Soluble immune checkpoint factors reflect exhaustion of antitumor immunity and response to PD-1 blockade.

BACKGROUNDPrecise stratification of patients with non-small cell lung cancer (NSCLC) is needed for appropriate application of PD-1/PD-L1 blockade therapy.METHODSWe measured soluble forms of the immune-checkpoint molecules PD-L1, PD-1, and CTLA-4 in plasma of patients with advanced NSCLC before PD-1/PD-L1 blockade. A prospective biomarker-finding trial (cohort A) included 50 previously treated patients who received nivolumab. A retrospective observational study was performed for patients treated with any PD-1/PD-L1 blockade therapy (cohorts B and C), cytotoxic chemotherapy (cohort D), or targeted therapy (cohort E). Plasma samples from all patients were assayed for soluble immune-checkpoint molecules with a highly sensitive chemiluminescence-based assay.RESULTSNonresponsiveness to PD-1/PD-L1 blockade therapy was associated with higher concentrations of these soluble immune factors among patients with immune-reactive (hot) tumors. Such an association was not apparent for patients treated with cytotoxic chemotherapy or targeted therapy. Integrative analysis of tumor size, PD-L1 expression in tumor tissue (tPD-L1), and gene expression in tumor tissue and peripheral CD8+ T cells revealed that high concentrations of the 3 soluble immune factors were associated with hyper or terminal exhaustion of antitumor immunity. The combination of soluble PD-L1 (sPD-L1) and sCTLA-4 efficiently discriminated responsiveness to PD-1/PD-L1 blockade among patients with immune-reactive tumors.CONCLUSIONCombinations of soluble immune factors might be able to identify patients unlikely to respond to PD-1/PD-L1 blockade as a result of terminal exhaustion of antitumor immunity. Our data suggest that such a combination better predicts, along with tPD-L1, for the response of patients with NSCLC.TRIAL REGISTRATIONUMIN000019674.FUNDINGThis study was funded by Ono Pharmaceutical Co. Ltd. and Sysmex Corporation.

Radiotherapy Patterns of Care for Locally-advanced Non-small Cell Lung Cancer in the Pre- and Post-durvalumab Era: A Region-wide Survey in a Japanese Prefecture.

The promising results of the PACIFIC study led to the approval of consolidation durvalumab for coverage by the National Health Insurance (NHI) in 2018 for patients with locally-advanced unresectable non-small cell lung carcinoma (NSCLC) treated with definitive concurrent chemoradiotherapy (CCRT). However, the effect of NHI coverage on the patterns of care for this population remains unclear. Here, we conducted a questionnaire-based survey to determine the patterns of care for patients with stage II-III NSCLC treated with definitive radiotherapy in 2017 (pre-durvalumab era) or in 2019 (post-durvalumab era). Data were obtained from 11 radiotherapy facilities in Gunma prefecture, which has a population of 1.94 million. We identified 80 and 83 patients with stage II-III NSCLC who received definitive radiotherapy in Gunma in 2017 and 2019, respectively. At a given facility, CCRT was the treatment of choice in a significantly greater proportion of patients in 2019 than in 2017 (66% ± 20% vs 51% ± 29%, P = 0.041). Intensity-modulated radiotherapy (IMRT) was more frequent in 2019 than in 2017 (24% vs 1.2%). Carboplatin plus paclitaxel was used for CCRT at higher rate in 2019 than in 2017 (73% vs 44%). Consolidation durvalumab was performed in 73% (40/55) of CCRT-treated patients in 2019, and the treatment was performed for the planned 12 months in 45% (18/40) of patients. These data indicate that NHI coverage of durvalumab might be a possible reason for choosing CCRT in patients with stage II-III NSCLC in the real-world setting.

The effects of PSA kinetics on the outcome of hypofractionated salvage radiotherapy for biochemical recurrence of prostate cancer after prostatectomy.

