Concordance of ALK fusion gene-rearrangement between immunohistochemistry and next-generation sequencing.

BACKGROUND: Although various companion diagnostic tests of ALK fusion gene-rearrangement are approved, few reports have assessed the concordance of ALK fusion gene-rearrangement in two companion diagnostic tests: next-generation sequencing (NGS) testing and immunohistochemistry (IHC). METHODS: The samples evaluated for gene alterations using NGS testing between May 2019 and November 2021 were included in this study. The inclusion criteria were as follows: samples were diagnosed with non-small cell lung cancer; the results of the NGS analysis were informative; and samples had residual specimens for IHC. We performed IHC on the residual specimens and retrospectively collected sample characteristics from medical records. RESULTS: A total of 185 samples were analyzed using NGS. Twenty-six samples were excluded because of failure to analyze gene alterations using NGS, no residual samples, and inadequate IHC. We analyzed 159 samples. The major histological type was adenocarcinoma (115 samples). The number of surgical and transbronchial lung biopsy specimens was 59 and 56, respectively. ALK fusion gene-rearrangement was detected in four samples using NGS, and five were detected using IHC. The sensitivity and specificity of IHC referred to by NGS were 75.0% and 98.7%, respectively. The concordance rate between IHC and NGS was 98.1%. ALK rearrangement was detected in two patients using IHC but not using NGS. In addition, ALK rearrangement was detected in one patient using NGS but not using IHC. CONCLUSION: Our results suggest that IHC and NGS might be complementary tests. In patients suspected of harboring ALK fusion gene-rearrangement, it should be analyzed using another diagnostic method.

The efficacy and safety of anamorelin among patients with diabetes.

BACKGROUND: Anamorelin is a selective ghrelin receptor agonist approved for cancer cachexia in Japan. Little is known about predictors of anamorelin efficacy. This study aimed to assess the effect of diabetes on the efficacy and safety of anamorelin in patients with cancer cachexia. METHODS: Medical records of patients with advanced non-small-cell lung, gastric, pancreatic, or colorectal cancer who received anamorelin between January 2021 and March 2023 were retrospectively reviewed. The diabetic (DM) group included patients with a confirmed diagnosis of type 2 diabetes mellitus, random plasma glucose of ≥ 200 mg/dL, or hemoglobin A1c of ≥ 6.5%. The maximum body weight gain and adverse events during anamorelin administration were compared between the DM and non-DM groups. Patients with a maximum body weight gain ≥ 0 kg were classified as the responders. RESULTS: Of 103 eligible patients, 31 (30.1%) were assigned to the DM group. The DM group gained less weight (median of -0.53% vs. + 3.00%, p < 0.01) and had fewer responders (45.2% vs. 81.9%, p < 0.01) than the non-DM group. The odds ratio for non-response in the DM group was 6.55 (95% confidential interval 2.37-18.06, p < 0.01), adjusted by age and performance status. The DM group had a higher cumulative incidence of hyperglycaemic adverse events (72.2% vs. 6.3%, p < 0.01) and more discontinuations due to hyperglycaemic adverse events (25.8% vs. 4.2%, p < 0.01) than the non-DM group. CONCLUSIONS: Patients with diabetes and cancer cachexia are less likely to gain weight with anamorelin despite a high risk of hyperglycaemic adverse events.

Long-term survival data of patients with limited disease small cell lung cancer: a retrospective analysis.

INTRODUCTION: In patients with limited disease small cell lung cancer (LD-SCLC) treated with concurrent chemoradiotherapy (CCRT), long-term survival data have not been fully evaluated. Moreover, the association between long-term prognosis and prognostic factors has not been sufficiently investigated. METHODS: In this retrospective study, we evaluated the efficacy of CCRT in 120 patients with LD-SCLC with a plan for curative CRT using concurrent accelerated hyperfractionated radiotherapy. RESULTS: The patients had a median age of 65.5 years, predominantly male (73%), and had clinical stage III disease (80%). The median follow-up time for overall survival (OS) was 72.2 months, median OS was 42.5 months, and the 3-year and 5-year survival rates were 52.4% and 41.8%, respectively. The median progression-free survival (PFS) was 12.5 months, and the 3-year and 5-year PFS rates were 37.6% and 33.6%, respectively. The 5-year OS rates of patients who achieved PFS at each time point were 70.9%, 83.6%, and 91.9% at 12, 24, and 36 months, respectively. The gradual increase in the 5-year OS rate following PFS extension and initial depression of the Kaplan-Meier curve showed disease progression frequently occurred in the first 2 years after initiation of CCRT. The Cox proportional hazards model showed no significant factors correlated with long-term survival through univariate and multivariate analyses. Although the prognostic factors associated with long-term prognosis in LD-SCLC were not identified, the 5-year survival rate was 41.8%, and among patients without disease progression at 2 years, the 5-year survival rate was 83.6%. CONCLUSION: These data suggested that the prognosis of patients with LD-SCLC was improving.

