Clinical significance of inter-assay discrepancy in PD-L1 evaluation for the efficacy of pembrolizumab in advanced NSCLC with high PD-L1 expression.

INTRODUCTION: Programmed cell death ligand-1 (PD-L1) expression is a predictive biomarker for the efficacy of anti-programmed cell death receptor-1/PD-L1 antibodies in advanced non-small cell lung cancer (NSCLC). Although several assays have been approved for evaluating PD-L1 expression status, inter-assay discordance has been observed between some assays. The clinical significance of these discrepancies is still unclear. METHODS: We retrospectively reviewed treatment-naïve NSCLC patients whose PD-L1 expression was evaluated using both 22C3 and SP142 assays. Among those, efficacy analysis was performed for patients with PD-L1 tumor proportion score (TPS) ≥ 50 % (22C3), who had received first-line pembrolizumab monotherapy. Additionally, transcriptome analysis was conducted in the available tumors with TPS ≥ 50 % to investigate the distinct immune profiles that accompany inter-assay discordance. RESULTS: In total, 611 patients were eligible. Among 198 patients with TPS ≥ 50 %, 91 (46 %) had tumor cell score ≤ 1 (SP142, i.e., inter-assay discrepancy). In the 52 patients who received first-line pembrolizumab monotherapy, treatment efficacy was significantly lower in patients with the discrepancy than that in those without (objective response rate: 18 % vs. 83 %, p < 0.001; median progression-free survival [months]: 3.2 vs. 8.3, p < 0.001). Transcriptome analysis revealed significantly more CD274 splice variants with aberrant 3'-terminal sequences in tumors with the inter-assay discrepancy than in those without. CONCLUSION: The inter-assay discrepancy in the PD-L1 status of tumor cells between the 22C3 and SP142 assays, reflecting an imbalance in the CD274 splice variants, could be a biomarker for primary resistance against pembrolizumab monotherapy in high PD-L1-expressing NSCLCs.

Adenocarcinoma originating in the anterior mediastinum diagnosed by endobronchial ultrasound-guided transbronchial cryobiopsy: a case report.

BACKGROUND: Endobronchial ultrasound-guided transbronchial cryobiopsy (EBUS-cryobiopsy) is advantageous for collecting larger specimens with minimal crushing; however, it has not been widely used for mediastinal tumors. CASE PRESENTATION: A 73-year-old woman with a history of left breast cancer underwent surgery followed by radiotherapy. Computed tomography showed a mass in the anterior mediastinum that was in extensive contact with the sternum on the ventral side and partly with the trachea on the dorsal side. Two computed tomography-guided needle biopsies (CTNBs) were performed on the mass; however, a definitive diagnosis was not made because of severe crush artifacts. Subsequently, we performed EBUS-cryobiopsy and safely obtained sufficient specimen volume with minimal crushing. The histopathological diagnosis was adenocarcinoma, with immunobiological features distinct from those of previous breast cancers. Her overall diagnosis was a rare tumor originating in the anterior mediastinum. CONCLUSIONS: EBUS-cryobiopsy can be safely performed in narrow areas surrounded by major blood vessels, and the obtained specimens may be superior to CTNBs for histopathological diagnosis.

Efficacy and safety of chemoimmunotherapy in advanced non-small cell lung cancer patients with antibiotics-induced dysbiosis: a propensity-matched real-world analysis.

