Dual inhibition of SUMOylation and MEK conquers MYC-expressing KRAS-mutant cancers by accumulating DNA damage.

BACKGROUND: KRAS mutations frequently occur in cancers, particularly pancreatic ductal adenocarcinoma, colorectal cancer, and non-small cell lung cancer. Although KRASG12C inhibitors have recently been approved, effective precision therapies have not yet been established for all KRAS-mutant cancers. Many treatments for KRAS-mutant cancers, including epigenome-targeted drugs, are currently under investigation. Small ubiquitin-like modifier (SUMO) proteins are a family of small proteins covalently attached to and detached from other proteins in cells via the processes called SUMOylation and de-SUMOylation. We assessed whether SUMOylation inhibition was effective in KRAS-mutant cancer cells. METHODS: The efficacy of the first-in-class SUMO-activating enzyme E inhibitor TAK-981 (subasumstat) was assessed in multiple human and mouse KRAS-mutated cancer cell lines. A gene expression assay using a TaqMan array was used to identify biomarkers of TAK-981 efficacy. The biological roles of SUMOylation inhibition and subsequent regulatory mechanisms were investigated using immunoblot analysis, immunofluorescence assays, and mouse models. RESULTS: We discovered that TAK-981 downregulated the expression of the currently undruggable MYC and effectively suppressed the growth of MYC-expressing KRAS-mutant cancers across different tissue types. Moreover, TAK-981-resistant cells were sensitized to SUMOylation inhibition via MYC-overexpression. TAK-981 induced proteasomal degradation of MYC by altering the balance between SUMOylation and ubiquitination and promoting the binding of MYC and Fbxw7, a key factor in the ubiquitin-proteasome system. The efficacy of TAK-981 monotherapy in immunocompetent and immunodeficient mouse models using a mouse-derived CMT167 cell line was significant but modest. Since MAPK inhibition of the KRAS downstream pathway is crucial in KRAS-mutant cancer, we expected that co-inhibition of SUMOylation and MEK might be a good option. Surprisingly, combination treatment with TAK-981 and trametinib dramatically induced apoptosis in multiple cell lines and gene-engineered mouse-derived organoids. Moreover, combination therapy resulted in long-term tumor regression in mouse models using cell lines of different tissue types. Finally, we revealed that combination therapy complementally inhibited Rad51 and BRCA1 and accumulated DNA damage. CONCLUSIONS: We found that MYC downregulation occurred via SUMOylation inhibition in KRAS-mutant cancer cells. Our findings indicate that dual inhibition of SUMOylation and MEK may be a promising treatment for MYC-expressing KRAS-mutant cancers by enhancing DNA damage accumulation.

Multi-institutional survey of cancer disparities in disabled patients in the region of northwestern Japan.

BACKGROUND: Potential disparities between cancer patients with and without disabilities remained to be validate in Japan. METHODS: We surveyed retrospective data on hospital cancer registration as well as information on disability certificates obtained through the Hokushin Ganpro database. In total, 93,545 cancer patients in 10 principal hospitals covering the region of northwestern Japan were registered with the Hokushin Ganpro database between 2010 and 2015. The database included the following data: diagnosis date, cancer type, staging, treatment, cancer detection process, and possession of a disability certificate. RESULTS: We found that 2983 patients, which accounted for 3.2% of the total patients, had disabilities. No significant differences in gender, age at diagnosis, cancer stage distribution, and cancer incidence rates were observed between the disabled and non-disabled patients. Even though the proportion of early-stage cancer among disabled patients differed only slightly from that in non-disabled patients, early-stage cancer was more frequently diagnosed in patients with disabilities during their regular hospital visits than in those without disabilities, who had more opportunity for early cancer detection during cancer screening. According to in-house data reflecting treatment period and process from a single hospital, all 16 disabled patients treated with chemotherapy completed the treatment until disease progression or end of predetermined cycles. CONCLUSION: These results indicate that deep disparities between cancer patients with and without disabilities are not apparent and that the disabled patients in the region of northwestern Japan receive appropriate hospital follow-up.