Increased extracellular vesicle miRNA-466 family in the bronchoalveolar lavage fluid as a precipitating factor of ARDS.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a life-threatening disease; however, its treatment has not yet been fully established. The progression of ARDS is considered to be mediated by altered intercellular communication between immune and structural cells in the lung. One of several factors involved in intercellular communication is the extracellular vesicle (EV). They act as carriers of functional content such as RNA molecules, proteins, and lipids and deliver cargo from donor to recipient cells. EVs have been reported to regulate the nucleotide-binding oligomerization like receptor 3 (NLRP3) inflammasome. This has been identified as the cellular machinery responsible for activating inflammatory processes, a key component responsible for the pathogenesis of ARDS. METHODS: Here, we provide comprehensive genetic analysis of microRNAs (miRNAs) in EVs, demonstrating increased expression of the miRNA-466 family in the bronchoalveolar lavage fluid of a mouse ARDS model. RESULTS: Transfection of bone marrow-derived macrophages (BMDMs) with miRNA-466 g and 466 m-5p resulted in increased interleukin-1 beta (IL-1ß) release after LPS and ATP treatment, which is an established in vitro model of NLRP3 inflammasome activation. Moreover, LPS-induced pro-IL-1ß expression was accelerated by miRNA-466 g and 466 m-5p in BMDMs. CONCLUSIONS: These findings imply that miRNA-466 family molecules are secreted via EVs into the airways in an ARDS model, and this exacerbates inflammation through the NLRP3 inflammasome. Our results suggest that the NLRP3 inflammasome pathway, regulated by extracellular vesicle miRNA, could act as a therapeutic target for ARDS.

Ethylene suppresses tomato (Solanum lycopersicum) fruit set through modification of gibberellin metabolism.

Fruit set in angiosperms marks the transition from flowering to fruit production and a commitment to seed dispersal. Studies with Solanum lycopersicum (tomato) fruit have shown that pollination and subsequent fertilization induce the biosynthesis of several hormones, including auxin and gibberellins (GAs), which stimulate fruit set. Circumstantial evidence suggests that the gaseous hormone ethylene may also influence fruit set, but this has yet to be substantiated with molecular or mechanistic data. Here, we examined fruit set at the biochemical and genetic levels, using hormone and inhibitor treatments, and mutants that affect auxin or ethylene signaling. The expression of system-1 ethylene biosynthetic genes and the production of ethylene decreased during pollination-dependent fruit set in wild-type tomato and during pollination-independent fruit set in the auxin hypersensitive mutant iaa9-3. Blocking ethylene perception in emasculated flowers, using either the ethylene-insensitive Sletr1-1 mutation or 1-methylcyclopropene (1-MCP), resulted in elongated parthenocarpic fruit and increased cell expansion, whereas simultaneous treatment with the GA biosynthesis inhibitor paclobutrazol (PAC) inhibited parthenocarpy. Additionally, the application of the ethylene precursor 1-aminocyclopropane-1-carboxylic acid (ACC) to pollinated ovaries reduced fruit set. Furthermore, Sletr1-1 parthenocarpic fruits did not exhibit increased auxin accumulation, but rather had elevated levels of bioactive GAs, most likely reflecting an increase in transcripts encoding the GA-biosynthetic enzyme SlGA20ox3, as well as a reduction in the levels of transcripts encoding the GA-inactivating enzymes SlGA2ox4 and SlGA2ox5. Taken together, our results suggest that ethylene plays a role in tomato fruit set by suppressing GA metabolism.

Efficacy of second-line chemotherapy in patients with pulmonary large cell neuroendocrine carcinoma.

