy, were performed. A total of 10 months after completion of chemotherapy, the disease recurred and the patient was treated with multimodal therapy for recurrence. DNA-based NGS detected TPM3-NTRK1 rearrangement and entrectinib therapy was initiated; however, the disease progressed despite 6 weeks of entrectinib administration, and 1 month after discontinuation of entrectinib, the patient died. After their death, immunohistochemistry with a pan-Trk monoclonal antibody was performed to determine the expression levels of TRK; however, immunohistochemistry was negative for TRK. In conclusion, the present case report described a rare case of recurrent ovarian cancer with TPM3-NTRK1 gene fusion, in which entrectinib was not effective. While NTRK gene fusion was detected by DNA-based NGS, immunohistochemistry was negative for TRK. These findings indicated that immunohistochemistry may be required for confirmation of TRK protein expression prior to entrectinib administration.

Risk of immunotherapy-related narcolepsy in genetically predisposed patients: a case report of narcolepsy after administration of pembrolizumab.

BACKGROUND: Immune-related adverse events associated with immune checkpoint therapy cause autoimmune disease-like symptoms. People who carry specific genotypes or haplotypes of human leucocyte antigen (HLA) are known to be predisposed to develop autoimmune diseases including narcolepsy. Immunotherapy could be a trigger to develop narcolepsy in predisposing HLA positive patients. CASE PRESENTATION: A 66-year-old woman with stage IVB endometrial carcinosarcoma experienced daytime sleepiness and temporary muscle weakness 14 days after the administration of an immune checkpoint inhibitor, pembrolizumab. These were consistent with the main symptoms of narcolepsy with cataplexy. This patient carried a highly predisposing HLA haplotype for narcolepsy; HLA-DQB1*06:02, DRB1*15:01, DQA1*01:02 and DRB5*01:01:01. A hypocretin-1/orexin-A concentration in the patient's cerebrospinal fluid was low at 9.6 pg/mL in ELISA, and 155.5 pg/mL in radioimmunoassay that was below the normal level of 200 pg/mL. Therefore, she was diagnosed with narcolepsy tentatively according to the International Classification of Sleep Disorders, third edition diagnostic criteria for narcolepsy. The onset of narcolepsy in the 60s is very rare, and narcoleptic symptoms in our patient were likely to be caused by pembrolizumab. CONCLUSIONS: This case suggests that treatment with immune checkpoint inhibitors potentially causes narcolepsy in genetically predisposed patients.

A Case of Squamous Cell Carcinoma of Unknown Primary that Responded to the Multi-Tyrosine Kinase Inhibitor Lenvatinib.

Lenvatinib is an oral tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, fibroblast growth factor receptors 1 through 4, as well as platelet-derived growth factor receptor α, RET, and KIT. At present, lenvatinib is used in the treatment of thyroid cancer and renal cell carcinoma. We herein report a case of a 67-year-old patient with squamous cell carcinoma of unknown primary who was effectively treated with lenvatinib. The patient was initially diagnosed as having undifferentiated thyroid cancer, and after total thyroidectomy and bilateral lymph node dissection, lenvatinib was administered for the treatment of residual lymph node metastasis. A computed tomography scan after 1 month of lenvatinib administration showed marked regression of the lymph nodes, but interstitial pneumonia was also detected. Because the drug lymphocyte stimulation test for lenvatinib was strongly positive, we concluded that the interstitial pneumonia was induced by lenvatinib. The interstitial pneumonia only improved by the withdrawal of lenvatinib. Finally, his thyroid tumor was diagnosed as a metastasis of squamous cell carcinoma; however, we were unable to identify the primary lesion. This is the first reported case of interstitial pneumonia induced by lenvatinib.

A phase II study of bevacizumab with modified OPTIMOX1 as first-line therapy for metastatic colorectal cancer: the TCOG-GI 0802 study.