Optogenetic Activation of the Sensorimotor Cortex Reveals "Local Inhibitory and Global Excitatory" Inputs to the Basal Ganglia.

To understand how information from different cortical areas is integrated and processed through the cortico-basal ganglia pathways, we used optogenetics to systematically stimulate the sensorimotor cortex and examined basal ganglia activity. We utilized Thy1-ChR2-YFP transgenic mice, in which channelrhodopsin 2 is robustly expressed in layer V pyramidal neurons. We applied light spots to the sensorimotor cortex in a grid pattern and examined neuronal responses in the globus pallidus (GP) and entopeduncular nucleus (EPN), which are the relay and output nuclei of the basal ganglia, respectively. Light stimulation typically induced a triphasic response composed of early excitation, inhibition, and late excitation in GP/EPN neurons. Other response patterns lacking 1 or 2 of the components were also observed. The distribution of the cortical sites whose stimulation induced a triphasic response was confined, whereas stimulation of the large surrounding areas induced early and late excitation without inhibition. Our results suggest that cortical inputs to the GP/EPN are organized in a "local inhibitory and global excitatory" manner. Such organization seems to be the neuronal basis for information processing through the cortico-basal ganglia pathways, that is, releasing and terminating necessary information at an appropriate timing, while simultaneously suppressing other unnecessary information.

[Future Images of General Hospital Psychiatry].

Now, the psychiatric departments of general hospitals are unpopular workplaces for psy- chiatrists in Japan. However, I think there is a constant need for psychiatric departments of general hospitals, because the number of psychiatric departments of general hospitals with no psychiatric beds is increasing, even though the number of psychiatric departments of general hospitals with psychiatric beds is decreasing. Recently, there has been a trend of reevaluating psychiatry in medical care, such as in the medical treatments fees or in health care planning, so we cannot talk about medical care without involving psychiatry. The participation of gen- eral hospital psychiatry with a medical cooperation function is necessary for psychiatric reform from hospital-based to community-based psychiatry, as well as for the promotion of self-suffi- cient medical care in local communities based on medical cooperation. For psychiatry corre- sponding to high-grade acute medical care, the existence of general hospital psychiatry is nec- essary which has close contact with medical care and has a psychiatric acute care function, and adequate measures should be adopted in the national medical care fee and medical policies for the enhancement of general hospital psychiatry.

[The Report of the Survey to the Members of the Society about the Functional Dissociation of the Psychiatric Hospital beds].

In 2014, Japanese Ministry of Health, Labour and Welfare published the guideline on the policy of the psychiatric hospitals. We executed a survey to the members of "The Japanese Society of Psychiatry and Neurology" about the impression of this guideline, especially about "The functional differentiation of psychiatric hospital beds". Nine questions were notified on the home page of the society. 862 answers (5.3% of the members) were corrected by website from 1st to 30th of May in 2015. Attribution of the answers : doctors working at the psychiatric hospitals (70.9%), the psychiatric clinics (20%), the others (9.1%). The questions which more than 80% of the answers agreed were "The reduction of the psychiatric beds should be stepwise under the rule of check & balance in the improvement of the psychiatric community treatment", "Improve the function of the recovery phase treatment" and "The adequate treat- ment for the patients of the severe and chronic phases". The questions more than 55% of the answers agreed were "The reduction of the chronic phase beds for the improvement of the function of the acute phase beds". The questions which opposites exceeded (almost 47%) were "The assessment of the psychiatric symptoms in the patients of the chronic phase should be done by the third party" and "The facility for social skill treatment should be placed in the community". We could know the mind of the members about the revolution of the psychiatric.

Prevalence, course and factors associated with delirium in elderly patients with advanced cancer: a longitudinal observational study.