The feasibility and efficacy of hypofractionated salvage radiotherapy (HS-RT) for prostate cancer (PC) with biochemical recurrence (BR) after prostatectomy, and the usefulness of prostate-specific antigen (PSA) kinetics as a predictor of BR, were evaluated in 38 patients who received HS-RT without androgen deprivation therapy between May 2009 and January 2017. Their median age, PSA level and PSA doubling time (PSA-DT) at the start of HS-RT were 68 (53-74) years, 0.28 (0.20-0.79) ng/ml and 7.7 (2.3-38.5) months, respectively. A total dose of 60 Gy in 20 fractions (three times a week) was three-dimensionally delivered to the prostate bed. After a median follow-up of 62 (30-100) months, 19 (50%) patients developed a second BR after HS-RT, but only 1 patient died before the last follow-up. The 5-year overall survival and BR-free survival rates were 97.1 and 47.4%, respectively. Late grade 2 gastrointestinal and genitourinary morbidities were observed in 0 and 5 (13%) patients, respectively. The PSA level as well as pathological T-stage and surgical margin status were regarded as significant predictive factors for a second BR by multivariate analysis. BR developed within 6 months after HS-RT in 11 (85%) of 13 patients with a PSA-DT < 10 months compared with 1 (17%) of 6 with a PSA-DT ≥ 10 months (median time to BR: 3 vs 14 months, P < 0.05). Despite the small number of patients, our HS-RT protocol seems feasible, and PSA kinetics may be useful for predicting the risk of BR and determining the appropriate follow-up schedule.

Analytical performance of a new automated chemiluminescent magnetic immunoassays for soluble PD-1, PD-L1, and CTLA-4 in human plasma.

Current clinically approved biomarkers for the PD-1 blockade cancer immunotherapy are based entirely on the properties of tumour cells. With increasing awareness of clinical responses, more precise biomarkers for the efficacy are required based on immune properties. In particular, expression levels of immune checkpoint-associated molecules such as PD-1, PD-L1, and CTLA-4 would be critical to evaluate the immune state of individuals. Although quantification of their soluble form leased from the membrane will provide quick evaluation of patients' immune status, available methods such as enzyme-linked immunosorbent assays to measure these soluble factors have limitations in sensitivity and reproducibility for clinical use. To overcome these problems, we developed a rapid and sensitive immunoassay system based on chemiluminescent magnetic technology. The system is fully automated, providing high reproducibility. Application of this system to plasma of patients with several types of tumours demonstrated that soluble PD-1, PD-L1, and CTLA-4 levels were increased compared to those of healthy controls and varied among tumour types. The sensitivity and detection range were sufficient for evaluating plasma concentrations before and after the surgical ablation of cancers. Therefore, our newly developed system shows potential for accurate detection of soluble PD-1, PD-L1, and CTLA-4 levels in the clinical practice.

Association Between Laryngopharyngeal Reflux and Radiation-induced Mucositis in Head and Neck Cancer.

BACKGROUND/AIM: We investigated whether laryngopharyngeal reflux (LPR) is a risk factor for radiation-induced mucositis. PATIENTS AND METHODS: This was a retrospective cohort study using our departmental database. The study included patients with stage I or II laryngeal and hypopharyngeal cancers treated with radiation therapy alone between April 2009 and March 2014. Based on endoscopic findings, baseline laryngeal signs were evaluated using the reflux finding score (RFS), and the severity of mucositis was assessed during and after radiation therapy. RESULTS: Fifty-eight patients were enrolled. Thirty-one patients were categorized as high RFS (LPR-likely), while 27 patients were categorized as low RFS (LPR-unlikely). Grade 3 mucositis occurred more frequently in the high RFS group (p<0.042). Furthermore, grade 3 mucositis developed earlier in the high RFS group (p<0.001). CONCLUSION: High RFS (i.e., increased likelihood of LPR) appears to be a potential risk factor for developing severe radiation-induced mucositis.

Successful treatment of radiation-induced mucositis with proton pump inhibitor administration: A report of two laryngeal cancer cases.

Presently, the relationship between laryngopharyngeal reflux (LPR) and radiation-induced mucositis has not been fully explored. In the present study, we report 2 cases of laryngeal cancer in which radiation-induced mucositis ameliorated after proton pump inhibitor (PPI) administration. Case 1 was diagnosed with T1aN0M0 right glottis carcinoma and was treated with radiation therapy. Grade 3 mucositis occurred after administration of 46Gy irradiation. PPI was administered and mucositis ameliorated quickly without cessation of radiation therapy. Case 2 was diagnosed with T2N0M0 supraglottic cancer and was treated with concurrent chemoradiation therapy. Grade 3 mucositis occurred after administration of 44Gy irradiation. PPI was administered and mucositis ameliorated quickly without cessation of chemoradiation therapy. In both cases, a remarkable therapeutic effect of PPI was observed in the perilaryngeal areas including the epiglottic vallecula, arytenoid, and postcricoid area. In both cases, LPR involvement was suspected before the onset of radiation therapy. The two cases presented here, indicated a causal relationship between LPR and radiation-induced mucositis. In cases of severe mucositis in the perilaryngeal area in patients with LPR prior to radiation therapy, PPI administration may be an effective therapeutic option.

