Malignancies In Japanese Patients Research Articles

Trends in risks of malignancies in Japanese patients with rheumatoid arthritis: Analyses from a 14-year observation of the IORRA cohort.

The aim is to investigate the trends in risks of overall and site-specific malignancies in patients with rheumatoid arthritis (RA). Among Japanese patients with RA enrolled in the Institute of Rheumatology, Rheumatoid Arthritis cohort, all malignancies that occurred from 2000 to 2013 were extracted. The standardized incidence ratios and 95% confidence intervals for overall and site-specific malignancies were calculated during three periods: pre-biologics, 2000-04; early biologics, 2005-09; and recent biologics, 2010-13. Risk factors for overall and specific malignancies were analysed using time-dependent Cox regression models. Among 11,299 patients with RA (68,483 person-years), 507 malignancies were confirmed. Similar risks were observed versus the general Japanese population for overall malignancies throughout the three periods, with standardized incidence ratios (95% confidence intervals) of 0.96 (0.80-1.14) in the pre-biologics period, 0.95 (0.82-1.09) in the early biologics period, and 0.87 (0.75-1.01) in the recent biologics period. A significantly increased risk for malignant lymphoma was observed throughout the observation period (standardized incidence ratio 4.61, 95% confidence interval 3.58-5.85). The disease activity was a significant risk factor for overall malignancies and lung cancer. Despite the expanding use of methotrexate and biologics, there were no increases in malignancy risk in Japanese patients with RA.

Clinical characteristics, prognostic factors, and outcomes of patients with essential thrombocythemia in Japan: the JSH-MPN-R18 study

We conducted a large-scale, nationwide retrospective study of Japanese patients who were diagnosed with essential thrombocythemia based on the diagnostic criteria in the World Health Organization classification. We investigated clinical characteristics, survival rates, and the incidence of thrombohemorrhagic events as well as risk factors for these events. A total of 1152 patients were analyzed in the present study. Median age at diagnosis was 65years, the median platelet count was 832 × 109/L, and the positive mutation rates of JAK2V617F, CALR, and MPL were 62.8, 25.1, and 4.1%, respectively. Compared with European and American patients, Japanese patients were more likely to have cardiovascular risk factors and less likely to have systemic symptoms including palpable splenomegaly. Thrombocytosis was identified as a risk factor for hemorrhagic events and prognosis, but not for thrombotic events. The prognostic factors and risk classifications reported in Europe and the United States were generally applicable to Japanese patients. Regarding transformations, secondary myelofibrosis progressed in a time-dependent manner, but progression to acute leukemia was low in "true" ET patients. Skin cancers were less common and gastrointestinal cancers more common as secondary malignancies in Japanese patients, suggesting ethnic differences.

Efficacy and Safety of Low-Molecular-Weight Heparin on Prevention of Venous Thromboembolism after Laparoscopic Operation for Gastrointestinal Malignancy in Japanese Patients: A Multicenter, Open-Label, Prospective, Randomized Controlled Trial

The risk of venous thromboembolism (VTE) after surgery for malignancy in Japanese patients is unclear; therefore, standard prevention protocols have not been established, especially for minimally invasive procedures. We aimed to investigate the additional effect of low molecular weight heparin (LMWH) on prevention of VTE after laparoscopic surgery for gastrointestinal malignancy. From February 2013 to January 2017, 400 patients scheduled for laparoscopic surgery were included. Cases were randomly allocated to the physical therapy group (Control group; 201 patients) or to the combination-therapy group (LMWH group; 199 patients), in which enoxaparin sodium (20 mg [= 2000 IU] twice a day) was administered for 1 week postoperatively in addition to the physical therapy. A diagnosis of VTE was made by contrast-enhanced CT or ultrasonography when symptomatic or D-dimer was ≥10 μg/mL. VTE was observed in 1.2% and 4.0% of patients in the LMWH and Control groups, respectively (odds ratio [OR] 0.3, 95% confidence interval [CI] 0.03-1.53). Pulmonary embolism was confirmed only in the Control group (1.7%). No major bleeding occurred in either group. Logistic multiple regression analysis revealed that surgical time extension (OR 1.02, 95% CI 1.00-1.04) was a risk factor of VTE, while administration of LMWH (OR 0.21, 95% CI 0.03-0.99), male sex (OR 0.12, 95% CI 0.01-0.60), and early cancer (OR 0.17, 95% CI 0.02-0.82) reduced the risk of VTE. Postoperative LMWH administration is safe. The additional effect of LMWH administration on the physical therapy was not statistically proven in this study. However, it could be useful for the patients with risk factors such as female sex, long operation time, and higher cancer stage.