BACKGROUND: Although bevacizumab plus FOLFOX is a standard treatment for metastatic colorectal cancer, oxaliplatin must be withdrawn in many patients because of cumulative neurotoxicity. We postulated that a reduced dose of oxaliplatin and modified treatment schedule would prolong the time to treatment failure and evaluated bevacizumab combined with a modified OPTIMOX1 regimen (mOPTIMOX1, oxaliplatin dose: 85 mg/m(2)). METHODS: Eligible patients had a histologically confirmed diagnosis of metastatic colorectal cancer and a performance status of 0-1. Patients were excluded if they had grade 1 or higher peripheral sensory neuropathy or had previously received chemotherapy for metastatic colorectal cancer. Patients received bevacizumab plus mFOLFOX6 every 2 weeks for 6 cycles, followed by 12 cycles of a simplified biweekly regimen of leucovorin and fluorouracil (sLV5FU2) plus bevacizumab. Oxaliplatin was then reintroduced, and bevacizumab plus mFOLFOX6 was continued until progressive disease. RESULTS: The median duration of disease control was 11.7 months (95 % confidence interval [CI], 9.7-13.5 months). The median overall survival was 23.1 months (95 % CI, 18.8-27.9 months). The overall response rate according to both the RECIST and WHO criteria was 51.3 %. The most common grade 3 or 4 toxicities were neutropaenia (32.5 %), hypertension (17.5 %), leukocytopaenia, sensory neuropathy, and diarrhoea (10.0 %). There were no treatment-related deaths. CONCLUSIONS: Bevacizumab plus mFOLFOX6 was well tolerated, and patients could continue chemotherapy for longer than with conventional FOLFOX regimens. This regimen might be an effective treatment option for patients with metastatic colorectal cancer.

Long-term complete remission in a patient with intravascular large B-cell lymphoma with central nervous system involvement.

This report describes a patient with intravascular large B-cell lymphoma (IVLBCL) with central nervous system involvement at the time of diagnosis who achieved complete remission for over 5 years in response to therapy. The patient, a 71 year-old woman, was previously healthy with the exception of taking verapamil for paroxysmal supraventricular tachycardia. She had presented with pyrexia and gradually progressive anemia. Brain magnetic resonance imaging revealed an infarct-like lesion in the pons, although no paralysis was observed. She was diagnosed with IVLBCL on the basis of random skin biopsy. After eight cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone therapy, abnormal laboratory data had normalized, and no pontine lesion was evident on magnetic resonance imaging without receiving any intrathecal chemotherapy. IVLBCL is associated with poor prognosis, particularly in patients with central nervous system involvement. Early initiation of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone therapy and drug interactions between anticancer agents and verapamil as a p-glycoprotein inhibitor were considered the possible reasons for favorable outcome in the present case.

Biweekly irinotecan plus cisplatin versus irinotecan alone as second-line treatment for advanced gastric cancer: a randomised phase III trial (TCOG GI-0801/BIRIP trial).

PURPOSE: We compared biweekly irinotecan plus cisplatin (BIRIP) with irinotecan alone as the second-line chemotherapy (SLC) for advanced gastric cancer (AGC). METHODS: Patients with metastatic or recurrent gastric cancer refractory to S-1-based first-line chemotherapy were randomly assigned to receive BIRIP (irinotecan 60mg/m(2) plus cisplatin 30mg/m(2), every 2weeks) or irinotecan alone (irinotecan 150mg/m(2), every 2weeks). The primary end-point was to show the superiority of BIRIP to irinotecan in terms of progression free survival (PFS). RESULTS: 130 patients were enrolled. PFS was significantly longer in the BIRIP group (3.8months [95% confidence interval (CI) 3.0-4.7]) than in the irinotecan group (2.8months [2.1-3.3]; hazard ratio 0.68, 95% CI 0.47-0.98; P=0.0398). Median overall survival was 10.7months in the BIRIP group and 10.1months in the irinotecan group (HR 1.00, 95% CI 0.69-1.44, P=0.9823). The objective response rate was 22% in the BIRIP group and 16% in the irinotecan group (P=0.4975). However, the disease control rate was significantly better in the BIRIP group (75%) than in the irinotecan group (54%, P=0.0162). The incidences of grade 3 or worse adverse events did not differ between the two groups. Any grade elevation of serum creatinine was more common in the BIRIP group (25% versus 8%, P=0.009), but any grade diarrhoea (17% versus 42%, P=0.002) was more common in the irinotecan group. CONCLUSION: BIRIP significantly prolonged PFS as compared with irinotecan alone and was tolerated as SLC, but did not demonstrate the survival benefit in this trial.

