Patient survey on cancer genomic medicine in Japan under the national health insurance system.

In Japan, comprehensive genomic profiling (CGP) tests have been reimbursed under the national health care system for solid cancer patients who have finished standard treatment. More than 50,000 patients have taken the test since June 2019. We performed a nation-wide questionnaire survey between March 2021 and July 2022. Questionnaires were sent to 80 designated Cancer Genomic Medicine Hospitals. Of the 933 responses received, 370 (39.7%) were web based and 563 (60.3%) were paper based. Most patients (784, 84%) first learned about CGP tests from healthcare professionals, and 775 (83.1%) gave informed consent to their treating physician. At the time of informed consent, they were most worried about test results not leading to novel treatment (536, 57.4%). On a scale of 0-10, 702 respondents (75.2%) felt that the explanations of the test result were easy to understand (7 or higher). Ninety-one patients (9.8%) started their recommended treatment. Many patients could not receive recommended treatment because no approved drugs or clinical trials were available (102/177, 57.6%). Ninety-eight patients (10.5%) did not wish their findings to be disclosed. Overall satisfaction with the CGP test process was high, with 602 respondents (64.5%) giving a score of 7-10. The major reason for choosing 0-6 was that the CGP test result did not lead to new treatment (217/277, 78.3%). In conclusion, satisfaction with the CGP test process was high. Patients and family members need better access to information. More patients need to be treated with genomically matched therapy.

Comprehensive genomic profiling from C-CAT database unveiled over 80% presence of oncogenic drivers in anaplastic thyroid carcinoma including BRAF, RAS family, NF1, and FGFR1.

OBJECTIVE: Anaplastic thyroid carcinoma (ATC) is considered a very aggressive carcinoma and has been difficult to treat with therapeutic strategies. This study examines the landscape of genomic alteration in ATC, including the BRAF V600E mutation, and its clinical implications. DESIGN, PATIENTS AND MESUREMENT: A retrospective observational study was conducted using collected at the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) in Japan, utilizing comprehensive genomic profiling data from 102 ATC cases. Additionally, AACR-GENIE data from 267 cases were analysed for validation. Statistical methods, including the conditional Kendall tau statistic and χ2 tests, were employed for survival analysis and gene mutation comparisons. RESULTS: Among 102 ATCs, BRAF, RAS, and other driver mutations were found in 83 cases (81.2%). The prevalence of BRAF V600E mutations was as high as 60%. Co-mutation analysis identified different genomic profiles in the BRAF, RAS, and wild-type groups. Despite the diverse molecular backgrounds, no significant differences in clinical variables and overall survival were observed. The analysis considering left-side amputation suggested that RAS mutations had a poorer prognosis. In the BRAF/RAS wild-type group, FGFR1 and NF1 were identified as driver mutations, with an accumulation of copy number variations and less TERT promoter mutations. This molecular subgrouping was also supported by the AACR-GENIE data. CONCLUSIONS: Comprehensive genomic analysis of ATC in Japan revealed distinct molecular subgroups, highlighting the importance of BRAF V600E mutations, particularly V600E, as potential therapeutic targets and suggest the relevance of tailor-made therapeutic strategies based on genomic profiling.

BRAF mutations and concurrent alterations in patients with soft tissue sarcoma.