Lack of Increased Risk of Lymphoma by Thiopurines or Biologics in Japanese Patients with Inflammatory Bowel Disease: A Large-Scale Administrative Database Analysis.

Background and AimsPatients with inflammatory bowel diseases may have higher incidences of non-melanoma skin cancers and non-Hodgkin lymphoma, potentially linked to underlying disease and treatments. This analysis assessed incidence rates of these malignancies in Japanese patients with ulcerative colitis or Crohn’s disease, and their association with thiopurine and/or anti-tumor necrosis factor-α treatment, using data from a nationwide administrative database in Japan.MethodsPatients diagnosed with inflammatory bowel disease without malignancy were identified from the Medical Data Vision database. Incident cases of non-melanoma skin cancers and non-Hodgkin lymphoma diagnosed after prescription of thiopurine and/or anti-tumor necrosis factor-α were identified between April 2008 and January 2018. Age- and sex-adjusted incidence rate ratios were calculated relative to the total treated patient population.ResultsA total of 75 673 eligible patients were identified at the index date. Thiopurine prescription with or without anti-tumor necrosis factor-α agents increased incidence rate ratios for non-melanoma skin cancers relative to the overall population (3.39 and 4.03, respectively). There were no notable differences in non-Hodgkin lymphoma incidence relative to the total population in any treatment subgroup, regardless of prescription of thiopurine and/or anti-tumor necrosis factor-α (all incidence rate ratios, ~1).ConclusionsThere is no evidence for an increased incidence of non-Hodgkin lymphoma attributable to thiopurine or anti-tumor necrosis factor-α treatment in Japanese patients with inflammatory bowel disease. The impact of racial differences on non-Hodgkin lymphoma incidences should be considered. Thiopurine therapy may be a risk factor for non-melanoma skin cancers in Japanese patients.

PALB2 mutation in a woman with bilateral breast cancer: A case report.

Partner and localizer of breast cancer 2 (PALB2) was identified as a moderate-risk gene of breast and pancreas cancer. The present authors previously reported that no PALB2 germline mutations with a deleterious frameshift or stop codons were identified in 155 Japanese patients with breast and/or ovarian cancer who were estimated to be at risk of hereditary cancer, according to the National Comprehensive Cancer Network (NCCN) criteria. In the present study, one patient with a deleterious mutation of PALB2 (c. 2834+2 T>C) has been identified from a study of an additional 128 cases. Therefore, the prevalence of PALB2 among Japanese patients is now estimated to be 0.35% (1/283). The proband was a 63-year-old woman with bilateral breast cancer, although she had experienced no other cancers. The proband had two elder sisters, the eldest of whom died from pancreatic cancer at 60 years of age. The proband's 40-year-old daughter was affected, but did not show any malignancies. There are only a few reports concerning PALB2 mutations in Japan. To the best of our knowledge, this is the first case study to reveal the significance of DNA-repair genes in the development of malignancies in Japanese patients with breast cancer.

Malignancies after living-donor and cadaveric lung transplantations in Japanese patients.

Lung transplant recipients are known to be at risk of a postoperative malignancy. In Western countries, skin cancer and post-transplant lymphoproliferative disorder (PTLD) are the most common malignancies in this cohort. We conducted this study to evaluate the characteristics of postoperative malignancies in Japanese patients following living-donor lobar lung transplantation (LDLLT) or cadaveric lung transplantation (CLT). We reviewed the medical records of 120 Japanese patients who underwent either LDLLT (n=62) or CLT (n=58) between April 2002 and July 2015. Postoperative malignancy developed in 11 patients (9.2%), as PTLD in 7, breast cancer in 1, gastric cancer in 1, glioblastoma in 1, and adenocarcinoma of unknown primary in 1. Twenty-six (21.7%) of the 120 transplant patients had a history of malignancy pre-transplant; however, the postoperative malignancies were all de novo without any recurrence of the original disease. The malignancies developed after LDLLT in six patients (9.7%) and after CLT in 5 patients (8.6%). Three of the four patients with solid organ malignancies had distant metastasis at diagnosis. Three patients died of PTLD and one patient died of gastric cancer. PTLD occurred after both LDLLT and CLT. There was no case of skin cancer in this series of Japanese patients, suggesting ethnic differences. Solid organ malignancies in lung transplant recipients tended to progress rapidly.