Inhaled aztreonam lysine versus inhaled tobramycin in cystic fibrosis. An economic evaluation.

RATIONALE: Pseudomonas aeruginosa infection is a significant cause of morbidity and mortality in patients with cystic fibrosis and is associated with a high economic burden. A recently published comparator trial demonstrated that outcomes in patients with cystic fibrosis with chronic P. aeruginosa infections switched from tobramycin solution for inhalation to aztreonam lysine for inhalation were better than those of patients who continued on tobramycin. OBJECTIVES: To compare overall costs of treatment of chronic inhaled tobramycin and aztreonam lysine in patient with cystic fibrosis who have chronic Pseudomonas infection, taking differences in outcomes into account. METHODS: A cost-effectiveness analysis with a 3-year time horizon was performed to simulate the economic consequences of either treatment from the perspective of a third party payer in the United States. We extrapolated results from the comparator trial and used data regarding clinical outcomes, quality of life, and costs from published literature and proprietary databases. A Markov structure was used to consider transitions between health states, defined principally by levels of percent predicted of FEV1. Extensive scenario and probabilistic sensitivity analyses were performed. MEASUREMENTS AND MAIN RESULTS: Use of aztreonam lysine for inhalation was associated with an average cost saving of $41,947 per patient over 3 years, as well as greater quality-adjusted life-years and total life-years. Scenario analyses demonstrated that these findings were robust to changes in key assumptions. CONCLUSIONS: It appears, with high likelihood, that the use of aztreonam solution for inhalation is associated with cost savings, an increase in quality-adjusted life-years, and improved clinical outcomes among patients with extensive prior use of tobramycin solution for inhalation who are naive to inhaled aztreonam lysine.

Prognosis was not deteriorated by multiple primary cancers in esophageal cancer patients treated by radiotherapy.

Esophageal cancer patients are often associated with multiple primary cancers (MPC). The aim of this study is to evaluate the effect of MPC on prognosis in esophageal cancer patients treated by radiotherapy. Between 2001 and 2008, esophageal cancer patients treated by definitive radiotherapy at Gunma Cancer Center were retrospectively reviewed. Exclusion criteria were preoperative or postoperative radiotherapy, palliative radiotherapy, follow-up of <6 months, radiation dose of <50 Gy and no information on MPC. We analyzed 167 esophageal cancer patients and 56 (33.5%) were associated with MPC. Gastric cancer was the most frequent tumor (38.2%), followed by head and neck cancer (26.5%). Median follow-up time was 31.5 months (range 6.1-87.3 months). Patients with MPC included more stage I/II esophageal cancer than those without MPC (66.1% vs. 36.9%, P < 0.01). The 5-year overall survival rate for esophageal cancer with MPC was relatively better than those without MPC (46.1% vs. 26.7%), although the difference did not reach statistical significance in univariate analysis (P = 0.09). Stage I/II esophageal cancer patients had a significantly better overall survival than stage III/IV patients (P < 0.01). Among esophageal cancer patients with MPC, there was no difference in overall survival between antecedent and synchronous cancer (P = 0.59). Our study indicated that the prognosis of esophageal cancer patients treated by radiotherapy was primarily determined by the clinical stage itself, but not the presence of MPC.

Health care utilization & costs for cystic fibrosis patients with pulmonary infections.