BRAF alterations, including V600E and non-V600E mutations and fusions, in soft tissue sarcoma (STS) have been identified in a limited case series. Here, we aimed to evaluate the frequency of BRAF mutations and concurrent alterations in STS to understand their therapeutic action. In this retrospective analysis, we included data from 1964 patients with advanced STS who underwent comprehensive genomic profiling tests at hospitals in Japan between June 2019 and March 2023. The prevalence of BRAF and recurrent concurrent gene alterations were also investigated. BRAF mutations were detected in 24 (1.2%) of 1964 STS patients, with a median age of 47 (range 1-69) years. BRAF V600E was detected in 11 (0.6%) of the 1964 patients with STS, BRAF non-V600E mutations in 9 (4.6%), and BRAF fusions were detected in 4 (0.2%). BRAF V600E was identified in 4 (0.2%) cases of malignant peripheral nerve sheath tumors. The most common concurrent alteration was CDKN2A (11 cases, 45.8%), and the frequency was equivalent to that of the BRAF V600E (5/11 cases, 45.5%) and non-V600E (5/9 cases, 55.6%) groups. Recurrent concurrent alterations, such as TERT promoter mutations (7 cases, 29.2%), were detected at the same frequency in the V600E and non-V600E groups. In contrast, TP53 alterations (4/9 cases, 44.4%) and mitogen-activated protein kinase (MAPK)-activating genes, including NF1, GNAQ, and GNA11 (3/9 cases, 33.3%), were identified as relatively higher in the non-V600E group than in the V600E group (each 1/11 case, 9.1%). We identified BRAF alterations at a rate of 1.2% in all patients with advanced STS. Among them, BRAF V600E and BRAF fusions account for 45.8% and 16.7%, respectively. Collectively, our findings support the clinical characteristics and therapeutic strategies for patients with BRAF-altered advanced STS.

Human resources for administrative work to carry out a comprehensive genomic profiling test in Japan.

Comprehensive genomic profiling (CGP) tests have been nationally reimbursed in Japan since June 2019 under strict restrictions, and over 46,000 patients have taken the test. Core Hospitals and Designated Hospitals host molecular tumor boards, which is more time-consuming than simply participating in them. We sent a questionnaire to government-designated Cancer Genomic Medicine Hospitals, including all 12 Core Hospitals, all 33 Designated Hospitals, and 117 of 188 Cooperative Hospitals. The questionnaire asked how much time physicians and nonphysicians spent on administrative work for cancer genomic medicine. For every CGP test, 7.6 h of administrative work was needed. Physicians spent 2.7 h/patient, while nonphysicians spent 4.9 h/patient. Time spent preparing for molecular tumor boards, called Expert Panels, was the longest, followed by time spent participating in Expert Panels. Assuming an hourly wage of ¥24,000/h for physicians and ¥2800/h for nonphysicians, mean labor cost was ¥78,071/patient. On a monthly basis, more time was spent on administrative work at Core Hospitals compared with Designated Hospitals and Cooperative Hospitals (385 vs. 166 vs. 51 h/month, respectively, p < 0.001). Consequently, labor cost per month was higher at Core Hospitals than at Designated Hospitals and Cooperative Hospitals (¥3,951,854 vs. ¥1,687,167 vs. ¥487,279/month, respectively, p < 0.001). Completing a CGP test for a cancer patient in Japan is associated with significant labor at each hospital, especially at Core Hospitals. Streamlining the exchange of information and simplifying Expert Panels will likely alleviate this burden.

Detection of multiple druggable mutations of lung cancer from cytology specimens by MINtS: An advanced medicine A trial.

Most multigene mutation tests require tissue specimens. However, cytological specimens are easily obtained in the clinical practice and provide high-quality DNA and RNA. We aimed to establish a test that utilizes cytological specimens and performed a multi-institutional study to investigate the performance of MINtS, a test based on next-generation sequencing. A standard procedure for specimen isolation was defined. The specimens were considered suitable for the test if >100 ng DNA and >50 ng RNA could be extracted from them. In total, 500 specimens from 19 institutions were investigated. MINtS detected druggable mutations in 63% (136 of 222) of adenocarcinomas. Discordant results between MINtS and the companion diagnostics were observed in 14 of 310 specimens for the EGFR gene, and 6 of 339 specimens for the ALK fusion genes. Confirmation by other companion diagnostics for the EGFR mutations or the clinical response to an ALK inhibitor all supported the results obtained by MINtS. MINtS along with the isolation procedure presented in the current study will be a platform to establish multigene mutation tests that utilize cytological specimens. UMIN000040415.