PURPOSE: The gut microbiota is hypothesized as a prognostic biomarker for cancer immunotherapy. Antibiotic-induced dysbiosis negatively affects the clinical outcomes of immunotherapy. However, the effect of dysbiosis on the efficacy and safety of Chemoimmunotherapy (chemo-IOs), the frontline standard of care, in advanced non-small cell lung cancer (NSCLC) remains unknown. We aimed to compare the efficacy and safety of chemo-IOs in patients exposed to antibiotics before treatment with those of patients who were not exposed. METHODS: We retrospectively reviewed patients with advanced NSCLC treated with first-line chemo-IOs between 2018 and 2020 at the National Cancer Center Hospital. The patients were divided into two groups: those exposed to antibiotics within 30 days before induction therapy (ABx group) and those did not antibiotics (Non-ABx group). Propensity score matching was used to control for potential confounding factors. Clinical outcomes including progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAEs) were compared. RESULTS: Of 201 eligible patients, 21 were in the ABx group, and 42 were in the non-ABx group after propensity score matching. No differences in PFS or OS emerged between the two groups (ABx group vs. Non-ABx group) (PFS:7.0 months vs. 6.4 months, hazard ratio [HR] 0.89; 95% confidence interval [CI], 0.49-1.63, OS:20.4 months vs. 20.1 months, HR 0.87; 95% CI 0.44-1.71). The frequency of irAEs before propensity score matching was similar across any-grade irAEs (39.4% vs. 42.9%) or grade 3 or higher irAEs (9.1% vs. 11.3%). CONCLUSION: Antibiotic-induced dysbiosis may not affect the efficacy of chemo-IOs in patients with advanced NSCLC.

Association Between Anterior Hip Capsule Thickening and Sagittal Pelvic Alignment Among Patients With Developmental Dysplasia of the Hip.

INTRODUCTION: The pathogenesis and pathology of secondary osteoarthritis (OA) of the hip, which is mainly due to developmental dysplasia of the hip (DDH), in Japan are obscure. There are some reports on the thickening of the hip capsule, but the relationship between the thickness of the hip capsule and the pelvic alignment due to hip deformity is not well known. This research investigated whether the capsular thickness of female DDH patients was related to pelvic alignment. METHODS: This single-center cross-sectional study included female patients aged 50-79 years (n=13) who had undergone primary total hip arthroplasty (THA) due to secondary hip OA with a background of DDH. The part of the hip capsule including the iliofemoral ligament was resected and measured directly with a digital caliper. The Sharp angle, center-edge (CE) angle, sacral slope (SS), pelvic tilt (PT), pelvic incidence (PI), and lumbar lordosis angle (LLA) were measured with an X-ray image to investigate the relationship between the capsular thickness and the pelvic posture. RESULTS: Pearson's correlation coefficient showed a negative correlation between hip capsular thickness and Sharp angle (r=-0.57, p>0.05). No significant correlation was found between the thickness of the hip capsule and the sagittal X-ray parameters including SS, PT, PI, LLA, and CE angle in the coronal plane. CONCLUSION: The thickness of the hip capsule is moderately associated with the Sharp angle on the coronal plane. The results of this study suggest that the thickness of the joint capsule does not necessarily relate to the degenerative process among patients with DDH and the process can be complex to apply two-dimensional postural indices for the explanation.

Distinct Progression and Efficacy of First-Line Osimertinib Treatment According to Mutation Subtypes in Metastatic NSCLC Harboring EGFR Mutations.

Introduction: Osimertinib (OSI), a third-generation EGFR tyrosine kinase inhibitor, is the standard treatment for patients with naive EGFR-mutant NSCLC. Nevertheless, information on how the mutation subtype affects disease progression after the failure of OSI treatment is scarce. Methods: We retrospectively reviewed patients with EGFR-mutant NSCLC who received OSI as a first-line treatment between April 2015 and December 2021. Results: This study included 229 patients. The objective response rate was 71%, with intracranial and extracranial response rates of 71% and 90%, respectively. The median progression-free survival was 23.3 mo (95% confidence interval [CI]: 19.6-26.7), and the median overall survival was 33.7 mo (95% CI: 31.3-58.6). Multivariate analysis revealed that the EGFR exon 21 L858R point mutation (L858R) (hazard ratio [HR] = 1.56, 95% CI: 1.04-2.34, p = 0.0328) and liver metastasis (HR = 2.63, 95% CI: 1.53-4.49, p = 0.0004) were significant predictors of progression-free survival in OSI treatment. The concomitant disease progression involving the central nervous system metastasis was significantly more common in patients with L858R (p = 0.048), whereas concomitant disease progression involving primary lesions was significantly more common in patients with exon 19 deletion mutation (p = 0.01). In addition, the probability of disease progression over time was higher for L858R compared with that for exon 19 deletion mutation, in patients with central nervous system metastasis (log-rank test, p = 0.027). Conclusions: The mutation subtype had an impact not only on the clinical outcome of the first-line OSI treatment but also on progression patterns after OSI treatment in patients with NSCLC harboring EGFR mutations.