Association of anti‐RNA polymerase III antibody and malignancy in Japanese patients with systemic sclerosis

Patients with systemic sclerosis (SSc) have an increased risk of malignancy compared with the general population. Recently, SSc patients with anti-RNA polymerase III antibody have been reported to have an increased risk of malignancy as compared with those with other disease-specific autoantibodies in US, European and Australian populations. Therefore, we studied the relationship between disease-specific autoantibodies and malignancy in 261 Japanese SSc patients. The prevalence of malignancy was significantly higher in patients with anti-RNA polymerase III antibody (7/22, 31.8%) than in those with anti-topoisomerase I antibody (2/82, 2.4%) and in those with anticentromere antibody (8/137, 5.8%). Importantly, among seven patients with anti-RNA polymerase III antibody and malignancy, three patients (42.9%) developed malignancy from 6months before to 12months after SSc onset. Thus, malignancy complication in Japanese SSc patients with anti-RNA polymerase III antibody is as high as that in other races, suggesting that SSc patients with anti-RNA polymerase III antibody share the same pathological process among different ethnic groups.

Long-term survey of survival time, histological transformation, and secondary malignancies in Japanese patients with advanced-stage follicular lymphoma in the rituximab era: Hokkaido Hematology Study Group.

Following the introduction of rituximab, the long-term overall survival (OS) rate of advanced-stage follicular lymphoma (FL) cases was expected to improve after the introduction of rituximab: however, there is a lack of large-scale survey data in Asia due to the relatively low incidence of FL. We conducted a retrospective survey to assess the treatment outcomes in patients with newly diagnosed advanced-stage FL in 29 institutions in Hokkaido from January 2001 to December 2010. The total number of patients was 443 (men 47.6%, women 52.4%), with a median age of 55 years (range 20-80 years). Of the cases examined, 42.2% had stage III and 57.8% had stage IV disease. Furthermore, 62.5, 19.7, 9.2, 5.2, and 3.4% had performance statuses of 0, 1, 2, 3, and 4, respectively. The 5-year OS was 91.2%, and no survival plateau was observed. Seventeen patients experienced secondary malignancies (six hematological diseases and 11 solid cancers; 5-year probability, 4.2%). Eighteen patients experienced transformation (5-year probability, 4.5%). The overall survival at 5 years after therapy for transformation was 50%. Before the introduction of rituximab, the 5- to 10-year OS of advanced-stage FL patients in Japan was reported to be about 30-60%. Although these data are limited, improvement in OS has been observed in Japan during the rituximab era.

THU0148 Tofacitinib, an Oral Janus Kinase Inhibitor: Analysis of Malignancies in Japanese Patients across the Rheumatoid Arthritis Clinical Programme

BackgroundTofacitinib is a novel, oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA).ObjectivesTo evaluate the malignancies that occurred in Japanese patients in the tofacitinib RA programme from the...

Negative human papillomavirus status and excessive alcohol consumption are significant risk factors for second primary malignancies in Japanese patients with oropharyngeal carcinoma.

To determine the clinical significance of human papillomavirus subclinical infection in patients with oropharyngeal squamous cell carcinoma in Japan. Over a 9-year period, a retrospective case comparison study of the pathology database was conducted at the University of Tokyo to identify samples of oropharyngeal squamous cell carcinoma. We performed in situ hybridization for human papillomavirus-DNA to identify subclinical human papillomavirus infections among patients with oropharyngeal squamous cell carcinoma. Second primary malignancies were classified as synchronous, if identified within 6 months of the diagnosis of the first tumor, or metachronous, if identified after this 6-month period. Univariate and multivariate analyses using logistic stepwise regression models were performed to identify factors associated with synchronous and metachronous second primary malignancy. Of the 150 patients with oropharyngeal squamous cell carcinoma, 14% (21/150) and 20.7% (31/150) developed synchronous and metachronous second primary malignancies, respectively. Esophageal carcinoma was the most frequent second primary malignancy (10/21 for synchronous and 10/31 for metachronous second primary malignancies). The prevalence of oropharyngeal squamous cell carcinoma positive for human papillomavirus was 31% (47/150). Multivariate analysis identified alcohol consumption as a significant unfavorable risk factor for the occurrence of synchronous second primary malignancy, and either a human papillomavirus-negative status or N0 classification was a significant unfavorable risk factor for the occurrence of metachronous second primary malignancy. Evaluation of the human papillomavirus status may help identify patients at risk for metachronous second primary malignancy. Upper gastrointestinal endoscopy is very important in the diagnosis of oropharyngeal squamous cell carcinoma among heavy drinkers in Japan.