Clinical utility of Todai OncoPanel in the setting of approved comprehensive cancer genomic profiling tests in Japan.

Comprehensive cancer genome profiling (CGP) has been nationally reimbursed in Japan since June 2019. Less than 10% of the patients have been reported to undergo recommended treatment. Todai OncoPanel (TOP) is a dual DNA-RNA panel as well as a paired tumor-normal matched test. Two hundred patients underwent TOP as part of Advanced Medical Care B with approval from the Ministry of Health, Labour and Welfare between September 2018 and December 2019. Tests were carried out in patients with cancers without standard treatment or when patients had already undergone standard treatment. Data from DNA and RNA panels were analyzed in 198 and 191 patients, respectively. The percentage of patients who were given therapeutic or diagnostic recommendations was 61% (120/198). One hundred and four samples (53%) harbored gene alterations that were detected with the DNA panel and had potential treatment implications, and 14 samples (7%) had a high tumor mutational burden. Twenty-two samples (11.1%) harbored 30 fusion transcripts or MET exon 14 skipping that were detected by the RNA panel. Of those 30 transcripts, 6 had treatment implications and 4 had diagnostic implications. Thirteen patients (7%) were found to have pathogenic or likely pathogenic germline variants and genetic counseling was recommended. Overall, 12 patients (6%) received recommended treatment. In summary, patients benefited from both TOP DNA and RNA panels while following the same indication as the approved CGP tests. (UMIN000033647).

CDK12 alterations and ARID1A mutations are predictors of poor prognosis and therapeutic targets in high-grade salivary gland carcinoma: analysis of the National Genomic Profiling Database.

BACKGROUND: Due to the diversity of histopathologic types in salivary gland carcinoma, genomic analysis of large cohorts with next-generation sequencing by histologic type has not been adequately performed. METHODS: We analysed data from 93 patients with salivary duct carcinoma and 243 patients with adenoid cystic carcinoma who underwent comprehensive genomic profiling testing in the Center for Cancer Genomics and Advanced Therapeutics database, a Japanese national genome profiling database. We visualised gene mutation profiles using the OncoPrinter platform. Fisher's exact test, Kaplan-Meier analysis, log-rank test and Cox regression models were used for statistical analysis. RESULTS: In salivary duct carcinoma, a population with CDK12 and ERBB2 co-amplification was detected in 20 of 37 (54.1%) patients with ERBB2 amplification. We identified five loss-of-function variants in genes related to homologous recombination deficiency, such as BRCA2 and CDK12. Cox survival analysis showed that CDK12 and ERBB2 co-amplification is associated with overall survival (hazard ratio, 3.597; P = 0.045). In salivary duct carcinoma, NOTCH1 mutations were the most common, followed by mutations in chromatin modification genes such as KMT2D, BCOR, KDM6A, ARID1A, EP300 and CREBBP. In the multivariate Cox analysis, activating NOTCH1 mutations (hazard ratio, 3.569; P = 0.009) and ARID1A mutations (hazard ratio, 4.029; P = 0.034) were significantly associated with overall survival. CONCLUSION: CDK12 and ERBB2 co-amplification is associated with a poor prognosis in salivary duct carcinoma. Chromatin remodelling genes are deeply involved in tumour progression in adenoid cystic carcinoma. One such gene, ARID1A, was an independent prognostic factor. In salivary duct carcinoma and adenoid cystic carcinoma, there might be minor populations with mutations that could be targeted for treatment with the synthetic lethality approach.

Integrin alpha 2 is associated with tumor progression and postoperative recurrence in non-small cell lung cancer.