OBJECTIVE: The aim of this study was to investigate the prevalence of delirium on admission, the course of delirium during a 2-week period after admission and factors associated with delirium on admission, among elderly patients with advanced cancer. METHODS: Patients aged ≥ 65 years with incurable lung or gastroenterological cancer and the Eastern Cooperative Oncology Group Performance Status 2 or greater were continuously sampled after admission to a university hospital. Participants were evaluated for DSM-IV-TR delirium by trained psychiatrists and the delirium subtype was assessed using the Delirium Motor Subtype Scale within 4 days after admission and again 2 weeks later. In addition, we assessed associated factors with delirium on admission. RESULTS: Among 73 eligible patients, complete data were available from 61 on admission and 49 after 2 weeks. Twenty-six patients (43%) met delirium criteria on admission (hypoactive: 58%, unspecified: 35%, hyperactive: 4%, mixed: 4%). Of these, 19 (73%) remained delirious 2 weeks later. Of 35 patients without delirium on admission, 21 (60%) remained delirium-free 2 weeks later and 7(20%) became delirious. Overall, 33/61 (54%) developed delirium at some point during the study. Patients receiving steroids at admission were more likely to have delirium (odds ratio = 5.0; 95% confidence interval = 1.5-16). CONCLUSIONS: Given the high prevalence of the delirium, all patients with advanced cancer should be screened for delirium both on admission and regularly thereafter. In addition, medical staff should be aware that steroid use on admission is an additional indicator of elevated risk for delirium.

Case report: Navigating treatment pathways for cardiac intimal sarcoma with PDGFRß N666K mutation.

In the realm of rare cardiac tumors, intimal sarcoma presents a formidable challenge, often requiring innovative treatment approaches. This case report presents a unique instance of primary intimal sarcoma in the left atrium, underscoring the critical role of genomic profiling in guiding treatment. Initial genomic testing unveiled a somatic, active mutation in PDGFRß (PDGFRß N666K), accompanied by MDM2 and CDK4 amplifications. This discovery directed the treatment course toward pazopanib, a PDGFRß inhibitor, following irradiation. The patient's response was remarkable, with the therapeutic efficacy of pazopanib lasting for 16.3 months. However, the patient experienced a recurrence in the left atrium, where subsequent genomic analysis revealed the absence of the PDGFRß N666K mutation and a significant reduction in PDGFRß expression. This case report illustrates the complexities and evolving nature of cardiac intimal sarcoma treatment, emphasizing the potential of PDGFRß signaling as a strategic target and highlighting the importance of adapting treatment pathways in response to genetic shifts.

Targeting WEE1 enhances the antitumor effect of KRAS-mutated non-small cell lung cancer harboring TP53 mutations.

The clinical development of Kirsten rat sarcoma virus (KRAS)-G12C inhibitors for the treatment of KRAS-mutant lung cancer is limited by the presence of co-mutations, intrinsic resistance, and the emergence of acquired resistance. Therefore, innovative strategies for enhancing apoptosis in KRAS-mutated non-small cell lung cancer (NSCLC) are urgently needed. Through CRISPR-Cas9 knockout screening using a library of 746 crRNAs and drug screening with a custom library of 432 compounds, we discover that WEE1 kinase inhibitors are potent enhancers of apoptosis, particularly in KRAS-mutant NSCLC cells harboring TP53 mutations. Mechanistically, WEE1 inhibition promotes G2/M transition and reduces checkpoint kinase 2 (CHK2) and Rad51 expression in the DNA damage response (DDR) pathway, which is associated with apoptosis and the repair of DNA double-strand breaks, leading to mitotic catastrophe. Notably, the combined inhibition of KRAS-G12C and WEE1 consistently suppresses tumor growth. Our results suggest targeting WEE1 as a promising therapeutic strategy for KRAS-mutated NSCLC with TP53 mutations.

Complications associated with endobronchial ultrasound-guided transbronchial needle aspiration: a nationwide survey by the Japan Society for Respiratory Endoscopy.