Incidence and the Risk Factor of Malignancy in Japanese Patients with Systemic Sclerosis

To evaluate the incidence and risk factors for malignancy in Japanese patients with systemic sclerosis (SSc). A cohort of 405 Japanese patients with SSc who visited Kitasato University hospital between 1973 and 2008 was analyzed retrospectively until the end of 2009. The incidence of malignancy was compared with that of the general population, with calculation of the standardized incidence ratio (SIR) and 95% confidence interval (CI). The cohort represented 4,787 person-years of total disease duration after the diagnosis of SSc. Of 27 malignancies clinically found, lung cancer (n=10, 37%), especially adenocarcinoma, was the most frequent, followed by breast (n=4, 15%) or gastric (n=3, 11%) cancer. SSc patients with overlapping CTD tended to have less malignancy. Multivariable analysis revealed heart involvement of SSc as a significant risk factor for breast cancer (RR 8.2, 95% CI 1.2-72.8). Other than gastric cancer, the calculated SIRs of malignancies in SSc patients were above 1 (SIR of overall malignancy 1.24, 95% CI 0.77-1.71), even though only lung cancer had a significantly elevated incidence (SIR 5.73, 95% CI 2.18-9.29). Every patient with lung cancer had interstitial lung disease (ILD) and every autopsy performed on patients with lung cancer found a primary lesion of lung cancer in their ILD lesion (n=4). Lung cancer was significantly frequent in SSc patients, which could develop on the basis of complicated ILD.

Incidence of malignancy in Japanese patients with rheumatoid arthritis

To determine the incidence of malignancy and site-specific malignancies in Japanese patients with rheumatoid arthritis (RA). In a prospective large observational cohort study named IORRA, 7,566 patients with RA were enrolled from April 2001 to April 2005 and were followed up to October 2005. Occurrence of malignancy was originally collected by patient reports of IORRA survey biannually from April 2001 to October 2005, and was confirmed by medical records. Standardized incidence rate (SIR) of the observed-to-expected cancer incidence and 95% confidence intervals (95% CI) were then calculated. Factors obtained at first enrollment in IORRA were assessed for association with risk of malignancy using the Cox proportional hazards model. A total of 177 malignancies in 173 patients (58 in men, 115 in women) were identified during the observation period of 25,567 person-years. The age- and sex-standardized incidence rate of malignancy was 437.1 (men, 706.8; women, 366.1) per 100,000 person-years. The SIR of malignancy was slightly excess (SIR 1.18, [95% CI 1.02-1.37]) in all patients, but 1.29 (95% CI 0.99-1.67) in men, and 1.13 (95% CI 0.94-1.36) in women. A significant excess of lymphoma (SIR 6.07, [95% CI 3.71-9.37]) and lung cancer (SIR 2.29, [95% CI 1.57-3.21]), whereas decreased incidence of colorectal cancer (SIR 0.49, [95% CI 0.26-0.83]), were found. Male gender and older age were identified as risk factors for malignancy. A slight excess in the incidence of overall malignancy and highly excess of lymphoma in Japanese RA patients was demonstrated.

Malignancy in Crohn’s Disease: Incidence and Clinical Characteristics in Japan

Background/Aims: This study investigated the occurrence of malignancies in Japanese patients with Crohn’s disease (CD) and compared the incidence with that in the general population. Methods: The medical records of 294 CD patients, treated between 1989 and 2009, were reviewed and the prevalence of malignancies was assessed. Registration of person-years at risk was calculated individually, from the year of CD diagnosis until the year of cancer diagnosis, death or end of follow-up. The observed number of cancer cases was compared with the expected number, calculated on the basis of the individually computed person-years at risk and the corresponding age- and sex-specific incidence rates in the background population. Results: Thirteen cancers developed in 12 patients among a total of 4,248 person-years available for analysis. There were six CRCs, two gastric cancers, two uterine cancers, one small bowel cancer, one biliary cancer, and one cancer of unknown primary site. The risk of cancer (all sites) was significantly increased from that of the background population; SIR 2.24 (95% CI 1.19–3.83). In particular, the risk of CRC significantly increased in comparison to that of the background population; SIR 5.80 (95% CI 2.13–12.68). Conclusions: Japanese patients with CD are at increased risk of cancer, particularly CRC.