BACKGROUND: Integrins are transmembrane proteins that mediate cell adhesion to extracellular matrix. Whereas expression of integrin alpha 2 is associated with motility, invasiveness and cellular differentiation in various tumors, the role of integrin alpha 2 in lung cancer has not been studied in detail. The aim of this study was to determine whether and how aberrant integrin alpha 2 expression in non-small cell lung cancer leads to different outcomes. METHODS: We measured expression of integrin alpha 2 by quantitative polymerase chain reaction in 100 samples collected from non-small cell lung cancer patients who had undergone surgical resection. We assigned patients to high and low expression groups and analyzed survival. Cellular morphology, adhesion, proliferation, migration and invasion were examined in human lung cancer cell lines. RESULTS: Among 100 cases, 41 were female, with a median age of 71 years. High expression of integrin alpha 2 in non-small cell lung cancer was associated with lower recurrence-free survival (P = 0.004). Overexpression of integrin alpha 2 in cell lines had no effect on cell proliferation or invasion but resulted in increased cell size (1416 µm2 versus 470 µm2 in H522 cells, P < 0.001; 1822 µm2 versus 1029 µm2 in H661 cells, P = 0.02), adhesion (P < 0.001 in H522 and H661 cells) and migration (gap area filled was 71% versus 36% in H522 cells, P < 0.001; 57% versus 26% in H661 cells, P = 0.001). These changes were suppressed by E7820, an inhibitor of integrin alpha 2. CONCLUSIONS: Integrin alpha 2 may play a significant role in lung cancer adhesion and migration, and may lead to a higher risk of recurrence.

FGF23-related hypophosphatemia in a patient with small cell lung cancer: a case report and literature review.

Although there are a few case reports of patients with small cell lung cancer developing hypophosphatemia, detailed information on this condition is scarce. A 52-year-old patient with advanced stage small cell lung cancer developed hypophosphatemia (1.1 mg/dL) during chemotherapy. A reduced level of the tubular reabsorption of phosphate concomitant with an inappropriately elevated level of fibroblast growth factor (FGF) 23 (48.4 pg/mL) was noted, leading to the diagnosis of FGF23-related hypophosphatemia. Laboratory data also showed hypercortisolemia with an elevated ACTH level and hyponatremia with an inappropriately unsuppressed level of antidiuretic hormone (ADH). These data suggested the overproduction of FGF23 in addition to ACTH and ADH. Because the octreotide loading test did not present a suppressive effect on ACTH or FGF23 levels, the patient was treated with phosphate supplementation, active vitamin D and metyrapone, which partially improved the serum phosphate and cortisol levels. Even after two subsequent courses of chemotherapy, the small cell lung cancer progressed, and the FGF23 level was further elevated (83.7 pg/mL). Although it is very rare, FGF23-related hypophosphatemia is one of the hormonal disturbances that could be observed in patients with small cell lung cancer. This article reviews similar clinical conditions and revealed that advanced states of malignancy seemed to be associated with the development of renal wasting hypophosphatemia, especially in lung cancer and prostate cancer. Therefore, the parameters related to hypophosphatemia should be monitored in patients with advanced small cell lung cancer to prevent the development of hypophosphatemic osteomalacia.

SEM Observation of the Filter after Administration of Blinatumomab: A Possibility of Leakage during Home Administration Using a Portable Infusion Pump.

Blinatumomab (Blincyto® injection solution) is classified as a bispecific T-cell engaging (BiTE) antibody and is intended for the treatment of relapsed/refractory acute lymphoblastic leukemia. It requires continuous infusion to maintain therapeutic levels. Therefore, it is often administered at home. Monoclonal antibodies, which are administered intravenously, have the potential to leak depending on the nature of the administration devices. Therefore, we investigated device-associated causes of blinatumomab leakage. We observed no apparent changes to the filter and its materials after exposure to the injection solution and surfactant. From scanning electron microscopic images, precipitate on the surface of the filters was observed after physical stimulation of the injection solution. Therefore, physical stimulations should be avoided during the prolonged administration of blinatumomab. In conclusion, the findings of this study assist in the safe administration of antibodies using portable infusion pumps, taking into consideration the composition of drug excipients and the choice of filter type and structure.

