Japanese version of The Cancer Genome Atlas, JCGA, established using fresh frozen tumors obtained from 5143 cancer patients.

This study aimed to establish the Japanese Cancer Genome Atlas (JCGA) using data from fresh frozen tumor tissues obtained from 5143 Japanese cancer patients, including those with colorectal cancer (31.6%), lung cancer (16.5%), gastric cancer (10.8%) and other cancers (41.1%). The results are part of a single-center study called "High-tech Omics-based Patient Evaluation" or "Project HOPE" conducted at the Shizuoka Cancer Center, Japan. All DNA samples and most RNA samples were analyzed using whole-exome sequencing, cancer gene panel sequencing, fusion gene panel sequencing and microarray gene expression profiling, and the results were annotated using an analysis pipeline termed "Shizuoka Multi-omics Analysis Protocol" developed in-house. Somatic driver alterations were identified in 72.2% of samples in 362 genes (average, 2.3 driver events per sample). Actionable information on drugs that is applicable in the current clinical setting was associated with 11.3% of samples. When including those drugs that are used for investigative purposes, actionable information was assigned to 55.0% of samples. Germline analysis revealed pathogenic mutations in hereditary cancer genes in 9.2% of samples, among which 12.2% were confirmed as pathogenic mutations by confirmatory test. Pathogenic mutations associated with non-cancerous hereditary diseases were detected in 0.4% of samples. Tumor mutation burden (TMB) analysis revealed 5.4% of samples as having the hypermutator phenotype (TMB ≥ 20). Clonal hematopoiesis was observed in 8.4% of samples. Thus, the JCGA dataset and the analytical procedures constitute a fundamental resource for genomic medicine for Japanese cancer patients.

Pharmacokinetics of S-1 monotherapy in plasma and in tears for gastric cancer patients.

BACKGROUND: S-1 is an oral anticancer drug composed of tegafur (FT), which is a prodrug of 5-FU, 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate. Recently, some studies have been reported on watering eyes caused by S-1. However, the mechanism of watering eyes caused by S-1 is still unclear. The aim of this study was to investigate the correlation between tears and plasma concentrations of FT, 5-FU, and CDHP, which are components and active modulator of S-1. METHODS: We prospectively investigated the pharmacokinetics (PK) of FT, 5-FU, and CDHP in plasma and in tears of gastric cancer patients who were treated with S-1 monotherapy at the dose of 80 mg/m2/day. Plasma and tears from both eyes were obtained 1, 2, 4, and 8 h after S-1 administration on day 1 and 14 of the first cycle. RESULTS: Total of eight patients were enrolled. All the FT, 5-FU and CDHP were detected both in plasma and in tears, and their PK parameters were measured. There was a positive correlation between the concentrations of FT, 5-FU and CDHP in the plasma and those in the tears on day 1 and day 14 (correlation coefficients r, right eye/left eye: r = 0.882/0.878, 0.877/0.890, and 0.885/0.878, respectively). CONCLUSION: There was a positive correlation between the concentrations of FT, 5-FU and CDHP in the plasma and those in the tears. The result is expected to facilitate the further investigation into the causes of watering eyes and the establishment of the effective methods for the prevention and the treatment.

The Japan Cornea Society Survey of the Current Status of Corneal and Conjunctival Disorders Due to Systemic Antitumor Drugs.

Purpose: To investigate the current status of corneal and conjunctival disorders due to antitumor drugs in Japan. Methods: Questionnaires on corneal and conjunctival disorders due to antitumor drugs were sent to members of the Japan Cornea Society, and data on patients' background, clinical findings, treatment and prognosis of cases between January 2009 and December 2011 were collected and analyzed. Results: Out of all 221 cases from 66 facilities, TS-1Ⓡ had been administered in 210 cases (95.0%). Corneal findings were noted in 192 cases (86.9%), including 161cases (72.9%) of superficial punctate keratopathy, 55 cases (24.9%) of epithelial crack line, 38 cases (17.2%) of sheet-like epithelial abnormality, and 15 cases (6.8%) of corneal erosion. Conjunctival and ciliary findings were observed in 49 cases (22.2%). Lacrimal obstruction and constriction were found in 81cases (36.7%). Logistic regression analyses revealed the discontinuation and switching of antitumor drugs as the significant factor of good prognosis of clinical signs and visual acuity in cases with TS-1Ⓡ administration. Conclusions: Although corneal and conjunctival disorders due to antitumor drugs, especially TS-1Ⓡ, are important adverse effects, the only effective treatment at this time is the discontinuation and switching of antitumor drugs. Future prospective studies are needed to elucidate pathogenesis, aiming to the prediction and prevention of the occurrence.

Excessive watering eyes in gastric cancer patients receiving S-1 chemotherapy.