BACKGROUND: With the recent widespread use of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), there have been occasional reports on complications associated with its use. Previous reviews on EBUS-TBNA have been limited to studies by skilled operators, thus the results may not always be applicable to recent clinical practice. To assess the safety of EBUS-TBNA for the staging and diagnosis of lung cancer in Japan, a nationwide survey on its current usage status and complications associated with its use was conducted by the Japan Society for Respiratory Endoscopy (JSRE). METHODS: A questionnaire about EBUS-TBNA performed between January 2011 and June 2012 was mailed to 520 JSRE-accredited facilities. RESULTS: Responses were obtained from 455 facilities (87.5%). During the study period, EBUS-TBNA was performed in 7,345 cases in 210 facilities (46.2%) using a convex probe ultrasound bronchoscope, for 6,836 mediastinal and hilar lesions and 275 lung parenchymal lesions. Ninety complications occurred in 32 facilities. The complication rate was 1.23% (95% confidence interval, 0.97%-1.48%), with hemorrhage being the most frequent complication (50 cases, 0.68%). Infectious complications developed in 14 cases (0.19%) (Mediastinitis, 7; pneumonia, 4; pericarditis, 1; cyst infection, 1; and sepsis, 1). Pneumothorax developed in 2 cases (0.03%), one of which required tube drainage. Regarding the outcome of the cases with complications, prolonged hospitalization was observed in 14 cases, life-threatening conditions in 4, and death in 1 (severe cerebral infarction) (mortality rate, 0.01%). Breakage of the ultrasound bronchoscope occurred in 98 cases (1.33%) in 67 facilities (31.9%), and that of the puncture needle in 15 cases (0.20%) in 8 facilities (3.8%). CONCLUSIONS: Although the complication rate associated with EBUS-TBNA was found to be low, severe complications, including infectious complications, were observed, and the incidence of device breakage was high. Since the use of EBUS-TBNA is rapidly expanding in Japan, an educational program for its safe performance should be immediately established.

Bronchoscopic practice in Japan: a survey by the Japan Society for Respiratory Endoscopy in 2010.

BACKGROUND AND OBJECTIVE: To ensure the safety of bronchoscopic practice, the Japan Society for Respiratory Endoscopy conducted a national survey to investigate the current state of procedure for this technique. METHODS: A questionnaire survey about procedures carried out during the whole of the year 2010 was mailed to 538 facilities accredited by the society. RESULTS: Responses were obtained from 511 facilities (95.0%). Rigid bronchoscopes were used in only 18.5% of the facilities, while mobile/thin bronchoscopes were used in ≥ 50%, and fluoroscopy systems were used in 99.8%. Biopsies were performed after discontinuation of therapy in patients receiving antiplatelet drugs and anticoagulants in 96.7% and 97.4% of the facilities, respectively. Atropine was administered for premedication in 67.5% of the facilities, a decrease from previous surveys. Intravenous sedation was given in 36.1% of the facilities. In 21.9% of these, the procedure was conducted in the outpatient clinic for ≥ 70% of patients. A bronchoscope was orally inserted in ≥ 70% of patients in 95.7% of the facilities. Intravenous access was maintained during the examination in 92.5% of the facilities, oxygen saturation was monitored during examinations in 99.0%, oxygen was administered in 97.6% and resuscitation equipment was available in 96%. In 98.6% of the facilities, bronchoscopes were disinfected using an automatic washing machine, with glutaraldehyde used in 42.2%. CONCLUSIONS: Japan-specific characteristics of bronchoscopic practice were identified. Whether procedures used in Japan meet international guidelines with respect to safety should be monitored continuously. In addition, a Japanese evidence-based consensus is needed.

Selected polymorphisms of base excision repair genes and pancreatic cancer risk in Japanese.

BACKGROUND: Although several reports have described a possible association between DNA repair genes and pancreatic cancer (PC) in smokers, this association has not been fully evaluated in an Asian population. We assessed the impact of genetic polymorphisms in the base excision repair (BER) pathway on PC risk among Japanese. METHODS: This case-control study compared the frequency of 5 single-nucleotide polymorphisms (SNPs) of BER genes, namely rs1052133 in OGG1, rs1799782 and rs25487 in XRCC1, rs1130409 in APE1, and rs1136410 in PARP1. SNPs were investigated using the TaqMan assay in 185 PC cases and 1465 controls. Associations of PC risk with genetic polymorphisms and gene-environment interaction were examined with an unconditional logistic regression model. Exposure to risk factors was assessed from the results of a self-administered questionnaire. We also performed haplotype-based analysis. RESULTS: We observed that the minor allele of rs25487 in XRCC1 was significantly associated with PC risk in the per-allele model (odds ratio = 1.29, CI = 1.01-1.65; trend P = 0.043). Haplotype analysis of XRCC1 also showed a statistically significant association with PC risk. No statistically significant interaction between XRCC1 polymorphisms and smoking status was seen. CONCLUSIONS: Our findings suggest that XRCC1 polymorphisms affect PC risk in Japanese.