Chronological improvement in precision oncology implementation in Japan.

In Japan, comprehensive genomic profiling (CGP) tests for refractory cancer patients have been approved since June 2019, under the requirement that all cases undergoing CGP tests are annotated by the molecular tumor board (MTB) at each government-designated hospital. To investigate improvement in precision oncology, we evaluated and compared the proportion of cases receiving matched treatments according to CGP results and those recommended to receive genetic counseling at all core hospitals between the first period (11 hospitals, June 2019 to January 2020) and second period (12 hospitals, February 2020 to January 2021). A total of 754 and 2294 cases underwent CGP tests at core hospitals in the first and second periods, respectively; 28 (3.7%) and 176 (7.7%) patients received matched treatments (p < 0.001). Additionally, 25 (3.3%) and 237 (10.3%) cases were recommended to receive genetic counseling in the first and second periods, respectively (p < 0.001). The proportion was associated with the type of CGP test: tumor-only (N = 2391) vs. tumor-normal paired (N = 657) analysis (10.0% vs. 3.5%). These results suggest that recommendations regarding available clinical trials in networked MTBs might contribute to increasing the numbers of matched treatments, and that tumor-normal paired rather than tumor-only tests can increase the efficiency of patient referrals for genetic counseling.

Expert panel consensus recommendations on the use of circulating tumor DNA assays for patients with advanced solid tumors.

Comprehensive genomic profiling is increasingly used to facilitate precision oncology based on molecular stratification. In addition to conventional tissue comprehensive genomic profiling, comprehensive genomic profiling of circulating tumor DNA has become widely utilized in cancer care owing on its advantages, including less invasiveness, rapid turnaround time, and capturing heterogeneity. However, circulating tumor DNA comprehensive genomic profiling has some limitations, mainly false negatives due to low levels of plasma circulating tumor deoxyribonucleic acid and false positives caused by clonal hematopoiesis. Nevertheless, no guidelines and recommendations fully address these issues. Here, an expert panel committee involving representatives from 12 Designated Core Hospitals for Cancer Genomic Medicine in Japan was organized to develop expert consensus recommendations for the use of circulating tumor deoxyribonucleic acid-based comprehensive genomic profiling. The aim was to generate guidelines for clinicians and allied healthcare professionals on the optimal use of the circulating tumor DNA assays in advanced solid tumors and to aid the design of future clinical trials that utilize and develop circulating tumor DNA assays to refine precision oncology. Fourteen clinical questions regarding circulating tumor deoxyribonucleic acid comprehensive genomic profiling including the timing of testing and considerations for interpreting results were established by searching and curating associated literatures, and corresponding recommendations were prepared based on the literature for each clinical question. Final consensus recommendations were developed by voting to determine the level of each recommendation by the Committee members.

Tumor mutational burden measurement using comprehensive genomic profiling assay.

BACKGROUND: Tumors with a high number of mutations in the genome, or tumor mutational burden, are presumed to be more likely to respond to immune checkpoint inhibitors. However, the optimal method to calculate tumor mutational burden using comprehensive genomic profiling assays is unknown. METHODS: Todai OncoPanel is a dual panel of a deoxyribonucleic acid panel and a ribonucleic acid panel. Todai OncoPanel deoxyribonucleic acid panel version 6 is an improvement over version 3 with increased number of targeted genes and limited targeting of intronic regions. We calculated tumor mutational burden measured by Todai OncoPanel deoxyribonucleic acid panel versions 3 and 6 using three different calculation methods: all mutations within the targeted region (target tumor mutational burden), all mutations within the coding region (all coding tumor mutational burden) and non-synonymous mutations (non-synonymous coding tumor mutational burden). We then compared them with whole exosome sequencing tumor mutational burden. In addition, 16 lung cancer patients whose samples were analyzed using Todai OncoPanel deoxyribonucleic acid version 3 were treated with anti-PD-1 or PD-L1 antibody monotherapy. RESULTS: When compared with whole exosome sequencing tumor mutational burden as the standard, tumor mutational burden measured by Todai OncoPanel deoxyribonucleic acid version 3 resulted in accuracy of 71% for all three calculation methods. In version 6, accuracy was 96% for target tumor mutational burden and all coding tumor mutational burden and 91% for non-synonymous coding tumor mutational burden. Patients with either partial response or stable disease had higher non-synonymous coding tumor mutational burden (6.7/Mb vs. 1.6/Mb, P = 0.02) and higher PD-L1 expression (40% vs. 3%, P = 0.01) and a trend toward higher target tumor mutational burden (9.2/Mb vs. 2.4/Mb, P = 0.09) compared with patients with progressive disease. CONCLUSIONS: Increase in targeted gene number and limiting intronic regions improved tumor mutational burden measurement by Todai OncoPanel when compared with whole exosome sequencing tumor mutational burden. Target tumor mutational burden may be the method of choice to measure tumor mutational burden.