Comparison of the specimen quality of endobronchial ultrasound-guided intranodal forceps biopsy using standard-sized forceps versus mini forceps for lung cancer: A prospective study.

BACKGROUND AND OBJECTIVE: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a diagnostic procedure with adequate performance; however, its ability to provide specimens of sufficient quality and quantity for treatment decision-making in advanced-stage lung cancer may be limited, primarily due to blood contamination. The use of a 0.96-mm miniforceps biopsy (MFB) permits true histological sampling, but the resulting small specimens are unsuitable for the intended applications. Therefore, we introduced a 1.9-mm standard-sized forceps biopsy (SFB) and compared its utility to that of MFB. METHODS: We prospectively enrolled patients from three institutions who presented with hilar/mediastinal lymphadenopathy and suspected advanced-stage lung cancer, or those who were already diagnosed but required additional tissue specimens for biomarker analysis. Each patient underwent MFB followed by SFB three or four times through the tract created by TBNA using a 22-gauge needle on the same lymph node (LN). Two pathologists assessed the quality and size of each specimen using a virtual slide system, and diagnostic performance was compared between the MFB and SFB groups. RESULTS: Among the 60 enrolled patients, 70.0% were diagnosed with adenocarcinoma. The most frequently targeted sites were the lower paratracheal LNs, followed by the interlobar LNs. The diagnostic yields of TBNA, MFB and SFB were 91.7%, 93.3% and 96.7%, respectively. The sampling rate of high-quality specimens was significantly higher in the SFB group. Moreover, the mean specimen size for SFB was three times larger than for MFB. CONCLUSION: SFB is useful for obtaining sufficient qualitative and quantitative specimens.

The humoral and cellular immune responses following booster vaccination with SARS-CoV-2 mRNA in people living with human immunodeficiency virus.

INTRODUCTION: People living with human immunodeficiency virus (PLWH) have higher mortality rates from COVID-19 than those without HIV. Additionally, the seroconversion rate of antibodies following a second dose of SARS-CoV-2 vaccine is lower in PLWH than non-infected individuals, indicating the need for booster vaccination. Here, we evaluated the humoral and cellular immune responses to booster SARS-CoV-2 vaccination in PLWH. METHODS: The dynamics of anti-spike IgG titers and antigen-specific interferon (IFN)-γ levels to SARS-CoV-2 vaccination were assessed over a 6-month period following a third vaccination of 34 PLWH. RESULTS: Antibody titers for humoral immunity were 50 % lower at 24 weeks post-vaccination than those at 12 weeks. However, those at 24 weeks after the booster vaccination were approximately eight times higher than before. Regarding cellular immunity, IFN-γ levels at 24 weeks after the third vaccination were lower than those at 12 weeks, but nearly 90 % of participants maintained a cut-off value of ≥0.15 IU/mL. A comparison between two groups with CD4+ T lymphocytes counts of <500/µL or ≥500/µL exhibited no statistically significant differences in antibody or IFN-γ levels. However, in the group with CD4+ T lymphocyte counts of <500/µL, the rate of IFN-γ above the cut-off value at 24 weeks after the booster vaccination was lower than that of ≥500/µL. CONCLUSION: An immune response is expected in PLWH given successful antiretroviral therapy with booster SARS-CoV-2 vaccination. However, caution should be exercised for cases with low CD4+ T-lymphocyte counts. (240/250 words).

Identifying factors causing failure of nodal staging by endobronchial ultrasound-guided transbronchial needle aspiration in non-small cell lung cancer.