A Multicenter and Open Label Clinical Trial of Zoledronic Acid 4 mg in Patients with Hypercalcemia of Malignancy

Hypercalcemia of malignancy is a serious complication of cancer. The objective of this study was to investigate the efficacy and safety of zoledronic acid, a new-generation bisphosphonate and the most potent inhibitor of bone resorption identified to date, for hypercalcemia of malignancy in Japanese patients. Patients with hypercalcemia of malignancy, defined as an albumin-corrected serum calcium level > or =12.0 mg/dl, were treated with a single dose of zoledronic acid, 4 mg, by 15 min infusion. Clinical end-points included the proportion of patients with complete response, which was defined as a decrease of corrected serum calcium < or =10.8 mg/dl by day 10, and time to relapse, which is defined as the duration in days between the date of infusion and last available corrected serum calcium <11.6 mg/dl. Twenty-seven patients were enrolled in this study and 25 patients were evaluable for the efficacy of zoledronic acid. The mean corrected serum calcium level decreased from 14.5 to 9.6 mg/dl by day 10. The complete response rate was 84%. The median time to relapse was 23 days, ranging from 0 to 56 days. The most frequently observed adverse event was fever (< or =38 degrees C). Electrolyte abnormalities suspected to be drug related including grade 3 or 4 hypocalcemia, hypophosphatemia and hypokalemia were observed in 11 patients; however, all patients were asymptomatic. No serious adverse events associated with renal toxicity were reported. Zoledronic acid is well tolerated and is effective for hypercalcemia of malignancy in Japanese patients.

Multiple primary malignancies in Japanese patients with renal cell carcinoma.

To evaluate the incidence, nature and prognosis of multiple primary malignancies involving renal cell carcinoma (RCC) in Japan. Between 1975 and 1998, 319 patients underwent an operation for RCC at Hokkaido University, Sapporo, Japan. The incidence of other primary malignancies was determined and classified as antecedent, synchronous or subsequent. Follow-up was obtained by thorough chart review or telephone interview, and ranged from 0 to 276 months (median 49.0 months). To analyze the influence of other primary malignancies on prognosis, overall and cause-specific survival rates of the patients with an antecedent or synchronous malignancy were compared to the remaining patients. Of the 319 patients there was at least one other malignancy in 38 patients (12%). Four patients had two other malignancies. The other malignancies were antecedent in 13, synchronous in 19 and subsequent in 10 patients. Twenty-two patients had gastrointestinal cancer. In cases of antecedent or synchronous diagnosis of other primary malignancies, RCC was commonly incidental, small or low-stage. Multivariate analysis using Cox's proportional hazards model showed that, for overall survival, the presence of other antecedent or synchronous malignancies was the second most significant prognostic factor, following the pathological stage of RCC. In Japanese patients with RCC, the incidence of other primary malignancies was not uncommon and these malignancies contributed to the prognosis of these patients. Therefore, the malignant potential of individual tumors should be paid careful attention in the management of these patients.

Frequency of HLA-A alleles in Japanese patients with head and neck cancer.

Association between certain human leukocyte antigen (HLA) types such as HLA-A1 and -A3 and squamous cell carcinoma of the head and neck (SCCHN) has been demonstrated in the Caucasian population. HLA typings in these studies were performed by conventional serological methods. However, recent comparison studies between serological and molecular typings have revealed that the former are often inaccurate. The frequency of HLA-A alleles in 100 Japanese patients with SCCHN and 100 control subjects was determined by the polymerase chain reaction, with primers specific for the HLA-A locus, in combination with dot-blot hybridization with 31 sequence-specific oligonucleotides. The frequencies of HLA-A*2602 and HLA-A*3303 were higher and those of HLA-A*2603 and HLA-A*3101 were lower in the patients with SCCHN than in healthy controls, but these differences were not statistically significant. In the 39 male patients with laryngeal carcinoma, the most common malignancies in Japanese patients with SCCHN, the frequency of HLA-A*2402 was significantly lower than that in the 80 male controls; however, after correction of the P value, statistical significance was not confirmed. In oral carcinoma patients, the frequency of HLA-A*2402 was significantly higher than that in healthy controls. These results suggest that the contribution of certain HLA-A alleles to susceptibility to SCCHN may differ between sites in the head and neck regions, despite these cancers being of an identical histological type, and that HLA-A*2402 may influence the development of oral carcinoma in Japanese patients.