PURPOSE: To examine patterns of health care utilization and costs among cystic fibrosis (CF) patients with pulmonary infections. DESIGN: Retrospective administrative claims database analysis. METHODOLOGY: We used administrative claims data (including both medical and pharmacy claims) to examine health care utilization and costs among CF patients with pulmonary infections over one year. We conducted a subgroup analysis in which we examined selected outcome measures among patients with tobramycin for inhalation (TIS) prescriptions by the number of TIS prescriptions filled. PRINCIPAL FINDINGS: Among 1,064 CF patients identified with pulmonary infections, 80% had at least one CF-related office visit, 34% had a CF-related hospital stay, and 95% filled at least one prescription over one year. Total annual CF-related health care costs averaged $29,000 plus $20,000 for prescription drugs. In the subgroup analysis, there was a trend towards longer lengths of stay and higher inpatient costs with fewer numbers of TIS prescriptions filled. CONCLUSION: CF patients with pulmonary infections have substantial levels of health care utilization and costs.

Comparison of chemoradiotherapy with radiotherapy alone in patients with esophageal adenocarcinoma.

Despite the wide use of definitive chemoradiotherapy (CRT) for locally advanced esophageal adenocarcinoma, there is little evidence that CRT improves the survival of patients with esophageal adenocarcinoma compared with radiotherapy (RT) alone. Therefore, we retrospectively evaluated the outcome of patients with esophageal adenocarcinoma treated by CRT and RT alone. Patients were treated at the Gunma Prefectural Cancer Center (Ota, Japan) and the Gunma University Hospital (Maebashi, Japan). Patients provided written informed consent before treatment. Patients with distant metastases were excluded. CRT consisting of RT, nedaplatin, and 5-fluorouracil has been performed since 2002 when patients have adequate bone marrow, liver, and renal function. Between November 1993 and April 2006, 8 patients were treated by CRT and 12 were RT alone. The median follow-up period of surviving patients was 19 months. CRT group had a significantly higher complete response rate than those RT alone group (87% vs. 33%, P = 0.05). Of all patients, 2-year overall survival rate was 41% and the median survival time was 18 months. The 2-year overall survival of patients treated by CRT was 58%, significantly better than 24% of those with RT alone (P = 0.02). CRT can improve outcomes of patients with esophageal adenocarcinoma compared with RT alone.

Dose-volume histogram parameters and clinical factors associated with pleural effusion after chemoradiotherapy in esophageal cancer patients.

PURPOSE: To investigate the dose-volume histogram parameters and clinical factors as predictors of pleural effusion in esophageal cancer patients treated with concurrent chemoradiotherapy (CRT). METHODS AND MATERIALS: Forty-three esophageal cancer patients treated with definitive CRT from January 2001 to March 2007 were reviewed retrospectively on the basis of the following criteria: pathologically confirmed esophageal cancer, available computed tomography scan for treatment planning, 6-month follow-up after CRT, and radiation dose ≥ 50 Gy. Exclusion criteria were lung metastasis, malignant pleural effusion, and surgery. Mean heart dose, mean total lung dose, and percentages of heart or total lung volume receiving ≥ 10-60 Gy (Heart-V(10) to V(60) and Lung-V(10) to V(60), respectively) were analyzed in relation to pleural effusion. RESULTS: The median follow-up time was 26.9 months (range, 6.7-70.2) after CRT. Of the 43 patients, 15 (35%) developed pleural effusion. By univariate analysis, mean heart dose, Heart-V(10) to V(60), and Lung-V(50) to V(60) were significantly associated with pleural effusion. Poor performance status, primary tumor of the distal esophagus, and age ≥ 65 years were significantly related with pleural effusion. Multivariate analysis identified Heart-V(50) as the strongest predictive factor for pleural effusion (p = 0.01). Patients with Heart-V(50) <20%, 20%≤ Heart-V(50) <40%, and Heart-V(50) ≥ 40% had 6%, 44%, and 64% of pleural effusion, respectively (p < 0.01). CONCLUSION: Heart-V(50) is a useful parameter for assessing the risk of pleural effusion and should be reduced to avoid pleural effusion.

Hypothalamic neuronal histamine signaling in the estrogen deficiency-induced obesity.

