A single arm Phase I/II trial on the combination of carboplatin, nab-paclitaxel and avastin as first-line treatment for advanced non-squamous non-small cell lung cancer (TORG1424/OLCSG1402: CARNAVAL).

BACKGROUND: Bevacizumab with platinum doublet therapy including paclitaxel + carboplatin improves the survival of patients with non-squamous non-small cell lung cancer. However, in a previous trial (CA031), paclitaxel + carboplatin led to Grade > 3 neutropenia in a Japanese population. Nanoparticle albumin-bound paclitaxel exhibits an improved toxicity profile. We evaluated the safety, dosage and response rate of the nanoparticle albumin-bound paclitaxel + carboplatin + bevacizumab combination in a Japanese population. METHODS: Chemotherapy-naive patients with advanced non-squamous non-small cell lung cancer were included. The dosage schedule was established in the Phase I trial as follows: 4-6 cycles of carboplatin (area under the concentration-time curve = 6 on Day 1) + nanoparticle albumin-bound paclitaxel (100 mg/m2 on Days 1, 8 and 15) + bevacizumab (15 mg/kg on Day 1), followed by maintenance therapy (nanoparticle albumin-bound paclitaxel + bevacizumab). The response rate and presence of adverse effects were evaluated in the Phase II trial. RESULTS: The overall response rate was 56.5% (90% confidence interval: 44.5-68.5), and 93% of patients (43/46) showed tumor shrinkage or maintained a stable disease course. The primary endpoint was achieved. At the median follow-up duration of 42 months, the median overall survival was 18.9 (range: 10.5-32.4) months. The most frequently observed Grade ≥ 3 adverse effects were neutropenia (72%), leukopenia (50%) and anemia (30%). CONCLUSIONS: All adverse effects were manageable and none resulted in patient death. In conclusion, the nanoparticle albumin-bound paclitaxel + carboplatin + bevacizumab combination is favorable and well tolerated in Japanese patients as first-line treatment for advanced non-squamous non-small cell lung cancer.

Biology and Development of DNA-Targeted Drugs, Focusing on Synthetic Lethality, DNA Repair, and Epigenetic Modifications for Cancer: A Review.

DNA-targeted drugs constitute a specialized category of pharmaceuticals developed for cancer treatment, directly influencing various cellular processes involving DNA. These drugs aim to enhance treatment efficacy and minimize side effects by specifically targeting molecules or pathways crucial to cancer growth. Unlike conventional chemotherapeutic drugs, recent discoveries have yielded DNA-targeted agents with improved effectiveness, and a new generation is anticipated to be even more specific and potent. The sequencing of the human genome in 2001 marked a transformative milestone, contributing significantly to the advancement of targeted therapy and precision medicine. Anticipated progress in precision medicine is closely tied to the continuous development in the exploration of synthetic lethality, DNA repair, and expression regulatory mechanisms, including epigenetic modifications. The integration of technologies like circulating tumor DNA (ctDNA) analysis further enhances our ability to elucidate crucial regulatory factors, promising a more effective era of precision medicine. The combination of genomic knowledge and technological progress has led to a surge in clinical trials focusing on precision medicine. These trials utilize biomarkers for identifying genetic alterations, molecular profiling for potential therapeutic targets, and tailored cancer treatments addressing multiple genetic changes. The evolving landscape of genomics has prompted a paradigm shift from tumor-centric to individualized, genome-directed treatments based on biomarker analysis for each patient. The current treatment strategy involves identifying target genes or pathways, exploring drugs affecting these targets, and predicting adverse events. This review highlights strategies incorporating DNA-targeted drugs, such as PARP inhibitors, SLFN11, methylguanine methyltransferase (MGMT), and ATR kinase.

Staphylococcus haemolyticus attenuates the antibacterial effect of teicoplanin via aggregates and biofilms.