BACKGROUND: Watering eyes is a common late adverse event associated with S-1 chemotherapy; however, the frequency and predictive factors are not known. METHODS: This study included 304 consecutive gastric cancer patients treated with adjuvant S-1 monotherapy for 1 year at Shizuoka Cancer Center. We retrospectively evaluated the frequency of watering eyes, and explored other nonhematological adverse events during the first course of S-1 monotherapy which could become predictive factors for watering eyes. RESULTS: The severest grade of watering eyes during S-1 monotherapy was grade 2 in 41 patients (13.5 %) and grade 3 in 36 patients (11.8 %). The median time to onset of grade 2 and grade 3 watering eyes was 82 days (range 6-344 days) and 249 days (range 84-653 days), respectively, and the median cumulative S-1 dose at the onset of grade 2 and grade 3 watering eyes was 4174 mg/m(2) (range 491-16,095 mg/m(2)) and 10,243 mg/m(2) (range 4943-16,341 mg/m(2)), respectively. Multivariate analysis showed that anorexia (odds ratio 2.37, P = 0.008), oral mucositis (odds ratio 3.86, P = 0.0003), skin hyperpigmentation (odds ratio 3.84, P = 0.0001), and rash (odds ratio 3.76, P = 0.01) observed during the first course were significantly associated with watering eyes. CONCLUSION: The risk of watering eyes was higher in patients who also had anorexia, oral mucositis, skin hyperpigmentation, or rash during first course of S-1 monotherapy than in those without them.

Evaluation of whole genome sequencing utility in identifying driver alterations in cancer genome.

In cancer genome analysis, identifying pathogenic alterations and assessing their effects on oncogenic processes is important. Although whole exome sequencing (WES) can effectively detect such changes, driver alterations could not be identified in 27.8% of the cases, according to a previous study. The objectives of the present study were to evaluate the utility of whole genome sequencing (WGS) and clarify its differences with WES in terms of driver alteration detection. For this purpose, WGS analysis was conducted on 177 driverless WES samples, selected from 5,480 fresh frozen samples derived from 5,140 Japanese patients with cancer. These samples were selected as primary tumor, both WES and transcriptome profiling were performed, estimated tumor content of ≥ 30%, and no driver alterations were identified by WES. WGS identified driver and likely driver alterations in 68.4 and 22.6% of the samples, respectively. The most frequent alteration type was oncogene amplification, followed by tumor suppressor gene deletion and small variants located outside the coding region. In the remaining 9.0% of samples, no such signals were identified; therefore, further investigations are required. The current study clearly demonstrated the role and utility of WGS in identifying genomic alterations that contribute to tumorigenesis.

Identification of tumor microenvironment-associated immunological genes as potent prognostic markers in the cancer genome analysis project HOPE.

Project High-tech Omics-based Patient Evaluation (HOPE), which used whole-exome sequencing and gene expression profiling, was launched in 2014. A total of ~2,000 patients were enrolled until March 2016, and the survival time was observed up to July 2019. In our previous study, a tumor microenvironment immune type classification based on the expression levels of the programmed death-ligand 1 (PD-L1) and CD8B genes was performed based on four types: A, adaptive immune resistance; B, intrinsic induction; C, immunological ignorance; and D, tolerance. Type A (PD-L1+ and CD8B+) exhibited upregulated features of T helper 1 antitumor responses. In the present study, survival time analysis at 5 years revealed that patients in type A had a better prognosis than those in other categories [5 year survival rate (%); A (80.5) vs. B (73.9), C (73.4) and D (72.6), P=0.0005]. Based on the expression data of 293 immune response-associated genes, 62 specific genes were upregulated in the type A group. Among these genes, 18 specific genes, such as activated effector T-cell markers (CD8/CD40LG/GZMB), effector memory T-cell markers (PD-1/CD27/ICOS), chemokine markers (CXCL9/CXCL10) and activated dendritic cell markers (CD80/CD274/SLAMF1), were significantly associated with a good prognosis using overall survival time analysis. Finally, multivariate Cox proportional hazard regression analyses of overall survival demonstrated that four genes (GZMB, HAVCR2, CXCL9 and CD40LG) were independent prognostic markers, and GZMB, CXCL9 and CD40LG may contribute to the survival benefit of patients in the immune type A group.

[Ocular disorders of anticancer drugs--ocular side effects].

Although there are some sporadic reports about the ocular side effects (see below-named ocular disorders) of anticancer drugs, extremely few well-organized reports have been published. We report have eye disorders caused by anticancer drugs on the ocular surface (eyelids, conjunctiva, cornea), retina, optic nerve, and sites of the lacrymal ducts. For disorders of the anterior ocular segment, we use gefitinib (Iressa®) and erlotinib (Tarceba®), cetuximab (Arbitax®) for trichomegaly while for lacrymal duct disorders and retinas with corneal problems revolt biochemistry, S-1 (TS-1®), erlotinib, docetaxel, paclitaxel and tamoxifen, paclitaxel, tamoxifen, optic neuropathy with 5-fluorouracil (5-FU), S-1 and docetaxel have been reported. Eye disorders can be relieved by discontinuation of the anticancer drug, but one may cause irreversible change, and early diagnosis and treatment are required. In future, there is a need for examinations for large-scale eye disorders due to anticancer drugs and their prevention (about S-1 in particular) including the provision of information to ophthalmologists.