Background: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is recommended for nodal staging in non-small cell lung cancer (NSCLC). Although this method may rarely fail, reports on the causes are few. We therefore retrospectively investigated the factors causing failure of nodal staging by EBUS-TBNA. Methods: Consecutive patients who underwent EBUS-TBNA at National Cancer Center Hospital between January 2017 and December 2020 for systematic nodal staging in NSCLC were extracted. The nodal stages at diagnosis including EBUS-TBNA and at treatment were investigated separately, and unmatched cases were defined as failures. Factors associated with them were explored while dividing the cases into punctured and not-punctured groups. Results: Of the 264 patients, 21 (8.0%) failed the nodal staging: 10 (3.8%) in the punctured group and 11 (4.2%) in the not-punctured group. The latter was subdivided into the following three categories: (I) difficult-to-reach; (II) omission due to false-positive rapid on-site cytologic evaluation (ROSE) results; and (III) non-significant EBUS findings. The nodal staging failure rate was significantly higher in cases with driver oncogenes positive than in those negative (16.1% vs. 3.3%, P=0.026) for adenocarcinomas. Note that all cases categorized as non-significant EBUS findings involved various driver oncogenes. Conclusions: The present study demonstrated the risk of false positives with ROSE and the involvement of driver oncogenes as factors associated with nodal staging failure in NSCLC by EBUS-TBNA, in addition to limitations of the procedure itself, including sampling performance and reachability. Especially in adenocarcinoma patients with driver oncogenes, their nodal staging results should be interpreted cautiously.

Utility of needle biopsy in centrally located lung cancer for genome analysis: a retrospective cohort study.

BACKGROUND: It is essential to collect a sufficient amount of tumor tissue for successful next-generation sequencing (NGS) analysis. In this study, we investigated the clinical risk factors for avoiding re-biopsy for NGS analysis (re-genome biopsy) in cases where a sufficient amount of tumor tissue could not be collected by bronchoscopy. METHODS: We investigated the association between clinical factors and the risk of re-genome biopsy in patients who underwent transbronchial biopsy (TBB) or endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and required re-genome biopsy in cases enrolled in LC-SCRUM Asia, a prospective nationwide genome screening project in Japan. We also examined whether the frequency of re-genome biopsy decreased between the first and second halves of the enrolment period. RESULTS: Of the 572 eligible patients, 236 underwent TBB, and 134 underwent EBUS-TBNA. Twenty-four TBBs required re-genome biopsy, and multivariate analysis showed that the risk of re-genome biopsy was significantly increased in lesions where the tumor lesion was centrally located. In these cases, EBUS-TBNA should be utilized even if the lesion is a pulmonary lesion. However, it should be noted that even with EBUS-TBNA, lung field lesions are at a higher risk of re-canalization than mediastinal lymph node lesions. It was also found that even when tumor cells were detected in rapid on-site evaluation, a sufficient amount of tumor tissue was not always collected. CONCLUSIONS: For centrally located pulmonary mass lesions, EBUS-TBNA, rather than TBB, can be used to obtain tumor tissues that can be analyzed by NGS.

Importance of Bowel Habits in Predicting Inadequate Bowel Preparation: A Prospective Observational Study.

OBJECTIVES: Inadequate bowel preparation (BP) negatively affects the efficacy and quality of colonoscopy. Although constipation has already been reported as one of the most important predictors of inadequate BP, there is limited information on the relation between inadequate BP and bowel habits including constipation-related symptoms, medications, and severity of constipation. METHODS: This single-center, prospective observational study was conducted between August 2019 and May 2020. All participants answered questionnaires regarding personal bowel habits and received low-volume polyethylene glycol plus ascorbic acid for outpatient colonoscopy. Severity of constipation was evaluated by constipation scoring system. Bowel preparation cleansing was evaluated using Boston Bowel Preparation Scale (BBPS). Potential predictors of inadequate BP were analyzed using multivariate logistic regression models. RESULTS: Overall, 1054 patients were enrolled, of which, 105 (10%) had inadequate BP (total BBPS ≤ 6 or any segmental BBPS < 2). The risk of inadequate BP increased with constipation severity (P = 0.01). Multivariate analysis showed that frequent straining (> 25% of defecations) (OR 2.09, 95% CI: 1.33-3.28) and chronic use of stimulant laxatives (OR 2.57, 95% CI: 1.59-4.17) were significant predictors of inadequate BP, among personal bowel habits. CONCLUSION: Frequent straining and chronic use of stimulant laxatives were predictors of inadequate BP. An intensified preparation regimen should be considered for severely constipated patients with straining and chronic use of stimulant laxatives.