Clinical outcomes with chemotherapy for advanced thymic carcinoma.

BACKGROUND: The clinical characteristics and prognostic factors of thymic carcinoma have not been investigated in detail because of its rarity. The aim of this study was to elucidate the disease profile, outcomes, and prognostic factors for survival among patients with advanced thymic carcinoma treated with palliative-intent chemotherapy. PATIENTS AND METHODS: A retrospective review was conducted of the medical records of 40 patients treated with palliative-intent chemotherapy for advanced thymic carcinoma between 1991 and 2011 in our institution. Clinical demographics, histology, overall survival, and factors expected to predict survival were analyzed. Differences in survival were assessed using Kaplan-Meier analysis and univariate and multivariate Cox proportional hazards regression analyses. RESULTS: The study included 22 males (55.0%) and 18 females (45.0%). The median age at diagnosis was 58.5 years. The most common metastatic sites at diagnosis were lung (45.0%), lymph nodes (20.0%), liver (15.0%), bone (15.0%), and brain (5.0%). The most common histological subtypes were squamous cell carcinoma (70.0%), followed by neuroendocrine carcinoma (17.5%), and mucoepidermoid carcinoma (7.5%). The response rate for first-line chemotherapy was 47.5%. The median survival time was 24.5 months (95% confidence interval 20.9-43.5 months). Overall survival rates at 1-, 2-, and 5-years were 72.5%, 52.5%, and 17.5%, respectively. In uni- and multivariate analyses, the only favorable prognostic factor for overall survival was response to first-line chemotherapy (p=0.01). CONCLUSION: Response to first-line chemotherapy may be implicated as a potential surrogate for survival in advanced thymic carcinoma.

[A case of gastric neuroendocrine cell carcinoma successfully treated by neoadjuvant chemotherapy].

A 74-year-old man, whose chief complaint was epigastralgia, was referred to our hospital and diagnosed gastric cancer with liver metastasis. Gastrointestinal endoscopy showed a tumor on the lesser curvature of cardia of stomach. He was diagnosed as neuroendocrine cell carcinoma by biopsy specimens. He was treated by combined chemotherapy of CPT-11 and CDDP. After 11 courses, endoscopic examination revealed a complete disappearance of the primary tumor. CT-scan and MRI showed that the liver metastasis had been disappeared. We diagnosed as clinical CR and performed total gastrectomy with lymph node dissection and partial hepatectomy. Histological findings revealed a few cells in stomach and no cancer cells in the liver. He was treated with adjuvant chemotherapy of S-1. After 3-course, he suffered from anemia of grade 3, thus we interrupted chemotherapy. The patient remains alive for 28 months without recurrence. We conclude that chemotherapy was effective for neuroendocrine cell carcinoma of the stomach, which was to be considered of poor prognosis, and that liver resectomy was often effective.

[A case of gastric endocrine cell carcinoma with liver metastases treated with S-1/CDDP].