IgG4-related sclerosing disease of the breast successfully treated by steroid therapy.

IgG4-related sclerosing disease was first identified and defined in the twenty-first century. In this pathology, the serum IgG4 level increases and IgG4-positive plasma cells and lymphocytes infiltrate organs such as the pancreas, salivary glands, lacrimal glands, kidneys, and the retroperitoneum. Presented in this report is a case of IgG4-related sclerosing disease that occurred in the breast and was treated successfully with steroid therapy. A 51-year-old woman presented with bilaterally swollen eyelids and an elevated serum IgG4 concentration. Screening CT revealed a lesion in her right breast but no other lesions. Mammography, ultrasonography, and MRI could not rule out malignancy, so a core needle biopsy was performed. Histologically, the lesion was composed of papilloma with fibrosis, adenosis, and severe lymphoplasmacytic infiltration. No malignant features were observed. Many plasma cells within the lesion were immunohistochemically positive for IgG4. IgG4-related sclerosing disease of the breast was diagnosed, and steroid therapy was initiated. During 4 weeks of steroid treatment the lesion became smaller in size, and at 7-months follow-up the lesion showed no new growth. Since steroid therapy is effective for this disease, IgG4-related sclerosing disease should be considered in the differential diagnosis of breast lesions in order to avoid unnecessary surgery.

High-dose proton beam therapy for sinonasal mucosal malignant melanoma.

BACKGROUND: The significance of definitive radiotherapy for sinonasal mucosal melanoma (SMM) is sill controvertial. This study was to evaluate the role of high-dose proton beam therapy (PBT) in patients with SMM. METHODS: The cases of 20 patients with SMM localized to the primary site who were treated by PBT between 2006 and 2012 were retrospectively analyzed. The patterns of overall survival and morbidity were assessed. RESULTS: The median follow-up time was 35 months (range, 6-77 months). The 5-year overall and disease-free survival rates were 51% and 38%, respectively. Four patients showed local failure, 2 showed regrowth of the primary tumor, and 2 showed new sinonasal tumors beyond the primary site. The 5-year local control rate after PBT was 62%. Nodal and distant failure was seen in 7 patients. Three grade 4 late toxicities were observed in tumor-involved optic nerve. CONCLUSION: Our findings suggested that high-dose PBT is an effective local treatment that is less invasive than surgery but with comparable outcomes.

Feasibility of proton beam therapy for chordoma and chondrosarcoma of the skull base.

We explored the general feasibility of proton beam therapy for chordoma and chondrosarcoma of the skull base. Clinical records and treatment-planning data of patients with the pathological diagnosis of chordoma or chondrosarcoma were examined. Proton beam therapy was administered for gross tumor mass as well as microscopic residual disease after surgery. The prescribed dose was determined to maximize the coverage of the target and to not exceed predefined constraints for the organs at risk. Eight cases of chordoma and eight cases of chondrosarcoma were enrolled. The median tumor volume was 40 cm(3) (range, 7 to 546 cm(3)). The prescribed dose ranged from 50 to 70 Gy (relative biological effectiveness [RBE]), with a median of 63 Gy RBE. The median follow-up duration was 42 months (range 9 to 80 months). The overall survival rate was 100%, and the local control rate at 3 years of chordoma and chondrosarcoma were 100% and 86%. None of the patients developed radiation-induced optic neuropathy, brain stem injury, or other severe toxicity. Proton beam therapy is generally feasible for both chordoma and chondrosarcoma of the skull base, with excellent local control and survival rates.

Transpupillary thermotherapy for vasoproliferative retinal tumor.

PURPOSE: To report the clinical course of a patient with vasoproliferative retinal tumor (VPRT) who was treated with transpupillary thermotherapy (TTT). METHODS: A 50-year-old asymptomatic woman who had undergone fundus examination as a part of a preventive medical examination and been diagnosed with a retinal tumor in the left eye was referred to our hospital. Photocoagulation failed to inhibit progression of the massive serous detachment that accompanied the tumor, and TTT was performed with an 810-nm diode laser with a 4.0-mm spot size at 500 mW to 750 mW for 60 seconds with a 1-month interval between 2 treatments. Four and two partially overlapping laser spots were applied to cover the entire tumor in the first and second treatment sessions, respectively. As a result, the laser was applied to the tumor until the lesion become white. RESULTS: The serous retinal detachment and macular edema had almost completely resolved after two sessions of TTT. Thirteen months after TTT, there was no recurrence of the tumor. CONCLUSION: There were no complications associated with TTT for VPRT. Further follow-up of this case as well as accumulative data from other case reports is still needed, but TTT may be effective for treating VPRT with severe retinal detachment.