OBJECTIVES: This study aimed to determine the inhibitory and bactericidal effects of teicoplanin (TEC) on TEC-susceptible Staphylococcus haemolyticus isolated from a patient with cancer in whom infection persisted despite TEC therapy. We also focused on the biofilm-forming ability of the isolate in vitro. METHODS: S. haemolyticus clinical isolate (strain 1369A) and its control strain, ATCC 29970 were cultured in Luria-Bertani (LB) broth with TEC. The inhibitory and bactericidal effects of TEC on planktonic, adherent, biofilm-dispersed, and biofilm-embedded cells of these strains were analyzed by using a biofilm formation/viability assay kit. The expression of biofilm-related genes was measured using quantitative real-time polymerase chain reaction (qRT-PCR). Biofilm formation was determined by using scanning electron microscopy (SEM). RESULTS: The clinical isolate of S. haemolyticus had enhanced ability to bacterial growth, adherence, aggregation, and biofilm formation, thus the inhibitory and bactericidal effects of TEC on planktonic, adherent, biofilm-dispersed, and biofilm-embedded cells of the isolate were attenuated. Additionally, TEC induced cell aggregation, biofilm formation, and some biofilm-related gene expression of the isolate. CONCLUSION: The clinical isolate of S. haemolyticus is resistant to TEC treatment due to cell aggregation and biofilm formation.

Plasma exosomal DOK3 reflects immunological states in lung tumor and predicts prognosis of gefitinib treatment.

To identify liquid biomarkers that predict clinical outcomes of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), we enrolled patients with EGFR gene mutation-positive non-small-cell lung cancer who were intended to receive gefitinib treatment. Using plasma samples obtained prior to gefitinib treatment from 12 enrolled patients, we performed comprehensive proteomic analysis of plasma exosomes to explore proteins correlating with tumor reduction rate (TRR), progression-free survival (PFS), or overall survival (OS). Of the detected 1769 proteins, 119, 130, or 119 proteins demonstrated a strong correlation (|r| > 0.5) with TRR, PFS, or OS, respectively. Interestingly, 34 (29%), 41 (32%), or 27 (23%) of them, respectively, were functionally involved in the regulation of the immune response. CD8α chain was consistently listed as a molecule positively correlated with PFS and OS, suggesting that the long-lasting effects of gefitinib may be due to the antitumor effects of CD8+ T cells, as well as the induction of immunogenic apoptosis of tumor cells by blocking the EGFR signaling pathway. Notably, Doking Protein 3 (DOK3), a molecule involved in B-cell receptor signaling, and some immunoglobulin and complement molecules exhibited a clear correlation with PFS longevity of gefitinib treatment. Indeed, the strong expression of DOK3 in B cells was confirmed within tertiary lymphoid structures of lung cancer tissues derived from patients with long PFS. These findings suggest that the patients with active B-cell and T-cell immunity as a host immunological feature are more likely to benefit from gefitinib therapy. Circulating exosomal DOK3 has the potential as a predictive marker of response to gefitinib indicating this immunological feature.

Diagnostic accuracy of the interferon-gamma release assay in acquired immunodeficiency syndrome patients with suspected tuberculosis infection: a meta-analysis.

PURPOSE: The diagnostic accuracy of the interferon-gamma release assay (IGRA) in immunosuppressed patients remains unclear. METHODS: A systematic review and meta-analysis were performed for diagnostic test accuracy of IGRA in tuberculosis (TB) infection among people living with HIV (PLWHIV). Summary estimates of sensitivity and specificity were calculated using both univariate and bivariate models. RESULTS: The meta-analysis included 45 of the 1,242 first-screened articles. The total number of PLWHIV was 6,525; 3,467 had TB disease, including 806 cases of LTBI and 2,661 cases of active TB. The overall diagnostic odds ratio (DOR) of IGRA in the diagnosis of TB disease was 10.0 (95% confidence interval (CI) 5.59, 25.07), with an area under the curve (AUC) of 0.729. The DOR was better for QFT (14.2 (95%CI 4.359, 46.463)) than T-SPOT (10.0 (95%CI 3.866 26.033)). The sensitivity and specificity of QFT and T-SPOT were 0.663 (95%CI 0.471, 0.813), 0.867 (95%CI 0.683 0.942), and 0.604 (95%CI 0.481, 0.715), 0.862 (95%CI 0.654, 0.954), respectively, in the bivariate model. The sensitivity of IGRA in the diagnosis of LTBI was 0.64 (95%CI 0.61, 0.66). CONCLUSION: IGRA was useful in the diagnostic of TB disease in PLWHIV, and QFT showed a better tendency of DOR than T-SPOT. IGRA showed a limited effect to rule out LTBI in PLWHIV.