The initial assessment of expert panel performance in core hospitals for cancer genomic medicine in Japan.

BACKGROUND: Since June 2019, cancer genomic profiling (CGP) tests have been reimbursed by the National Health Insurance system in Japan, with restrictions for government-designated hospitals with a molecular tumor board composed of multidisciplinary specialists, known as an expert panel (EP). The standardization of EPs is a critical challenge for implementing precision oncology in the clinical setting. METHODS: Data on consecutive cases who underwent the CGP tests at 11 core hospitals between June 2019 and January 2020 were collected. We evaluated the proportions of cases that received genomically matched treatments, including investigational new drugs (INDs) based on CGP results, and/or for which genetic counseling was recommended. Two simulated cases were annotated by each EP. The annotated reports were then centrally assessed. RESULTS: Each EP mainly discussed the applicability to genomically matched treatments and the necessity of performing genetic counseling. A pre-review of the report by key members in each EP reportedly made the EP conference more interactive and efficient, and thereby saved time. A total of 747 cases underwent CGP tests, 28 cases (3.7%) received genomically matched treatment, and 17 cases (2.3%) were referred for genetic counseling. Annotated reports for the simulated cases varied across the EPs, particularly the number of recommended IND trials, which seemed to be associated with the actual number of participants in IND trials. CONCLUSIONS: This investigation provides reference data for the application of precision oncology in a clinical setting. Further investigations on the standardization of clinical annotations are warranted.

Development of a simple compatibility inspection method using pressure in a BD PhaSeal™ system and hazardous drug vials.

BACKGROUND: Many reports support the use of closed system drug transfer devices (CSTDs) to protect against exposure to hazardous drugs during their preparation. However, leakage may occur if the CSTD fails to maintain hermeticity when fitted into the vial. Our aims were to devise a measure to prevent HD exposure and to develop a test method to verify CSTD function when a BD PhaSeal™ protector is used in HD preparation. METHODS: We selected the BD PhaSeal™ System, which is the most commonly used CSTD device in Japan. The sealability of the BD PhaSeal™ protector and vial is considered to be due to the hermeticity of the protector and the rubber stopper of the vial. We constructed a protector with a damaged sealing rim and monitored the pressure fluctuation 10 times when the BD PhaSeal™ injector was connected to the pressurized vial. RESULTS: The reduction in pressure of the protector in the group without a damaged sealing rim was 5%, while that in the group with the damaged sealing rim was 84.9%. CONCLUSION: It was suggested that leakage occurred through the gap between the protector and the rubber stopper when using a vial that was not in close contact with the sealing rim. In this study, we developed a test that can be easily used to verify the compatibility of the BD PhaSeal™ protector and a vial in the clinical setting. Thus, when new hazardous drugs are being prepared, these measures can be taken to ensure that the risk of exposure is reduced or eliminated.

Integrin α11 in non-small cell lung cancer is associated with tumor progression and postoperative recurrence.