Tumor microenvironment-mediated immune profiles and efficacy of anti-PD-L1 antibody plus chemotherapy stratified by DLL3 expression in small-cell lung cancer.

BACKGROUND: Delta-like ligand 3 (DLL3) is a therapeutic target in small-cell lung cancer (SCLC). However, how DLL3 expression status affects the tumor microenvironment (TME) and clinical outcomes in SCLC remains unclear. METHODS: This retrospective study included patients with postoperative limited-stage (LS)-SCLC and extensive-stage (ES)-SCLC treated with platinum and etoposide (PE) plus anti-programmed cell death ligand 1 (PD-L1) antibody. We investigated the relationship of DLL3 expression with TME, mutation status, tumor neoantigens, and immunochemotherapy. RESULTS: In the LS-SCLC cohort (n = 59), whole-exome sequencing revealed that DLL3High cases had significantly more neoantigens (P = 0.004) and a significantly higher rate of the signature SBS4 associated with smoking (P = 0.02) than DLL3Low cases. Transcriptome analysis in the LS-SCLC cohort revealed that DLL3High cases had significantly suppressed immune-related pathways and dendritic cell (DC) function. SCLC with DLL3High had significantly lower proportions of T cells, macrophages, and DCs than those with DLL3Low. In the ES-SCLC cohort (n = 30), the progression-free survival associated with PE plus anti-PD-L1 antibody was significantly worse in DLL3High cases than in DLL3Low cases (4.7 vs. 7.4 months, P = 0.01). CONCLUSIONS: Although SCLC with DLL3High had a higher neoantigen load, these tumors were resistant to immunochemotherapy due to suppressed tumor immunity by inhibiting antigen-presenting functions.

Suitability of respiratory endoscopy for sampling malignant thoracic tumors for comprehensive genomic profiling.

Comprehensive genomic profiling (CGP) is implemented to detect actionable gene aberrations and design matched therapies. Although malignant thoracic tumors are commonly detected through respiratory endoscopy, it is questionable whether the small specimens obtained thereof are sufficient for CGP. Therefore, this study aimed to investigate the suitability of respiratory endoscopy for sampling primary and metastatic thoracic tumors for CGP. Patients whose specimens were collected through respiratory endoscopy and assessed by pathologists to determine their suitability for CGP at our institution between June 2019 and May 2022 were reviewed retrospectively. The suitability of each procedure as a sampling technique for CGP and, in the cases actually analyzed, the distribution of the detected gene aberration were assessed. In total, 122 patients were eligible for analysis; the median age was 61 (range, 29-86) years, and 71 (58.2%) patients were male. Primary intrathoracic tumors were found in 91 (74.6%) cases, including 84 (68.9%) primary lung cancers; the remaining thoracic metastases of extrathoracic origin included various types. The suitability rates of specimens obtained using conventional bronchoscopy with and without cryobiopsy, endobronchial ultrasound-guided transbronchial needle aspiration, and medical thoracoscopy were 82.8% (24/29), 70.4% (19/27), 72.9% (35/48), and 100% (18/18), respectively. Of the 96 cases judged suitable, 83 were subjected to CGP, and all but one were successfully analyzed. Finally, 47 (56.6%) patients had at least one actionable gene aberration and eight (9.6%) were treated with the corresponding targeted therapies. In conclusion, specimens obtained through respiratory endoscopy are suitable for CGP; medical thoracoscopy and cryobiopsy in conventional bronchoscopy are particularly useful.

Whole Exome Sequencing of Thymoma Patients Exhibiting Exceptional Responses to Pemetrexed Monotherapy.