Phase I/II study of erlotinib plus S-1 for patients with previously treated non-small cell lung cancer: Thoracic Oncology Research Group (TORG) 0808/0913.

Introduction In preclinical data, the combination therapy with S-1 and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) had a synergistic antitumor effect on non-small cell lung cancer (NSCLC), regardless of the EGFR mutation status. Patients and Methods Patients with previously treated NSCLC and adequate organ function regardless of EGFR mutation status were eligible for the phase I study, with wild-type EGFR were eligible for the phase II study. Treatment consisted of erlotinib 150 mg/body orally once every day and S-1 60 mg/m2, 70 mg/m2, or 80 mg/m2 (level 0, level 1, or level 2) orally on days 1-14 every three weeks. The primary endpoint for the phase I study was the determination of the recommended dose (RD), the phase II study was the overall response rate (ORR). Results A total of 7 patients with performance-status (PS) 0 or 1 were enrolled as subjects in phase I. Five of these subjects were EGFR-mutation positive. Four subjects were enrolled at S-1 dose level 1 and 3 were enrolled at S-1 dose level 2. No dose-limiting toxicities were observed in these subjects. The RD was decided as erlotinib 150 mg/body and S-1 80 mg/m2. In phase I, 5 subjects achieved partial response, and the ORR was 71.4%. A total of 10 patients with PS 0, 1, or 2 EGFR-wild type NSCLC were enrolled in phase II. In phase II, the ORR was 10.0%, and the disease control rate (DCR) was 40.0%. After the enrollment of 10 subjects, enrollment was stopped based on two treatment-related deaths. Conclusion The combination therapy of erlotinib plus S-1 was not feasible in the EGFR wild-type NSCLC at least and early stopped. Trial registration: UMIN-CTR Identifier: 000003421 (2010/03/31, phase I), 000003422 (2010/03/31, Phase II).

Phase II study of amrubicin plus erlotinib in previously treated, advanced non-small cell lung cancer with wild-type epidermal growth factor receptor (TORG1320).

Background Amrubicin (AMR) is a completely synthetic 9-aminoanthracycline and clinically active against non-small cell lung cancer (NSCLC). We conducted a phase I study of AMR and erlotinib (ERL) combination therapy in previously treated patients with advanced NSCLC and have already reported the safety and effectiveness. Methods We conducted a multi-center, single-arm phase II trial to evaluate the efficacy of AMR and ERL combination therapy in patients with previously treated, advanced NSCLC harboring wild-type EGFR, PS 0-1 and < 75 years of age. Patients were treated at 3-week intervals with AMR plus ERL. The primary endpoint was the PFS, and the secondary endpoints were the response rate (RR), disease control rate (DCR), overall survival (OS) and toxicity. The trough ERL concentration (Ctrough) was measured as an exploratory study to analyze the relationship between the efficacy/safety and pharmacokinetics. Results From June 2013 to July 2016, 25 patients were enrolled in this trial. The PFS according to the central test was 3.6 months (95% confidence interval 2.1-5.1). The RR and DCR were 24.0% and 64.0%, respectively. We had no treatment-related deaths in this study. Conclusions The PFS of AMR and ERL combination therapy was superior to that of AMR monotherapy in the historical setting, but the primary endpoint was not met in this trial. In our study, the pharmacokinetic analysis showed that the Ctrough of ERL was elevated with combination therapy. This combination therapy might be a viable treatment for previously treated NSCLC patients without a driver oncogene mutation. Clinical trial information UMIN 000010582.

[Strategy with Immune Checkpoint Inhibitors for ES‒SCLC].