Gastric endocrine cell carcinoma is known to be highly malignant with a poor prognosis, and no standard treatment has been established. We experienced a case of gastric endocrine cell carcinoma with liver and lymph node metastases. The lesions became resectable after chemotherapy with S-1/cisplatin (CDDP). The patient was a 68-year-old male. He had gastrointestinal endoscopy for screening without complains. The endoscopy findings showed that a type 3 gastric cancer on lesser curvature of ventricular angle of the stomach, and was histologically diagnosed as an endocrine cell carcinoma by the biopsy specimen. A computed tomography (CT) scan showed metastatic lesions at S2 and S3 of the liver, and No.6 lymph node enlargement. Thus he was diagnosed as gastric endocrine cell carcinoma with liver and lymph node metastases. He was treated chemotherapy with S-1/CDDP every 5 weeks. After these courses of treatment, liver and lymph node metastatic lesions had reduced in size, but the primary lesion was still remained. Then he suffered from a drug induced eruption due to S-1. We changed the chemotherapy to biweekly CPT-11/CDDP. After 21 courses, he underwent distal gastrectomy with lymph node dissection and a partial liver resection. Histological findings revealed that there were no cancer cells in removed specimens. He had treated 8 courses of CPT-11/CDDP therapy after the surgery, and survived for 5 years without recurrence.

Phase II study of S-1 as first-line treatment for elderly patients over 75 years of age with advanced gastric cancer: the Tokyo Cooperative Oncology Group study.

PURPOSE: This prospective multicenter phase II study was carried out to investigate the efficacy, safety and pharmacokinetics of S-1 monotherapy in elderly patients over 75 years of age, with unresectable advanced or recurrent gastric cancer. METHODS: Patients had measurable or evaluable lesions according to the Japanese Classification of Gastric Carcinoma. S-1 (25-60 mg determined by the body surface area and creatinine clearance) was given orally, twice daily. A course of treatment consisted of 4-week administration followed by a 2-week rest period, and the patients received repeated courses. RESULTS: Thirty-three patients were enrolled. Pharmacokinetics of S-1 was studied in six patients, and the maximum plasma concentrations of respective metabolites after S-1 administration were found to be similar to those reported for younger cancer patients. The overall response rate in 33 patients was 21.2% (95% CI, 10.7-37.8%), and median progression-free survival was 3.9 months, with a median overall survival of 15.7 months. Frequently noted adverse events include leukopenia, neutropenia, anemia, anorexia, and fatigue. As for serious adverse events, relatively higher frequencies of anemia (9%) and anorexia (12%) of grade 3 severity were found, but there were no grade 4 episodes. CONCLUSIONS: The results suggest that S-1 monotherapy is safe and useful for elderly patients with unresectable advanced or recurrent gastric cancer when the dose is selected with caution, taking into account renal function.

[A case of colon cancer with reversible posterior leukoencephalopathy syndrome following 5-FU and oxaliplatin (FOLFOX regime)].

We report a rare case of reversible posterior leukoencephalopathy syndrome (RPLS) induced by 5-FU and oxaliplatin (FOLFOX regime). A 35-year-old woman with ileus was diagnosed with sigmoid cancer Stage IV (T4N4M0P2H0), and excision of the sigmoid colon, and left ureteroureteral anastomosis was performed. Postoperative chemotherapy with FOLFOX4 was performed. Complications of hypertension were seen on day 6, and convulsions on day 11 after chemotherapy. Headache and visual disturbance were also complications. MRI of the brain revealed bilateral high signal intensities of posterior lobes on T2 weighted and FLAIR images without enhancement. The patient was treated with antihypertensive therapy and anticonvulsive therapy. Her symptoms entirely disappeared, including the bilateral posterior lesions on MRI after two weeks. This report would suggest that medical oncologists should be aware that multidrug chemotherapies may increase the risk of fatal neurological complications like RPLS.

[Discussion of the treatment of esophageal carcinoma,especially in the point of non-surgical treatments, from the viewpoint of medical oncology].