Deaths and complications associated with respiratory endoscopy: a survey by the Japan Society for Respiratory Endoscopy in 2010.

BACKGROUND AND OBJECTIVE: In order to survey the current status of the use and complications associated with respiratory endoscopy, the Japan Society for Respiratory Endoscopy conducted a nationwide postal questionnaire survey. METHODS: The survey was mailed to all 538 facilities certified by the society. The subjects were patients who underwent respiratory endoscopy in 2010. The numbers of procedures, and associated complications and deaths were investigated according to lesion and procedure using a specific inventory. RESULTS: The inventory was completed by 483 facilities (89.8%). The total number of diagnostic flexible bronchoscopy procedures performed was 103 978, and four patients died (0.004%). The complication rate according to lesion ranged from 0.51% to 2.06%, with the highest rate being observed in patients with diffuse lesions. The complication rate according to procedure ranged from 0.17% to 1.93%, with the highest rate being observed in patients who underwent forceps biopsy. The complication rate after forceps biopsy of solitary peripheral pulmonary lesions was 1.79% (haemorrhage: 0.73%, pneumothorax: 0.63%), and that after endobronchial ultrasound-guided transbronchial needle aspiration of hilar and/or mediastinal lymph node lesions was 0.46%. Therapeutic bronchoscopy was performed in 3020 patients; one patient (0.03%) died due to haemorrhage induced by insertion of an expandable metallic stent. The complication rate according to procedure was highest for foreign body removal (2.2%). Medical pleuroscopy was performed in 1563 patients. The highest complication rate was for biopsy without electrocautery (1.86%). A total of 228 facilities (47.2%) experienced breakage of bronchoscopes and/or devices. CONCLUSIONS: Respiratory endoscopy was performed safely, but education regarding complications caused by new techniques is necessary.

Mediastinal Malignant Melanoma Markedly Shrinking in Response to Nivolumab.

Primary malignant melanoma (MM) of the mediastinum is rare, and there is a lack of consensus regarding the preferred treatment because non-cutaneous MM demonstrates an inferior response to systemic therapy. Herein, we describe the case of a 73-year-old man with MM of the anterior mediastinum with multiple liver metastases. Even though the size of lesions increased rapidly following diagnosis, nivolumab monotherapy caused remarkable tumor shrinkage. This is the first report of mediastinal MM showing a significant response to nivolumab. We, therefore, suggest that immunotherapy may be one of the treatment options for primary mediastinal MM.

Evaluation of two semi-supervised learning methods and their combination for automatic classification of bone marrow cells.

Differential bone marrow (BM) cell counting is an important test for the diagnosis of various hematological diseases. However, it is difficult to accurately classify BM cells due to non-uniformity and the lack of reproducibility of differential counting. Therefore, automatic classification systems have been developed in which deep learning is used. These systems requires large and accurately labeled datasets for training. To overcome this, we used semi-supervised learning (SSL), in which learning proceeds while labeling. We used three methods: self-training (ST), active learning (AL), and a combination of these methods, and attempted to automatically classify 16 types of BM cell images. ST involves data verification, as in AL, before adding them to the training dataset (confirmed self-training: CST). After 25 rounds of CST, AL, and CST + AL, the initial number of training data increased from 425 to 40,518; 3682; and 47,843, respectively. Accuracies for the test data of 50 images for each cell type were 0.944, 0.941, and 0.976, respectively. Data added with CST or AL showed some imbalances between classes, while CST + AL exhibited fewer imbalances. We suggest that CST + AL, when combined with two SSL methods, is efficient in increasing training data for the development of automatic BM cells classification systems.

ABO blood group alleles and the risk of pancreatic cancer in a Japanese population.