As a treatment strategy for various carcinoma, immune checkpoint inhibitors(ICIs)can prolong overall survival with ICI monotherapy, ICIs combination therapy, or chemotherapy and ICI combination therapy. It has been validated in clinical trials and is recognized as a key drug in the treatment of cancer. In two large phase Ⅲ trials(IMpower133 and CASPIAN), the strategy of anti PD‒L1 antibody, such as atezolizumab and durvalumab, with chemotherapy was prolonged overall survival compared with the chemotherapy alone in extensive stage small cell lung cancer. Although attention should be paid to immune‒related adverse events, treatment discontinuation rates for adverse events in both trials were considered to be comparable to those in the chemotherapy alone group, indicating that treatment was tolerated. Currently, carboplatin plus etoposide plus atezolizumab combination therapy or platinum agent(carboplatin or cisplatin)plus etoposide plus durvalumab combination therapy is recommended grade 1A in the Guidelines for Diagnosis and Treatment of the Lung Cancer/ Malignant Pleural Mesothelioma/Thymic Tumors 2020 as the first‒line treatment for extensive stage small cell lung cancer in Japan. This article presents an overview of each clinical trials and clinical questions.

aCGH Analysis of Predictive Biomarkers for Response to Bevacizumab plus Oxaliplatin- or Irinotecan-Based Chemotherapy in Patients with Metastatic Colorectal Cancer.

BACKGROUND: The randomized phase III study (WJOG4407G) showed equivalent efficacy between FOLFOX and FOLFIRI in combination with bevacizumab as the first-line treatment for metastatic colorectal cancer (mCRC). We studied whole genome copy number profiles using array-based comparative genomic hybridization (aCGH) analysis of tumor tissue samples obtained in this study. The aim of this study was to identify gene copy number alterations that could aid in selecting either FOLFOX or FOLFIRI in combination with bevacizumab for patients with mCRC. MATERIALS AND METHODS: DNA was purified from 154 pretreatment formalin-fixed paraffin-embedded tissue samples (75 from the FOLFOX arm and 79 from the FOLFIRI arm) of 395 patients enrolled in the WJOG4407G trial and analyzed by aCGH. Genomic regions greater than 1.2-fold were regarded as copy number gain (CNG). RESULTS: Patient characteristics between the treatment arms were well balanced except for tumor laterality (left side; 64% in FOLFOX arm and 80% in FOLFIRI arm, p = .07). FOLFIRI showed a trend toward better response rate (RR), progression-free survival (PFS) and overall survival (OS) than FOLFOX in the patients with CNG of chromosome 8q24.1 (Fisher's exact test, p = .134 for RR; interaction test, p = .102 for PFS and p = .003 for OS) and 8q24.2 (Fisher's exact test, p = .179 for RR; interaction test, p = .144 for PFS and p = .002 for OS). CONCLUSION: Chromosome 8q24.1-q24.2 may contain genes that could potentially serve as predictive markers for selecting either FOLFOX or FOLFIRI in combination with bevacizumab for treatment of patients with mCRC. IMPLICATIONS FOR PRACTICE: Bevacizumab has been used as a standard first-line treatment for patients with metastatic colorectal cancer (mCRC) in combination with either oxaliplatin-based or irinotecan-based chemotherapy. Until now, there has been no predictive marker to choose between the two combination chemotherapies. This array-based comparative genomic hybridization analysis revealed that the difference in therapeutic effect between the two combination chemotherapies is prominent in patients with mCRC with gene copy number gain in chromosome 8p24.1-p24.2. Such patients showed more favorable response and survival when treated with irinotecan-based combination chemotherapy. Overlapping genes commonly found in this region may be predictive biomarkers of the efficacy of the combination chemotherapy with bevacizumab.

Risk factors associated with chemotherapy-induced nausea and vomiting in the triplet antiemetic regimen including palonosetron or granisetron for cisplatin-based chemotherapy: analysis of a randomized, double-blind controlled trial.