Integrins are transmembrane proteins that mediate cell adhesion to the extracellular matrix. Integrin α11 (ITGA11) is not expressed in normal alveolar epithelial cells and is a known receptor for collagen. While integrin α11ß1 overexpression in the tumor stroma has been associated with tumor growth and metastatic potential of non-small cell lung cancer (NSCLC), little is known about the role of ITGA11 in tumor cells. Thus, we examined the RNA expression of ITGA11 by quantitative RT-PCR in 80 samples collected from NSCLC patients who had undergone surgical resection and analyzed the clinical outcomes. We found that high expression of ITGA11 was associated with lower recurrence-free survival in all NSCLC patients (P = 0.043) and in stage I NSCLC patients (P = 0.049). These results were consistent with in silico analyses of the Cancer Genome Atlas database. We also analyzed cell proliferation, migration and invasion capacity in lung cancer cell lines after overexpression of ITGA11. Overexpression of ITGA11 in lung cancer cell lines had little effect on cell proliferation but resulted in increased migration and invasion capacity. Our findings suggest that ITGA11 plays a significant role in cancer migration and invasion, leading to higher recurrence. ITGA11 expression may be a predictor of poor prognosis in patients with surgically resected NSCLC.

Early Arterial Embolization and Mortality in Mechanically Ventilated Patients With Hemoptysis: A Nationwide Retrospective Cohort Study.

OBJECTIVES: Hemoptysis, a symptom common across various respiratory diseases, can cause airway obstruction leading to a life-threatening condition. Arterial embolization has been used to control bleeding from the lower airways. However, limited studies have evaluated its effects on in-hospital mortality in patients with hemoptysis requiring mechanical ventilation. The objective of this study was to clarify whether early intervention by arterial embolization reduced mortality in mechanically ventilated patients with hemoptysis. DESIGN: Retrospective cohort study from July 2010 to March 2017. SETTING: More than 1,200 acute-care hospitals, comprising approximately 90% of all tertiary-care emergency hospitals in Japan. PATIENTS: The study cohort was patients with pulmonary diseases hospitalized for hemoptysis and mechanically ventilated within 2 days of admission. INTERVENTIONS: We compared patients who had undergone arterial embolization within 3 days of endotracheal intubation (early embolization group) with patients who did not (control group). MEASUREMENTS AND MAIN RESULTS: A total of 12,287 patients with hemoptysis requiring mechanical ventilation were analyzed. After 1:4 propensity score matching, there were 226 and 904 patients in the early embolization and control groups, respectively. The early embolization group was associated with lower 7-day and 30-day mortalities (7-d mortality: 1.3% vs 4.0%; odds ratio, 0.39; 95% CI, 0.16-0.97; p = 0.044 and 30-d mortality: 7.5% vs 16.8%; odds ratio, 0.45; 95% CI, 0.28-0.73; p = 0.001) and shorter duration of mechanical ventilation (median 6 d, interquartile range 4-13 d vs 8 d, interquartile range 4-19 d; p = 0.003) compared with the control group. CONCLUSIONS: Our results show that early intervention by arterial embolization may be effective in reducing 7-day and 30-day mortalities in patients with life-threatening hemoptysis requiring mechanical ventilation.

Genomic profiling of multiple primary cancers including synchronous lung adenocarcinoma and bilateral malignant mesotheliomas: Identification of a novel BAP1 germline variant.

We report a case with a rare combination of synchronous lung adenocarcinoma and bilateral malignant pleural mesotheliomas in a 70-year-old male without asbestos exposure. He metachronously developed peritoneal malignant mesothelioma, intrahepatic cholangiocarcinoma, urothelial carcinoma of the bladder and prostatic adenocarcinoma. Immunohistochemistry revealed complete loss of BAP1 expression in all seven lesions. Targeted next generation sequencing using Todai OncoPanel identified a novel germline variant (c.1565_1566del, p.P522Rfs*14) of BAP1. Additionally, different nonsynonymous somatic mutations of BAP1 were identified in four lesions including lung adenocarcinoma, malignant pleural and peritoneal mesotheliomas, and bladder cancer. The remaining two lesions had different somatic mutations in genes other than BAP1. Multiple BAP1-deficient cancers that developed in a single patient suggest the newly identified germline variant of BAP1 gene to be pathogenic and this case expands the clinical spectrum of BAP1-tumor predisposition syndrome. Screening for BAP1 status is highly recommended in cases with a similar combination of cancers.