Several studies have investigated a possible association between the ABO blood group and the risk of pancreatic cancer (PC), but this association has not been fully evaluated in Asian populations. The present study aimed to assess the impact of genotype-derived ABO blood types, particularly ABO alleles, on the risk of PC in a Japanese population. We conducted a case-control study using 185 PC and 1465 control patients who visited Aichi Cancer Center in Nagoya, Japan. Using rs8176719 as a marker for the O allele, and rs8176746 and rs8176747 for the B allele, all participants' two ABO alleles were inferred. The impact of ABO blood type on PC risk was examined by multivariate analysis, with adjustment for potential confounders to estimate odds ratios (OR) and 95% confidence intervals (CI). An increased risk of PC was observed with the addition of any non-O allele (trend P = 0.012). Compared with subjects with the OO genotype, those with AO and BB genotypes had significantly increased OR of 1.67 (CI, 1.08-2.57) and 3.28 (CI, 1.38-7.80), respectively. Consistent with earlier reports showing a higher risk of PC for individuals with the non-O blood type, the previously reported protective allele (T) for rs505922 was found to be strongly correlated (r(2) = 0.96) with the O allele. In conclusion, this case-control study showed a statistically significant association between ABO blood group and PC risk in a Japanese population. Further studies are necessary to define the mechanisms by which the ABO gene or closely linked genetic variants influence PC risk.

Mycobacterium shinjukuense sp. nov., a slowly growing, non-chromogenic species isolated from human clinical specimens.

Seven isolates of a slowly growing, non-chromogenic Mycobacterium species were obtained from sputum and bronchial lavage fluid samples from elderly patients in different regions of Japan. These isolates were distinguished from related non-tuberculous species by colony morphology, positive results for Tween hydrolysis, catalase at 68 °C, nitrate reductase and pyrazinamidase and negative results for semi-quantitative catalase, urease and arylsulfatase. The mycolic acid pattern obtained by HPLC revealed a single cluster of late-eluting mycolic acids similar to but different from those of Mycobacterium malmoense ATCC 29571(T). The 16S rRNA gene, 16S-23S internal transcribed spacer (ITS), rpoB and hsp65 sequences were unique in comparison with those of other mycobacteria. Comparison of 16S rRNA gene sequences showed that the isolates were most closely related to Mycobacterium tuberculosis H37Rv(T) (21 base differences in 1508 bp; 98.6 % 16S rRNA gene sequence similarity). A representative strain, GTC 2738(T), showed 91.9 % rpoB sequence similarity with Mycobacterium marinum strain M, 95 % hsp65 sequence similarity with Mycobacterium kansasii CIP 104589(T) and 81.1 % 16S-23S ITS sequence similarity with Mycobacterium gordonae ATCC 14470(T). Phylogenetic analysis of concatenated sequences of the 16S rRNA, rpoB and hsp65 genes showed that strain GTC 2738(T) was located on a distinct clade adjacent to M. tuberculosis, M. ulcerans and M. marinum, with bootstrap values of 81 %. DNA-DNA hybridization demonstrated less than 70 % reassociation with type strains of genetically related species and supported the novel species status of the isolates. On the basis of this evidence, a novel species with the name Mycobacterium shinjukuense sp. nov. is proposed. The type strain, isolated from a sputum sample, is strain GTC 2738(T)( = JCM 14233(T) = CCUG 53584(T)).

Comparison of QuantiFERON-TB Gold and the tuberculin skin test for detecting previous tuberculosis infection evaluated by chest CT findings in Japanese rheumatoid arthritis patients.