PURPOSE: The triplet antiemetic regimen is recommended for cisplatin-based highly emetogenic chemotherapy, in the current guidelines for antiemetic prophylaxis. Although risk factors related to chemotherapy-induced nausea and vomiting (CINV) have been identified by several prior studies, there are only few studies evaluating risk factors associated with the prophylactic triplet antiemetic therapy, particularly in palonosetron use. The present study aimed to reveal the risk factors related to CINV development in patients receiving cisplatin and to compare CINV risk factors between palonosetron and granisetron use. METHODS: In total, 825 patients in a phase III trial receiving palonosetron with graniestron were evaluated. Multivariate logistic regression models were used to predict risk factors associated with CINV development. Additionally, risk factors associated with CINV development were separately evaluated in each treatment group. RESULTS: Multivariate analysis of the entire study group revealed that sex, age, cisplatin dose, and granisetron use were significant and independent factors affecting CINV development in the overall phase. Similarly, sex and age were risk factors for CINV in both treatment groups. Kaplan-Meier curves classified by each treatment group showed no significant difference between the groups among patients without any risk factors for CINV (P = 0.353). Conversely, complete response rates for patients with at least one risk factor were higher in patients receiving palonosetron (P = 0.049). CONCLUSIONS: This analysis revealed the importance of previously reported CINV risk factors when using triplet antiemetics. Palonosetron might be preferred for patients with at least one risk factor.

Alteration of circulating type 2 follicular helper T cells and regulatory B cells underlies the comorbid association of allergic rhinitis with bronchial asthma.

Allergic rhinitis (AR), the most common allergic disorder of the airway, is often accompanied by bronchial asthma. However, little is known about the mechanism by which AR advances to AR comorbid with bronchial asthma (AR+Asthma). To determine the pathophysiologic features of AR and AR+Asthma, we examined subsets of follicular helper T (Tfh) cells and regulatory B (Breg) cells in peripheral blood from AR and AR+Asthma patients. The results showed polarization of Tfh2 cells within Tfh cell subsets in both AR and AR+Asthma cases. Interestingly, the %Breg cells in total B cells were decreased in AR cases and, more extensively, in AR+Asthma cases. Moreover, we found significant correlations of fractional exhaled nitric oxide and blood eosinophil levels with the index %Tfh2 cells per %Breg cells. Our findings indicate that relative decrease in Breg cells under the condition of Tfh2 cell skewing is a putative exaggerating factor of AR to bronchial asthma.

Feasibility study of docetaxel plus bevacizumab as first line therapy for elderly patients with advanced non-small-cell lung cancer: Thoracic Oncology Research Group (TORG) 1014.

BACKGROUND: Docetaxel monotherapy is one of the standard treatments for non-small-cell lung cancer in elderly patients. The addition of bevacizumab to docetaxel seems promising; however, the feasibility of this combination has not been investigated in such patients. METHODS: Patients with advanced non-squamous non-small-cell lung cancer aged 70 years or older who had not previously received cytotoxic chemotherapy were enrolled. Patients in the Level 0 cohort received docetaxel 60 mg/m(2) and bevacizumab 15 mg/kg, whereas those in the Level-1 cohort received docetaxel 50 mg/m(2) and bevacizumab 15 mg/kg. Chemotherapy was repeated 3 weekly for six cycles. The primary endpoint was toxicity and the secondary endpoints were response rate, progression-free survival, overall survival, and proportion of patients who underwent three or more cycles of chemotherapy. RESULTS: Twenty-one patients were enrolled from December 2010 to September 2012 at six institutes. Of the nine patients enrolled in Level 0, two experienced dose-limiting toxicity (febrile neutropenia and prolonged Grade 4 neutropenia in one patient, and Grade 3 infection in another patient) during the first cycle. Enrollment to the Level 0 cohort was terminated because two patients developed Grade 4 sepsis during later cycles. The remaining 12 patients were enrolled in the Level-1 cohort, in which two dose-limiting toxicities (prolonged Grade 4 neutropenia and Grade 3 increased aminotransferase level) were observed. No patient in the Level-1 cohort experienced Grade 4 nonhematologic toxicity. Grade 4 neutropenia occurred in 89 % of Level 0 patients and 50 % of Level-1 patients. The proportion of patients who experienced Grade 3/4 infection, febrile neutropenia or sepsis was 44 % in the Level 0 cohort, and 8 % in the Level-1 cohort. The overall response rate to chemotherapy and progression-free survival were 29 % (95 % CI, 11-52 %) and 5.9 months (95 % CI, 3.6-9.1 months), respectively. Efficacy outcomes did not differ significantly between the cohorts. CONCLUSIONS: Toxicities were tolerable in level-1 cohort. The recommended dose of combination chemotherapy with docetaxel and bevacizumab for elderly patients was determined as 50 mg/m(2) of docetaxel and 15 mg/kg of bevacizumab and toxicities were tolerable. Further studies are warranted. TRIAL REGISTRATION: UMIN Clinical Trial Registry; UMIN000004240 .