Menopause is one of the triggers that induce obesity. Estradiol (E2), corticotropin-releasing hormone (CRH), and hypothalamic neuronal histamine are anorexigenic substances within the hypothalamus. This study examined the interactions among E2, CRH, and histamine during the regulation of feeding behavior and obesity in rodents. Food intake was measured in rats after the treatment of E2, alpha-fluoromethyl histidine, a specific suicide inhibitor of histidine decarboxylase that depletes hypothalamic neuronal histamine, or CRH antagonist. We measured food intake and body weight in wild-type mice or mice with targeted disruption of the histamine receptors (H1-R) knockout (H1KO mice). Furthermore, we investigated CRH content and histamine turnover in the hypothalamus after the E2 treatment or ovariectomy (OVX). We used immunohistochemical staining for estrogen receptors (ERs) in the histamine neurons. The E2-induced suppression of feeding was partially attenuated in rats pre-treated with alpha-fluoromethyl histidine or CRH antagonist and in H1KO mice. E2 treatment increased CRH content and histamine turnover in the hypothalamus. OVX increased food intake and body weight, and decreased CRH content and histamine turnover in the hypothalamus. In addition, E2 replacement reversed the OVX-induced changes in food intake and body weight in wild-type mice but not in H1KO mice. Immunohistochemical analysis revealed ERs were expressed on histamine neurons and western blotting analysis and pre-absorption study confirmed the specificity of ER antiserum we used. These results indicate that CRH and hypothalamic neuronal histamine mediate the suppressive effects of E2 on feeding behavior and body weight.

Histopathological variation of primary mucosa-associated lymphoid tissue lymphoma of the oral cavity.

Primary mucosa-associated lymphoid tissue (MALT) type lymphoma arising in the oral cavity is rare. We examined histopathologic, immunohistological and genotypic findings of seven cases of intraoral MALT lymphoma using formalin-fixed paraffin-embedded tissues. Histologically, two variants have been delineated. (i) In four cases of minor salivary gland type, the lymphoid follicles were surrounded by centrocyte-like (CCL) cells with occasional follicular colonization. The CCL cells invaded the residual salivary gland duct resulting in a lymphoepithelial lesion. CCL cells frequently showed plasmacytic differentiation. (ii) In three cases of follicular growth type, the lesion was characterized by follicular growth pattern resulting from prominent follicular colonization. CCL cells showed minimal plasma cell differentiation. There was no residual epithelial component detected even by cytokeratin immunostaining. There were no Epstein-Barr virus-encoded small RNA-positive cells detected by in situ hybridization. API2-MALT1 fusion transcript does not appear to be associated with either histological variant of primary intraoral MALT lymphoma.

A multicenter phase II study of local radiation therapy for stage IEA mucosa-associated lymphoid tissue lymphomas: a preliminary report from the Japan Radiation Oncology Group (JAROG).

PURPOSE: The aim of this study was to evaluate the efficacy and toxicity of moderate dose radiation therapy (RT) for mucosa-associated lymphoid tissue (MALT) lymphoma in a prospective multicenter phase II trial. METHODS AND MATERIALS: The subjects in this study were 37 patients with MALT lymphoma between April 2002 and November 2004. There were 16 male and 21 female patients, ranging in age from 24 to 82 years, with a median of 56 years. The primary tumor originated in the orbit in 24 patients, in the thyroid and salivary gland in 4 patients each, and 5 in the others. The median tumor dose was 30.6 Gy (range, 30.6-39.6 Gy), depending on the primary site and maximal tumor diameter. The median follow-up was 37.3 months. RESULTS: Complete remission (CR) or CR/unconfirmed was achieved in 34 patients (92%). The 3-year overall survival, progression-free survival, and local control probability were 100%, 91.9%, and 97.3%, respectively. Thirteen patients experienced Grade 1 acute toxicities including dermatitis, mucositis, and conjunctivitis. One patient developed Grade 2 taste loss. Regarding late toxicities, Grade 2 reactions including hypothyroidism, and radiation pneumonitis were observed in three patients, and Grade 3 cataract was seen in three patients. CONCLUSIONS: This prospective phase II study demonstrated that moderate dose RT was highly effective in achieving local control with acceptable morbidity in 37 patients with MALT lymphoma.

Initial experience with the quality assurance program of radiation therapy on behalf of Japan Radiation Oncology Group (JAROG).