The aim of the study was to compare the usefulness of the QuantiFERON-TB Gold (QFT-2G) with that of the tuberculin skin test (TST) for detecting previous infection of tuberculosis (TB) in Japanese rheumatoid arthritis (RA) patients. Before receiving biologic therapy, 97 RA patients were divided into two groups based on their chest computed tomography (CT) findings: the TB past infection group (n = 48), with old inflammatory changes due to prior pulmonary TB; and the non-TB infection group (n = 49), without such findings. The QFT-2G was not affected by methotrexate or prednisolone. Indeterminate results with a positive control had a low incidence (5.2%). A positive QFT-2G for the TB past infection group at cutoffs of 0.35 and 0.1 IU/ml (intermediate range) was seen in 5.8% and 20.8%, respectively. A TST >20 mm was significantly higher in the non-TB infection group (31%) than in the TB past infection group (13%). The correlation between the QFT-2G and TST was poor among all patients. Disagreement between these tests in the non-TB infection group was caused by the false-positive TST induced by previous Bacillus Calmette-Guérin (BCG) vaccination. Only 12 (12.4%) of 97 patients had a positive QFT-2G (≥0.1 IU/ml) and a negative TST (<20 mm), but in this subgroup, a high incidence (10, 83.3%) was detected in the TB past infection group. QFT-2G may be a good alternative to the TST to evaluate previous TB infection when it is necessary to determine whether isoniazid (INH) prophylaxis is needed before biologic therapy is begun.

[The clinical application of quantiferon TB-2G: its usefulness and limitations].

UNLABELLED: QuantiFERON TB-2G (QFT) is widely used in clinical settings for the identification of tuberculosis infection because of its high level of utility. It is well known that QFT stimulates peripheral blood lymphocytes in vitro by means of M. tuberculosis-specific protein, and that infection is identified by measuring the interferon-gamma released. Interpretation of QFT results is therefore difficult in immunosuppressed subjects in whom the function of immunocompetent cells, including lymphocytes, is suppressed, making it difficult for them to produce interferon-gamma. There is a high incidence of tuberculosis among hemodialysis patients. It has been conjectured that the use of powerful immunosuppressive agents following kidney transplantation results in a high risk of tuberculosis. How QFT results change immediately following kidney transplantation is an extremely interesting question. In recent years, an increasing number of institutions have been using TNF-alpha inhibitors to treat rheumatoid arthritis patients. Is QTF useful for identifying whether patients have latent tuberculosis infection before the administration of anti-TNF antibodies? In particular, many rheumatoid arthritis patients may have been given methotrexate or glucocorticoids, which suppress the immune system, prior to the administration of TNF-alpha inhibitors, possibly making it difficult to interpret the QFT results. We must be aware of this limitation when performing QFT on immunosuppressed patients. It is also important that we understand the clinical parameters influencing QFT results (such as lymphocyte counts). The morbidity rate of tuberculosis is high among healthcare workers, particularly nurses. A number of studies have reported that QFT is useful in hospital infection control for tuberculosis, but the effectiveness of QFT for monitoring the health of healthcare workers is still not fully understood. In this symposium, we will debate how far QFT can be used and the extent of its usefulness under exceptional circumstances. (1) How do we manage kidney transplant recipients with latent tuberculosis infection?: Norihiko GOTO (Transplant Surgery, Nagoya Daini Red Cross Hospital) It is unclear whether QuantiFERON-second generation (QFT-2G) is useful for diagnostic screening and follow up of latent tuberculosis infection (LTBI) in immunosuppressed kidney transplant (KTx) recipients. The QFT-2G assay that included response to mitogen stimulation was performed before and 6 months after KTx. Non responder was 0 (0%) at baseline, 3 (3%) at 6 months. Response to mitogen stimulation was 9.7 +/- 5.3 IU/mL at baseline vs. 10.4 +/- 5.0 IU/mL at 6 months after KTx (p = 0.29). QFT-2G is a useful screening test for LTBI and active tuberculosis (TB) even during maintenance of immunosuppression of KTx. (2) QuantiFERON-TB Gold in Japanese rheumatoid arthritis patients for assessing latent tuberculosis infection prior treatment of anti-tumor necrosis factor antibody: Shogo BANNO (Division of Rheumatology and Nephrology, Department of Internal Medicine, Aichi Medical School of Medicine) To determine the positive rate of LTBI in RA patients using the QFT-2G test, we divided RA patients into two groups: with or without old TB findings by chest CT. With a cutoff level set at 0.35 IU/ml, the positive rate of QFT-2G in LTBI was detected only 5.8%, when setting cutoff at 0.1 IU/ml (lower cutoff level), 23.1% was detected in LTBI patients. The positive TST results were significantly increased in non-LTBI patients compared than in LTBI patients. The QFT-2G test was not affected by the treatment of MTX, and the incidence of indeterminate result was low. The QFT-2G was useful compared to TST before administration of TNF inhibitors in RA patients, because of superior specificity of QFT-2G. (3) Clinical parameters that influence the sensitivity of T-cell assays: Haruyuki ARIGA (National Hospital Organization Tokyo National Hospital) The detection of tuberculosis (TB) infection in compromised hosts is essential for TB control, but T cell assay might be influenced by the degree of cell-mediated immunosuppression. The relationship between immunocompetence and specific interferon (IFN)-gamma response in whole blood QuantiFERON-TB Gold (QFT) is uncertain. Immune-related clinical indicators associated with the degree of antigen-specific IFN-gamma production were analysed using a large immunologically-unselected population with obvious TB infection. The absolute number of blood lymphocyte in TB patients was significantly associated with specific IFN-gamma production in a linear regression model. Sensitivity of 2 IFN-gamma Release Assays, QFT and ELISPOT, partly depends on peripheral lymphocyte counts. At low lymphocyte count conditions, ELISPOT assay is superior to whole blood QFT for detecting tuberculosis infection. (4) QuantiFERON TB-2G among staffs in the hospitals of Nationao Hospital Organization: Susumu OGURI, Chihiro NISHIO, Kensuke SUMI, Masayoshi MINAGUCHI, Tomomasa TSUBOI, Atuo SATOU, Osamu TOKUNAGA, Takeshi MIYAMOMAE, Takuya KURASAWA (National Hospital Organization Minami-Kyoto National Hospital) PURPOSE: To investigate the infection rate of tuberculosis among staffs working in the hospitals of NHO. METHOD: Questionnaires were sent to the hospitals and the responses were analyzed. RESULT: Among the staffs working in the hospitals with tuberculosis wards, positive rate of QuantiFERON TB-2G was 6.9%, probable positive rate was 5.6%. On the other hand, among the staffs working in the hospitals without tuberculosis wards, positive rate was 4.4%, probable positive rate was 3.9%. CONCLUSION: It is necessary to monitor the infection rate among hospital staffs.