The efficacy of second-line chemotherapy in patients with pulmonary large cell neuroendocrine carcinoma (LCNEC) is unclear. This study aimed to evaluate the efficacy of second-line chemotherapy in patients with pulmonary LCNEC. We retrospectively reviewed patients with pulmonary LCNEC or possible LCNEC (pLCNEC) who received platinum-based chemotherapy as the first-line treatment. Among these patients, we evaluated the efficacy of second-line treatment by comparing patients with small cell lung cancer (SCLC group). Of the 61 patients with LCNEC or pLCNEC (LCNEC group) who received first-line chemotherapy, 39 patients were treated with second-line chemotherapy. Among the 39 patients, 61.5% received amrubicin monotherapy. The median progression-free survival (PFS) and overall survival (OS) in the LCNEC groups were 3.3 and 8.3 months, respectively. No significant differences in the PFS (hazard ratio [HR]: 0.924, 95% confidence interval [CI] 0.647-1.320; P = 0.664) and OS (HR: 0.926; 95% CI 0.648-1.321; P = 0.670) were observed between the LCNEC and SCLC groups. In patients treated with amrubicin, the PFS (P = 0.964) and OS (P = 0.544) were not different between both the groups. Second-line chemotherapy, including amrubicin, may be considered as a treatment option for patients with pulmonary LCNEC.

Relationship between patterns of immunohistochemical conventional neuroendocrine markers and efficacy of immune check point inhibitors in patients with extensive disease small cell lung cancer.

BACKGROUND: Which patients benefit from the addition of immune checkpoint inhibitors (ICIs) to chemotherapy for small cell lung cancer (SCLC) remains unclear. There have been few reports on the efficacy of ICIs based on conventional immunohistochemical neuroendocrine (NE) markers (synaptophysin, chromogranin A, and neural cell adhesion molecule [NCAM]). In the present study, we aimed to analyze the relationship between the expression of immunohistochemical NE markers and the efficacy of ICIs in patients with extensive disease (ED)-SCLC, to assess whether conventional NE markers are predictive of ICIs. METHODS: Patients with untreated ED-SCLC who received first-line therapy at the Shizuoka Cancer Center between November 2002 and July 2021 were retrospectively reviewed. We evaluated the efficacy of first-line chemotherapy according to the expression status of each immunohistochemical NE marker in patients treated with ICI plus chemotherapy (ICI-chemo group) and with chemotherapy alone (chemo group). RESULTS: A total of 227 patients were included in the ICI-chemo and chemo groups, respectively. The progression-free survival (PFS) tended to be better in patients in the ICI-chemo group than those treated with chemotherapy alone in patients with NE marker-positive SCLC. In particular, it was statistically significant in patients with chromogranin A-positive SCLC (p = 0.036). In patients with NE marker-negative SCLC, no significant differences were observed in PFS between the two groups. There were no significant differences in overall survival (OS), regardless of the expression of any conventional NE marker. CONCLUSION: Our study suggests that the efficacy of ICIs in addition to chemotherapy may be poor in patients with NE marker-negative SCLC.

[Kinking of the endotracheal tube in a prone patient associated with the inadequate withdrawal maneuver of the Pentax-AWS Airway Scope].

We report a case of intraoperative kinking of an endotracheal tube (ETT) in a prone patient during spine surgery. We postulate that one of the risk factors involved with kinking was the inadequate withdrawal maneuver of Pentax-AWS Airway Scope (AWS). Patient was a 69-year-old woman with hypertension, diabetes mellitus, and rheumatoid arthritis, undergoing C4-6 laminoplasty under general anesthesia in the prone position. A 7.0-mm polyvinyl endotracheal tube (Paker Flex-Tip Tube) was placed to 21 cm at the right angle of the mouse without difficulty using the AWS. Both peak inspiratory pressure (PIP) and partial pressure of end-tidal carbon dioxide began to rise gradually from 24 to 28 cmH2O and 38 to 44 mmHg, respectively. Although over 30 cmH2O in PIP repeatedly appeared after that, we did not find any remarkable change of ventilation except for weak breath sound. Thereafter, when we checked the tube with a flexible fiberoptic bronchoscope, it could not pass through the tube. At first, we asked the surgeon to release neck flexion as much as possible. This procedure could not correct the kink completely but allowed the passage of bronchoscope in the ETT. Then, we tried to reposition the ETT by inserting the bronchoscope beyond the point of kinking for maintaining luminal patency and adequate ventilation. The subsequent anesthetic course was uneventful. Kinking of the ETT in the oral cavity is an uncommon problem but we must keep in mind as one of the differential diagnoses. When using the AWS for endotracheal intubation, we recommend the confirmation of the position of the ETT to be normal in the oral cavity by direct laryngoscopy.