Leukotriene E4 induces MUC5AC release from human airway epithelial NCI-H292 cells.

BACKGROUND: Hypersecretion of mucin in the airway epithelium is an important feature of allergic airway diseases. Of the 3 cysteinyl leukotrienes (CysLTs; LTC4 LTD4 and LTE4), only LTE4 is sufficiently stable to be detectable in extracellular fluids. However, LTE4 has received little attention because it binds poorly to the CysLT1 and CysLT2 receptors; therefore, little is known about the effects of LTE4 on mucous secretion. Recently, studies have focused on the P2Y12 receptor as a potential receptor for LTE4, because this receptor is required for LTE4-mediated pulmonary inflammation. In our previous study, we confirmed the expression of P2Y12 receptor in human airway epithelial cells. To clarify the roles of LTE4 in airway epithelial cells, we investigated mucus secretion by LTE4 in vitro. METHODS: Confluent NCI-H292 cells were stimulated with LTE4 (0.01-1 µM) for 24 h. The release and production of MUC5AC protein, a gel-forming mucin, were evaluated with an enzyme-linked immunosorbent assay. RESULTS: Western blot analysis revealed that NCI-H292 cells expressed P2Y12 receptor protein. LTE4 significantly induced the release of MUC5AC mucin in a dose-dependent manner. Th2 cytokines such as IL-4 (10 ng/mL) and IL-13 (10 ng/mL) accelerated the LTE4-induced release of MUC5AC protein. MRS2935, a P2Y12 receptor antagonist, partially inhibited the LTE4-induced release of MUC5AC protein in the airway. In contrast, MK571, a CysLT1 receptor antagonist, did not affect the release of MUC5AC protein elicited by LTE4. CONCLUSIONS: These results suggest that LTE4 may play some important roles in allergic mucus secretion partially via activation of P2Y12 receptor.

Evaluation of submandibular versus labial salivary gland fibrosis in IgG4-related disease.

The newly comprehensive diagnostic criteria in 2011 emphasize the importance of IgG4-positive plasmacyte infiltration along with storiform or swirling fibrosis and obliterative phlebitis in diagnosing IgG4-related disease(RD). Although labial salivary gland (LSG) biopsy is a minimally invasive and convenient procedure for obtaining tissues, LSG fibrosis is thought to be inconspicuous or absent in IgG4-RD cases. In this study we evaluated 15 patients with IgG4-RD, in whom both submandibular gland (SMG) and LSG biopsies were performed at the same time. Histological evaluation revealed fibrosis in all the SMG specimens but in only one LSG specimen (6.7%). The diagnosis of IgG4-RD is primarily based on its morphological appearance on biopsy. The results of this study demonstrated that although more invasive than LSG biopsy, SMG biopsy is recommended for accurate diagnosis of IgG4-related MD and to exclude malignant diseases.

The clinical characteristics of patients with IgG4-related disease with infiltration of the labial salivary gland by IgG4-positive cells.