BACKGROUND: Pemetrexed is used for the chemotherapy of advanced thymoma. Exceptional responses of thymoma to pemetrexed treatment are not frequently observed. The underlying genetic mechanism of the exceptional responses remains unclear. We used whole-exome sequencing to explore the specific genomic aberrations that lead to an extreme and durable response. METHODS: Whole-exome sequencing using NovaSeq6000 (150 bp paired-end sequencing) was performed on nine formalin-fixed paraffin-embedded tissues from patients with advanced thymomas treated with pemetrexed (two exceptional responders and seven typical responders). RESULTS: We identified 284 somatic single-nucleotide variants (SNVs; 272 missense, 8 missense/splice-site, 3 stop-gain, and 1 stop-gain/splice-site), 34 insertions and deletions (Indels; 33 frameshift and one splice region), and 21 copy number variations (CNVs; 15 gains and six losses). No difference in the number of SNVs variants and distribution of deleterious Indels was observed between the exceptional and typical responders. Interestingly, arm-level chromosomal CNVs (15 gains and six losses) were detected in four patients, including an exceptional responder. The highest number of arm-level CNVs was observed in an exceptional responder. CONCLUSION: Exceptional responders to pemetrexed for metastatic thymomas may be characterized by arm-level CNVs. Further, whole-genome and RNA sequencing studies should be performed.

Distinct metastatic spread and progression patterns in patients treated with crizotinib for ROS1- and ALK-rearranged non-small cell lung cancer: a single-center retrospective study.

Background: Crizotinib has been approved for C-ros oncogene 1 (ROS1)- and anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) patients. Few studies have examined the differences in crizotinib treatment outcomes between these patients and the progression sites during treatment. We investigated the metastatic spread, crizotinib efficacy, and progression patterns during crizotinib treatment in ROS1- and ALK-rearranged NSCLC patients. Methods: We retrospectively reviewed crizotinib-treated ROS1- and ALK-rearranged NSCLC patients between January 2011 and March 2021. Patient characteristics, clinical outcomes, and progression patterns during treatment were collected from medical records. The metastasis extent, crizotinib response, and progression patterns between the groups were compared. Results: We identified 26 patients with ROS1- and 42 with ALK-positive NSCLC. The baseline proportion of central nervous system (CNS) metastases did not differ between the groups (12% vs. 29%, P=0.10), but the proportion of extrathoracic metastases, including CNS metastases, was significantly higher in ALK-positive than in ROS1-positive NSCLC patients (35% vs. 71%, P=0.003). Regarding the response to crizotinib, the objective response rate (ORR), progression-free survival (PFS), or overall survival (OS) did not significantly differ between the groups (ROS1 vs. ALK, ORR: 69% vs. 69%, P=0.987; PFS: median 10.9 vs. 10.7 months, P=0.232; median OS: not reached vs. 67.7 months, P=0.495). The CNS was the most common metastasis site in both groups [ROS1 vs. ALK, 69% (11/16) vs. 46% (17/37), P=0.127], and the cumulative incidence of CNS metastasis did not differ between the groups (P=0.914). Conclusions: Crizotinib treatment outcomes, including progression patterns, were similar between ROS1- and ALK-positive NSCLC patients.

Exploratory analysis to predict pneumonitis during durvalumab consolidation therapy for patients with locally advanced non-small cell lung cancer from proteomic profiling of circulating extracellular vesicles.