Dichotomous roles of claudins as tumor promoters or suppressors: lessons from knockout mice.

Claudins are a family of integral tight junction proteins that regulate paracellular permeability in polarized epithelia. Overexpression or reduction of claudins can both promote and limit cancer progression, revealing complex dichotomous roles for claudins depending on cellular context. In contrast, recent studies demonstrating tumor formation in claudin knockout mouse models indicate a role for several claudin family members in suppressing tumor initiation. For example, intestine-specific claudin-7 knockout mice spontaneously develop atypical hyperplasia and intestinal adenomas, while claudin-18 knockout mice develop carcinomas in the lung and stomach. Claudin-4, -11, and -15 knockout mice show increased cell proliferation and/or hyperplasia in urothelium, Sertoli cells, and small intestinal crypts, respectively, possibly a precursor to cancer development. Pathways implicated in both cell proliferation and tumorigenesis include Yap/Taz and insulin-like growth factor-1 receptor (IGF-1R)/Akt pathways, among others. Consistent with the tumor suppressive role of claudins shown in mice, in humans, claudin-low breast cancer has been described as a distinct entity with a poor prognosis, and claudin-18-Rho GTPase activating protein 26 (CLDN18-ARHGAP26) fusion protein as a driver gene aberration in diffuse-type gastric cancer due to effects on RhoA. Paradoxically, claudins have also garnered interest as targets for therapy, as they are sometimes aberrantly expressed in cancer cells, which may or may not promote cancer progression. For example, a chimeric monoclonal antibody which targets cells expressing claudin-18.2 through antibody-dependent cell-mediated cytotoxicity has shown promise in multiple phase II studies. In this review, we focus on new findings supporting a tumor suppressive role for claudins during cancer initiation.

Small lung tumor biopsy samples are feasible for high quality targeted next generation sequencing.

Next-generation sequencing (NGS) has been implemented in clinical oncology to analyze multiple genes and to guide therapy. In patients with advanced lung cancer, small biopsies such as computed tomography-guided needle biopsy (CTNB), endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and transbronchial biopsy (TBB) are less invasive and are preferable to resection to make a pathological diagnosis. However, the quality of DNA/RNA and NGS from small lung tumor biopsy samples is unknown. Between April 2017 and March 2018, 107 consecutive samples were obtained from thoracic tumors or metastatic sites for targeted NGS analysis. Fifteen samples were obtained through CTNB, 11 through EBUS-TBNA, 11 through TBB and 70 through surgical resection. All samples were formalin-fixed and paraffin-embedded. DNA and RNA quality was measured using the ddCq method and the percentage of RNA fragments above 200 nucleotides (DV200), respectively. Our custommade probes were designed to capture exon sequences of 464 cancer-related genes and transcripts of 463 genes. DNA and RNA yield from the 3 biopsy methods were similar, and less than the yield obtained from resected samples. The quality of DNA and RNA was similar across all methods. Overall, 12 of 15 CTNB samples (80%), all 11 EBUS-TBNA samples, and 9 of 11 TBB samples (82%) underwent successful NGS assays from DNA. NGS analysis from RNA was successful in all 12 CTNB samples, 9 of 11 EBUS-TBNA samples (82%), and 8 of 11 TBB samples (73%). CTNB, EBUS-TBNA and TBB mostly resulted in adequate DNA and RNA quality and enabled high-quality targeted NGS analysis.