BACKGROUND: We evaluated the efficacy of our quality assurance (QA) program of radiation therapy (RT) in a prospective phase II study. This is the first description of the experience of the Japan Radiation Oncology Group (JAROG) with this program. METHODS: Clinical records, all diagnostic radiological films or color photos that depicted the extent of disease of 37 patients with stage IEA extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) were collected for review. Radiation therapy charts, simulation films or digitally reconstructed radiographs, portal films and isodose distributions at the central axis plan were also reviewed. All documents were digitally processed, mounted on Microsoft PowerPoint, and for security returned from researchers by mail in CD-ROM format. The QA committee members reviewed all documents centrally, utilizing the slide show functionality. RESULTS: All patients were prescribed their specified dose to the dose specification point in accordance with the protocol. Three patients were regarded as deviations, because of a smaller margin than that specified in the protocol (n = 2) or a prolonged overall treatment time (n = 1). No violations were observed in this study. CONCLUSIONS: This is the first report with regard to the QA program in MALT lymphoma. We demonstrated that our QA program was simple and inexpensive. We also confirmed that the radiation oncologists in Japan adhered closely to the protocol guidelines.

Multi-institutional study of radiation therapy for isolated para-aortic lymph node recurrence in uterine cervical carcinoma: 84 subjects of a population of more than 5,000.

PURPOSE: Most patients who had any recurrent sites of cancer have been considered to be in their last stage of life. However, recent advances of clinical research reveal some patients achieve long-term survival even in recurrence. Furthermore, for patients who had only one recurrent region, radiation therapy could play an important role. As for uterine cervical carcinoma, the most common recurrent site other than the pelvis is the para-aortic lymph nodes. Thus we conducted the current study. PATIENTS AND METHODS: Between 1994 and 2003, more than 5,000 uterine cervical carcinoma patients were treated with curative intended treatments at 13 Japanese hospitals. Of these patients, 84 developed para-aortic lymph node recurrence as the only site of initial tumor progression. These patients were treated with external beam radiation therapy. Radiation therapy protocol was as follows: 1.7-2.0 Gy per fraction, 5 fractions per week, and the mean total dose was 50.8 Gy (25-60 Gy). RESULTS: Three- and 5-year overall survival rates of all patients were 49.5% and 31.3%, respectively. Stratified by symptom sign, 3-year overall survival rate of symptom positive was 27.6% and those of the negative was 56.1% (p = 0.018). Three-year overall survival rates of the total dose > or =51 Gy and that of < or =50 Gy were 58.0% and 42.8%, respectively (p = 0.07). As for morbidity, no patients received Grade 3 or greater late toxicity. CONCLUSIONS: The current study suggested that radiation therapy for isolated para-aortic lymph node recurrence in uterine cervical carcinoma could have a significant impact on survival.

Radiation therapy alone for stage I (UICC T1N0M0) squamous cell carcinoma of the esophagus: indications for surgery or combined chemoradiotherapy.

BACKGROUND AND AIM: The aim of this study was to clarify the efficacy and limitations of radiation therapy (RT) for superficial esophageal carcinoma, and to explore the indications for more aggressive therapy, such as combined chemo-radiotherapy. METHODS: Sixty-eight patients with stage I (UICC T1N0M0) esophageal squamous cell carcinoma treated by definitive RT alone were analyzed. Brachytherapy was administered in 36 patients as a boost, and the prescribed doses were 10 Gy (5 Gy x 2 times) at a low dose rate (19 patients) and 9 Gy (3 Gy x 3 times) at a high dose rate (17 patients). Recurrence patterns and survival rates were assessed and the factors predisposing to recurrences after RT were statistically investigated by univariate analysis. RESULTS: The 5-year cause-specific survival rate and the locoregional control rate were 79.9% and 82.1%, respectively. No case of recurrence or disease-related death was observed in any of the patients with mucosal cancer. Among the cases with the cancer invading the submucosa, there were 12 cases with locoregional recurrence and two cases with distant metastases. In cases of submucosal esophageal cancer, the tumor length was the only statistically significant factor predicting locoregional control. The 5-year locoregional control rate in cases with a short length of the tumor (5 cm in length was 57.8% (P = 0.036). Patients treated by additional brachytherapy exhibited better cause-specific survival and locoregional control rates than those receiving external RT alone, however, the addition had no statistically significant influence on the outcome. CONCLUSIONS: RT was a successful treatment for stage I esophageal cancer, and the treatment outcome using RT was nearly comparable to that of surgery. However, it is suggested that chemo-radiation should be considered in inoperable cases of submucosal cancer when the tumor is more than 5 cm in length.