OBJECTIVES: Mikulicz's disease (MD) is an immunoglobulin (Ig) G4-related disease with systemic symptoms. Submandibular gland (SMG) biopsy is recommended for patients with possible IgG4-related MD for accurate differential diagnosis; however, it is difficult for certain patients to undergo this procedure. In contrast, labial salivary gland (LSG) biopsy is more convenient. Here we present an analysis of patients with IgG4-related MD whose LSG specimens were infiltrated with abundant IgG4-positive plasma cells. METHODS: Sixteen patients diagnosed with IgG4-related MD underwent simultaneous SMG and LSG biopsies. We evaluated patients' serological and (18)F-fluoro-2-deoxyglucose-positron emission tomography/computed tomography ((18)F-FDG-PET/CT) and grouped them as LSG+ (LSG specimens with > 40% IgG4-positive plasma cells/IgG-positive plasma cells, 11 patients) or LSG- (LSG specimens with < 40% IgG4-positive plasma cells/IgG-positive plasma cells, 6 patients). RESULTS: There were not significant differences in serum IgG and IgG4 levels between the two groups; however, serum concentrations of soluble interleuikin-2 receptor (sIL-2R) were significantly higher in the LSG+ group. All patients with increased (18)F-FDG uptake in their parotid glands were a part of the LSG+ group. CONCLUSIONS: When a SMG biopsy is not possible, the serum concentration of sIL-2R and (18)F-FDG-PET/CT findings may predict whether LSG biopsy will facilitate the diagnosis of IgG4-related MD.

A study of infraorbital nerve swelling associated with immunoglobulin G4 Mikulicz's disease.

OBJECTIVES: Recent studies revealed that Mikulicz's disease (MD) should be considered as an immunoglobulin (Ig) G4-related disease with aspects of systemic disorders involving the orbit. This study aimed to analyze the relationship between Immunoglobulin G4 (IgG4)-related MD and infraorbital nerve thickness. METHODS: We measured infraorbital nerve thickness in 68 patients diagnosed as IgG4-related MD at our hospital and performed computed tomography scans of the head and neck region before treatment and compared these scans with those of the control group. RESULTS: The mean infraorbital nerve diameter (± standard deviation) was 3.2 ± 1.2 mm in patients with IgG4-related MD, and 2.6 ± 0.3 mm in the control group. Infraorbital nerves were significantly thicker in patients with IgG4-related MD. Nerve swelling was found in 20 of 68 patients (29.4%) with a cutoff value of 3.3 mm because this value was obtained from diameter of nerves in the control group + 2 standard deviation mm. No patients in the control group showed nerve swelling. In addition, we found significant correlations between infraorbital nerve swelling and serum IgG4 levels as well as the existence of multiple organ lesions. CONCLUSIONS: We found that significant infraorbital nerve swelling occurred in patients with IgG4-related MD and was thought to be a part of IgG4-related disease.

The role of cytotoxic T cells in IgG4-related dacryoadenitis and sialadenitis, the so-called Mikulicz's disease.

OBJECTIVES: Immunoglobulin (Ig) G4-related dacryoadenitis and sialadenitis, the so-called Mikulicz's disease (MD), is a chronic inflammatory disease. However, little is known about its pathogenesis and pathological condition. In the present study, we used immunohistological techniques to compare the roles of cytotoxic T lymphocytes (CTLs) in MD and primary Sjogren's syndrome (SS). We examined the state of CTLs [cytotoxic granule-positive rate and programmed death-1 (PD-1) expression rate] in the salivary glands. METHODS: The study samples comprised 12 submaxillary glands from untreated MD patients and 12 labial glands from SS patients. We performed immunofluorescence and multicolor immunofluorescence to stain CD8, perforin (PRF), granzyme B (GZMB), and PD-1. We measured the total number of CTLs as well as the PRF(+)CTLs, GZMB(+)CTLs, and PD-1(+)CTLs. RESULTS: We found that the degree of infiltration of CTLs was equal in MD and SS, but the rate of CTLs with cytotoxic granules, especially PRF, in MD was less than in SS. In addition, the frequency of PD-1(+)CTLs in MD was higher than that in SS. CONCLUSIONS: Cytotoxic granule-positive CTLs were in the minority in D salivary glands, and this regulation might relate to PD-1 signals like the state of exhaustion and anergy.

[A relationship between birch pollen counts and meteorological factors in Sapporo].