BACKGROUND: Risk factors for predicting pneumonitis during durvalumab consolidation after chemoradiotherapy (CRT) in locally advanced non-small cell lung cancer (LA-NSCLC) are still lacking. Extracellular vesicles (EVs) play a crucial role in intercellular communication and are potential diagnostic tools for various diseases. METHODS: We retrospectively collected predurvalumab treatment serum samples from patients treated with durvalumab for LA-NSCLC, isolated EVs using anti-CD9 and anti-CD63 antibodies, and performed proteomic analyses. We examined EV proteins that could predict the development of symptomatic pneumonitis (SP) during durvalumab treatment. Potential EV-protein biomarkers were validated in an independent cohort. RESULTS: In the discovery cohort, 73 patients were included, 49 with asymptomatic pneumonitis (AP) and 24 with SP. Of the 5797 proteins detected in circulating EVs, 33 were significantly elevated (fold change [FC] > 1.5, p < 0.05) in the SP group, indicating enrichment of the nuclear factor kappa B (NF-κB) pathway. Patients with high levels of EV-RELA, an NF-κB subunit, had a higher incidence of SP than those with low levels of EV-RELA (53.8% vs. 13.4%, p = 0.0017). In the receiver operating characteristic analysis, EV-RELA demonstrated a higher area under the curve (AUC) than lung V20 (0.76 vs. 0.62) and was identified as an independent risk factor in the multivariate logistic regression analysis (p = 0.008, odds ratio 7.72). Moreover, high EV-RELA was also a predictor of SP in the validation cohort comprising 43 patients (AUC of 0.80). CONCLUSIONS: Circulating EV-RELA may be a predictive marker for symptomatic pneumonitis in patients with LA-NSCLC treated with durvalumab.

Concordance between cryobiopsy and forceps biopsy specimens in assessment of immunohistochemistry staining for non-small cell lung carcinoma.

Background: Cryobiopsy is recently being promoted for biopsy of tumors in the lung periphery in precision medicine for lung cancer; the obtained tissue samples have been reported to be more useful compared to those obtained using forceps, because of the larger volume and higher quality. However, the influence of freezing and thawing of tissues when performing cryobiopsy on the results of immunohistochemistry (IHC) has not been completely understood. Methods: In this study, consecutive patients who underwent diagnostic bronchoscopy with cryobiopsy for peripheral pulmonary lesions (PPLs) at our institution between June 2017 and November 2021 were reviewed retrospectively. Specimens of diagnosed cases of unresectable or recurrent non-small cell lung carcinoma (NSCLC) were selected. We compared the results of IHC assessment for programmed death-ligand 1 (PD-L1), human epidermal growth factor receptor 2 (HER2), and human epidermal growth factor receptor 3 (HER3) in cryobiopsy specimens versus conventional forceps biopsy specimens from the same site in the same procedure. Results: Twenty-four of 40 patients were male (60%). The most frequent histologic type of cancer was adenocarcinoma (n=31, 77.5%), followed by NSCLC (n=4, 10%), squamous cell carcinoma (n=3, 7.5%), and others (n=2, 5%). The concordance rates of the tumor proportion scores (TPSs) for PD-L1, IHC score for HER2 and, IHC scores for HER3 were 85%, 72.5%, and 75%, respectively; the weighted kappa were 0.835, 0.637, and 0.697, respectively. Conclusions: Freezing and thawing associated with cryobiopsy had virtually no effect on the results of IHC. We suggest that cryobiopsy specimens would therefore be ideal for precision medicine and translational research.

Diagnostic Utility and Safety of Non-Intubated Cryobiopsy Technique Using a Novel Ultrathin Cryoprobe in Addition to Conventional Biopsy Techniques for Peripheral Pulmonary Lesions.