[A case of T-cell lymphoblastic lymphoma with multiple patchy shadows in both lung fields].

A 54-year-old man was admitted to our hospital because of a nonproductive cough and back pain.Chest computed tomography (CT) showed an anterior mediastinal mass, multiple patchy lesions in both lung fields and left-sided pleural effusion. CT-guided biopsy specimens from the anterior mediastinal mass and pleural effusion samples were shown to be T-cell lymphoblastic lymphoma. Treatment with JALSG-ALL202 protocol resulted in diminishing all lesions remarkably. This is a rare case of T-cell lymphoblastic lymphoma with pulmonary infiltration.

Clinical outcome of patients with inoperable pancreatic cancer treated with FOLFIRINOX or gemcitabine plus Nab­paclitaxel as a first­line therapy: A retrospective analysis.

The present study aimed to evaluate the clinical benefits of leucovorin, 5-fluorouracil, irinotecan and oxaliplatin (FOLFIRINOX) vs. gemcitabine plus Nab-paclitaxel (GnP) as a first-line therapy for patients with inoperable pancreatic cancer. For this purpose, in-house data available for 45 patients who received FOLFIRINOX or GnP as first-line treatment between 2014 and 2019 were retrospectively analyzed. In total, 21 and 24 patients received FOLFIRINOX and GnP, respectively. Although there were no significant differences in the median progression-free survival, the median overall survival was longer in the FOLFIRINOX group than in the GnP group (16.7 vs. 7.2 months). A total of 14 patients received FOLFIRINOX followed by GnP, whereas 3 patients received GnP followed by FOLFIRINOX. All patients who did not switch to second-line therapy owing to poor feasibility were included in the GnP group. The data indicated that patients receiving GnP as first-line therapy were less likely to switch to FOLFIRINOX and, consequently, had a worse prognosis.