Occurrence of airborne pollen in Sapporo has been studied for 19 years during the period between 1995 and 2013. There are wide year-to-year variations in the quantities of birch pollens. A simple linear regression with the least squares method was used for studying correlations between the annual quantities of birch pollens and the meteorological factors. A significant positive correlation was found between the hours of sunlight in June of the preceding year and the annual birch pollen concentrations with the correlation coefficient, R = 0.667. Also, we found the significant positive correlation between the hours of sunlight in March and the annual birch pollen concentrations with the correlation coefficient, R = 0.684. These results suggest that the atmospheric birch pollen counts can be predicted from meteorological factors.

The value of high-risk clinicopathologic features for chemotherapy in stage I non-small cell lung cancer: a propensity score-matched study.

Background: Surgical resection is the main treatment for early-stage non-small cell lung cancer (NSCLC), but recurrence remains a concern. Adjuvant chemotherapy has been shown to have survival benefits for resected stage II and III NSCLC, but debate continues regarding its use in stage I NSCLC. High-risk features, such as tumor size and stage, are considered in deciding whether to administer adjuvant chemotherapy. Methods: The data of 666,689 patients diagnosed with lung cancer from 2004 to 2016 were collected from the Surveillance, Epidemiology, and End Results database. Ultimately, 26,160 patients diagnosed with stage I NSCLC were included in the study based on a screening procedure. Results: After matching, 4,285 patients were identified, of whom 1,440 (33.6%) received chemotherapy. High-risk clinicopathologic features, including a high histologic grade, visceral pleural invasion (VPI), the examination of an insufficient number of lymph nodes (LNs), and limited resection, were independent risk factors for a poor prognosis. Chemotherapy significantly improved lung cancer-specific survival (LCSS) and overall survival (OS) in stage I patients with VPI [LCSS: hazard ratio (HR): 0.839, 95% confidence interval (CI): 0.706-0.998, P=0.047; OS: HR: 0.711, 95% CI: 0.612-0.826, P<0.001], regardless of whether or not the patient had fewer than 11 LNs (LCSS: HR: 0.809, 95% CI: 0.664-0.986, P=0.04; OS: HR: 0.677, 95% CI: 0.570-0.803, P<0.001). Chemotherapy was only observed to improve OS for stage IB patients with a high histologic grade when combined with either or both of the following high-risk factors: the presence of VPI and fewer than 11 LNs examined. Conclusions: The presence of VPI was the dominant predictor and the examination of an insufficient number of LNs was the secondary indicator, and a high histologic grade was a potential indicator of the need to administer chemotherapy in the treatment of stage I NSCLC.

Necessity of early intervention for IgG4-related disease--delayed treatment induces fibrosis progression.

OBJECTIVE: Despite ongoing research, the clinical and histopathological natural history of immunoglobulin (Ig) G4-related disease (IgG4-RD) remains unclear and the optimal time to initiate treatment is unknown. A focus on clinical symptoms rather than image finding is recommended for therapeutic initiation in autoimmune pancreatitis, but evidence for this approach is lacking. We aimed to retrospectively analyse disease duration, efficacy of treatment with glucocorticoids and results of histopathological examination of submandibular gland specimens to clarify the necessity for early intervention in IgG4-RD. METHODS: Salivary secretions were assessed before and after treatment in 26 cases of IgG4-related Mikulicz's disease (IgG4-MD). Relationships between disease duration, amount of salivary secretion before treatment, improvement of salivary secretion and ratios of areas of residual acini, fibrosis and lymphoid follicles in the involved submandibular gland specimens were analysed. RESULTS: Salivary secretions were significantly reduced in cases with illness of >2 years (P < 0.05). An inverse correlation was seen between improved amount of salivary secretion and amount of salivary secretion before treatment (r = -0.60). Improved amount of salivary secretion was also associated with each histological factor (acini, r = 0.29; fibrosis, r = -0.23; lymphoid follicles, r = -0.31), which showed interrelationships (acini and lymphoid follicles, r = -0.23; acini and fibrosis, r = 0.42; lymphoid follicles and fibrosis, r = 0.30). CONCLUSION: Salivary secretion can be improved even in cases with lower levels of salivary secretion before treatment in IgG4-RD, but improvements in the amount of salivary secretion decrease with histological changes with delayed therapeutic intervention. These data suggest that early intervention is needed to improve outcomes in patients with IgG4-MD.