BACKGROUND: Transbronchial cryobiopsy enables high-quality sample collection around the probe tip. Meanwhile, existing cryoprobes have less flexibility and a higher risk of bleeding. The ultrathin cryoprobe with a 1.1-mm diameter addresses these problems and allows specimens to be directly retrieved through the working channel of a thin bronchoscope. OBJECTIVE: This study evaluated the diagnostic utility and safety of non-intubated cryobiopsy using an ultrathin cryoprobe added to conventional biopsy for diagnosing peripheral pulmonary lesions (PPLs). METHODS: The data of patients who underwent conventional biopsy followed by non-intubated cryobiopsy to retrieve specimens through the thin bronchoscope's working channel for diagnosing PPLs at Osaka Metropolitan University Hospital from July 2021 to June 2022 were retrospectively collected. They were analyzed to evaluate the diagnostic utility and safety of adding non-intubated cryobiopsy to conventional biopsy for PPLs. The characteristics of PPLs that obtain additional diagnostic benefits from cryobiopsy over conventional biopsy were also investigated. RESULTS: The analysis included 113 patients. The diagnostic yields of conventional biopsy and non-intubated cryobiopsy were 70.8% and 82.3%, respectively (p = 0.009). The total diagnostic yield was 85.8%, higher than conventional biopsy alone (p < 0.001). Although one moderate bleeding occurred, no severe complications developed. The additional diagnostic benefits of non-intubated cryobiopsy over conventional biopsy were demonstrated when the radial endobronchial ultrasound (R-EBUS) showed "adjacent to" (60.3% vs. 82.8%, p = 0.017). CONCLUSIONS: Non-intubated cryobiopsy using an ultrathin cryoprobe has high diagnostic utility and safety for diagnosing PPLs, with additional diagnostic benefits over conventional biopsy depending on the R-EBUS image.

Utility of the endobronchial Watanabe spigot for intractable cancer-related pneumothorax: a retrospective observational study.

BACKGROUND: The use of endobronchial Watanabe spigots for intractable secondary pneumothorax in patients with cancer has not been adequate. This study aimed to investigate the use of endobronchial Watanabe spigots for intractable pneumothorax in patients with malignant tumors. METHODS: Consecutive patients with malignant tumors who underwent occlusion with an endobronchial Watanabe spigot for intractable pneumothorax associated with perioperative treatment or drug therapy at our institution between January 2014 and February 2022 were reviewed. RESULTS: Of the 32 cases in which an endobronchial Watanabe spigot was used, six were excluded; we thus evaluated 26 cases in which the chest tube was removed. Chest tubes were removed in 19 cases (73.1%) and could not be removed and required surgical treatment under general anesthesia in seven patients (26.9%), of which four (14.8%) underwent open-window thoracostomy. Half of the patients were treated with both an endobronchial Watanabe spigot and pleurodesis. Although thin-slice chest computed tomography revealed a fistula in 15 patients, the chest tube was removed in 11 (57.9%) patients. A significant difference was only observed in patients with a history of heavy smoking. CONCLUSIONS: The chest tube removal rate was comparable to those reported in previous studies. An endobronchial Watanabe spigot may be a useful treatment option for intractable cancer-related pneumothorax.

Clinical Characteristics and Pharmacokinetics Change of Long-Term Responders to Antiprogrammed Cell Death Protein 1 Inhibitor Among Patients With Advanced NSCLC.

Introduction: Immune checkpoint inhibitors (ICIs) induce long-term, durable responses in patients with advanced NSCLC. Nevertheless, these responses are limited to a few patients, and most responders have disease progression. The purpose of this study was to determine the differences in clinical factors and blood drug concentrations between long-term responders (LTRs) and non-LTRs. Methods: We retrospectively analyzed consecutive patients with advanced NSCLC who received antiprogrammed cell death protein 1 (PD-1) inhibitor monotherapy (nivolumab) from December 22, 2015, to May 31, 2017. Patients who obtained a clinical benefit for more than 6 months were referred to as "responders"; among these, individuals who had a durable response for more than 2 years were defined as "LTRs." Those with a clinical benefit for less than 2 years were defined as "non-LTRs." Results: A total of 212 patients received anti-PD-1 inhibitor monotherapy. The responders accounted for 35% (75 of 212) of the patients. Of these, 29 (39%) were LTRs and 46 (61%) were non-LTRs. The overall response rate and median tumor shrinkage in the LTR group were significantly higher than those in the non-LTR group (76% versus 35%, p < 0.0001, and 66% versus 16%, p < 0.001, respectively). The groups had no significant difference in PD-L1 expression and serum drug concentration at 3- and 6-month post-treatment initiation. Conclusions: Significant tumor shrinkage was associated with a long-term response to an anti-PD-1 inhibitor. Nevertheless, the PD-L1 expression level and pharmacokinetic profile of the inhibitor could not be used to predict the durable response among the responders.