Frequency and characteristics of isolated para-aortic lymph node recurrence in patients with uterine cervical carcinoma in Japan: a multi-institutional study.

OBJECTIVE: In most cases of uterine cervical carcinoma recurrence, the first site of distant metastasis or recurrence is reported to be the para-aortic region. Some reports have demonstrated that, in cases of isolated para-aortic lymph node recurrence treated by radiation therapy, patients survived for a long period, which suggests that isolated para-aortic lymph node recurrence in uterine cervical carcinoma is a regional disease rather than systemic disease. Determining the predictive characteristics of isolated para-aortic lymph node recurrence in patients at the time of the initial treatment for primary uterine cervical carcinoma is important, so we conducted the current multi-institutional study. PATIENTS AND METHODS: Patients (n=3137) with uterine cervical carcinoma of stages Ia to IVa were treated in twelve Japanese hospitals between 1994 and 2003. The current study investigated the frequency and characteristics of patients with isolated para-aortic lymph node recurrence as well as the characteristics of clinical stage, histopathology, serum squamous cell carcinoma antigen level, the treatment method at the initial treatment, the duration between the initial treatment and the recurrence, and the serum squamous cell carcinoma antigen level at the recurrence. RESULTS: Of the 3137 patients with uterine cervical carcinoma in stages Ia-IVa, 67 (2.1%) experienced recurrence in isolated para-aortic lymph nodes. Stratified by clinical stage, none of the 613 patients with stage Ia experienced recurrence in isolated para-aortic lymph nodes. However, recurrence was experienced by 14 (1.4%) of the 966 patients with stage Ib, 7 (3.5%) of the 199 patients with stage IIa, 14 (2.3%) of the 613 patients with stage IIb, 1 (2.1%) of the 48 patients with stage IIIa, 26 (4.6%) of the 538 patients with stage IIIb, and 5 (5%) of the 100 patients with stage IVa. The mean duration time between the initial treatment and isolated para-aortic recurrence was 20 months (range, 2-49 months). The correlations between duration time and the clinico-pathological factors (clinical stage, histopathology, serum squamous cell carcinoma antigen level, and treatment method) at the initial treatment were investigated. No statistically significant factors have been revealed in the current study. CONCLUSIONS: The frequency of isolated para-aortic lymph node recurrence was 2.1% and increased with increasing clinical stage at the initial treatment (stage IVa: 5%) in the current study.

Malignant lymphoma in patients with systemic rheumatic disease (rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, and dermatomyositis): a clinicopathologic study of 24 Japanese cases.

We conducted clinicopathologic and immunohistochemical analyses of the prevalence of Epstein-Barr virus (EBV) among 24 patients with malignant lymphoma complicating systemic rheumatic diseases. (SRD) These 24 patients included 17 with rheumatoid arthritis (RA), 3 with systemic lupus erythematosus (SLE), 2 with systemic sclerosis (SS), and 2 with dermatomyositis (DM). There were 2 men and 22 women ranging in age from 30 to 86 years (mean: 64 years). The interval between the onset of rheumatic disease and that of malignant lymphomas ranged from 3 months to 35 years (mean: 142 months). The use of immunosuppressive drugs before the onset of malignant lymphoma was recorded in 15 patients. Among them, 5 patients received methotrexate (MTX) therapy. Malignant lymphomas were found at extranodal sites in 9 patients, and the disease was in the advanced stage in 17 patients. Histologic and immunohistochemical studies demonstrated that 18 cases (75%) were B-cell lymphoma (RA=12, SLE=2, SS=2, DM=2), 3 (12.5%) were peripheral T-cell lymphoma (RA=3), and 3 (12.5%) were classical Hodgkin lymphoma (RA=2, SLE=1). As in previous reports, there was an increased frequency of diffuse large B-cell lymphoma (50%) in the present series. Moreover, a majority of the diffuse large B-cell lymphomas exhibited activated B-cell phenotype. EBV-encoded small RNAs (Epstein-Barr early region [EBER]-) and/or LMP-1+tumor cells were identified in only 3 cases of classical Hodgkin lymphomas. Our findings suggested EBV-associated lymphoma comprised only a small fraction of all non-Hodgkin's lymphomas in the general SRD patient population.