Recently,remarkable advances of non-surgical treatments such as endoscopic treatment and chemoradiotherapy (CRT) are made in the treatment of esophageal carcinoma. Endoscopic treatment is recognized a standard for m 1, m 2 esophageal carcinoma, and it's indication is being extended for sm esophageal carcinoma in combination with chemoradiotherapy. In stage I and stage II, treatment result of CRT is comparative with that of surgical resection. In patients with T 4 esophageal carcinoma, it is already accepted that CRT is a standard therapy. This progress of non-surgical treatments contributes to preservation of esophagus in the treatment of esophageal carcinoma. But various problems such as technical problems, complication of CRT and salvage surgery for non-CR or recurrent case also remain. To improve results in treatment of esophageal carcinoma,it is necessary that we make an effort to cooperate with surgeons and radiation oncologists, further.

[Comparison the standard therapies of gastric cancer in Japan with those in the West].

We compare Japanese practice guidelines for gastric cancer with those published from National Comprehensive Cancer Network (NCCN). In surgery, D1 dissection is referred as standard in NCCN, because mortality of D2 dissection was higher than that of D1 (10% vs 4%). However, Japanese investigators show lower mortality rate (0.8%) of D2 dissection, so D2 dissection is referred as standard for stage II/III disease in Japan. Chemoradiotherapy is chosen for residual disease or unresectable disease (M0) in NCCN, but these categories are required D2 dissection or extensive resection in Japan. Because Japanese D2 dissection has better optimized survival rate than chemoradiotherapy,chemoradiotherapy will not be introduced to Japan. In chemotherapy, ECF or taxanes (e.g., DCF) is referred as a prior therapy in NCCN, but 5-FU contain regimen (e.g., FP, LV/5-FU, S-1, or S-1/CDDP) as a prior therapy in Japan. Both ECF and DCF are too toxic regimen for Japanese patient to use. Difference of race seem to be relevant to difference of mortality or toxicities. From the results of ACTS-GC, we think that adjuvant chemotherapy is referred as standard in Japan. Future, results of JCOG 9912 and many other trials will be coming soon, so the guidelines will be changed.

[Clinicopathological characteristics of gastric cancer in elderly patients].

Careful consideration must be given to the efficacy of treatment for elderly patients with advanced gastric cancer. Thirty-two elderly patients, 75 years of age or older with gastric cancer, were treated in Tokyo Metropolitan Komagome Hospital,Department of Chemotherapy, between January, 1993 to December, 2002. We analyzed the data of these patients retrospectively. The male/female ratio was 13:3, and 90.6% of the patients developed complications. Some 29 patients were treated with 5-FU regimen. The response rate was 17.2%, median survival time was 201 days, and 5 PR pts had 421 days' survival time. Patients with good PS had long survival times. A comparative study was conducted between 15 cases treated with cisplatin (CDDP) regimen and 14 cases without CDDP. Among them, 13 pts were given a low dose and 16 pts a full dose of chemotherapy (5-FU+/-CDDP). No differences were found between the two groups in overall survival time. No patients showed a severe adverse effect and some exhibited improvement by the chemotherapy. Therefore, the choice of chemotherapy for an elderly gastric cancer patient mostly depends on the patient' s general condition. Elderly patients can develop many complications, so the organ function test should be carefully evaluated. Development of an oral anticancer drug for gastric cancer is in progress and promises to show good results in the near future. Chemotherapy appears able to preserve good "Quality of Life" and will play an important role in the treatment of gastric cancer in elderly patients.

[The present state and future of home care for gastric cancer patients].

Recently, cancer treatment has been shift from inpatient chemotherapy to outpatient chemotherapy, because of various medical circumstances. In chemotherapy of gastric cancer, outpatient chemotherapy was not spread in the last decade, because the chemotherapy protocol of gastric cancer was not fit for outpatient chemotherapy. But the development of new drugs as TS-1 make outpatient chemotherapy more frequent. So home care of patients has been important for management of gastric cancer. Various symptoms due to obstruction at primary lesion or other lesion prevent patients from living at home in gastric cancer. But recently, technical development and spread of home parenteral nutrition make a possible home care of patients with gastric cancer. It is necessary to make a system that supports patient life at home.