[A case of late drug-eluting stent thrombosis during postoperative period after 5 years of stent implantation].

Stent thrombosis during perioperative period is a critical complication for patients treated with drug-eluting stent (DES). We experienced a case of late DES thrombosis 5 years after initial implantation. A 48-year-old man with familial hyperlipidemia, angina pectoris and chronic pulmonary emphysema, was diagnosed with esophageal carcinoma, and scheduled for esophagectomy. He was first treated with DES 5 years ago, and he underwent repeated revascularization for re-stenosis. He had received anti-platelet therapy up to 1 week prior to the current operation, which was replaced by heparin administration. The surgical procedure was uneventful, and he tolerated it well. Immediately after his admission to ICU, sporadic premature ventricular contraction and ST-elevation occurred, leading to ventricular fibrillation. Emergent coronary angiography revealed re-stenosis of the right coronary artery treated with DES 5 years ago. At present, there was no definite guideline, on the management of DES during perioperative period. It is important for us to decide continuing antiplatelet therapy balancing the risk of stent thrombosis with surgical bleeding in each patient.

[A case of transient postoperative median nerve palsy due to the use of the wrist holder to stabilize an intra-arterial catheter].

We experienced a case of right median nerve palsy at the distal forearm following abdominal surgery. We postulate that the cause of the median nerve palsy is overextension of the wrist by the inappropriate fixation with a holder. The patient was a 46-year-old man with habit of smoking receiving low-anterior resection of the rectum under general and epidural anesthesia in lithotomy position. During surgery his upper limbs were placed on padded arm board abducted about 80 degrees and affixed with soft cotton. His forearms were slightly supinated, whereas his elbows were not over-extended. A 22 G cannula was inserted in the right radial artery and the right wrist was fixed with plastic-holder with soft pad. This position was maintained throughout the operation approximetly for 250 minutes. During anesthesia any special events regarding hemodynamic variables were not observed. He complained of numbness in the palmar side of the digits 1-3 on his right hand without motor disturbance 4 hours after the operation. Examination by the anesthesiologist revealed median nerve palsy. Fortunately, this symptom gradually but completely resolved over the next few days. The possible causes of this neuropathy include the overextension of the wrist or the unexpected extension of the elbow beyond the acceptable range by the supination of forearm, which was induced by the attachment used to stabilize an intra-arterial catheter. Therefore, in the current case we should have returned the wrists promptly to the neutral position following arterial catheter placement to prevent the median nerve palsy. This case suggests the importance of holding the proper position of the arm during surgery.

[Survey of the preoperative smoking cessation in patients for elective surgery in a university hospital].

BACKGROUND: In 2006, we reported the smoking status of surgical patients, and the factors relating to preoperative abstinence from cigarettes. Recently implementation of smoke-free policies has increased in Japan. Therefore we performed preoperative interview of 1,124 patients scheduled for elective surgery in 2011 (during 6 months), and compared the results with those of the same interview of 1,968 patients in 2006 (during 12 months). METHODS: Anesthesiologists interviewed all patients using a standardized questionnaire regarding: medical history, smoking history, and awareness of the risks of perioperative smoking. RESULTS: Current smoking rate was not different between 2006 (7%) and 2011 (7%). It was more difficult to quit smoking preoperatively for female patients in 2011 (P = 0.030), and those with benign disease in both 2006 (P = 0.006) and 2011 (P = 0.050) [smoker vs ex-smoker (< three months)]. There was no improvement in awareness of the perioperative risk of smoking between 2006 and 2011. CONCLUSIONS: At present, the importance of perioperative smoking cessation has not been sufficiently well-known for the surgical patients. Health care workers should be more aware of the importance of informing patients that preoperative abstinence from cigarettes may decrease perioperative complications.

Efficacy and safety of carboplatin and etoposide in older extensive-stage small-cell lung cancer patients with a poor performance status.

Carboplatin plus etoposide is a standard treatment for older extensive-stage small-cell lung cancer (ES-SCLC) patients with performance status (PS) 2. However, older patients often exhibit poor PS (3, 4), and the treatment effect in them is poorly understood. To determine the therapeutic efficacy and safety of carboplatin plus etoposide therapy for this population, we retrospectively analyzed 63 patients with ES-SCLC with PS ≥2, aged ≥71 years, who had received first-line carboplatin plus etoposide therapy. We compared the treatment efficacy and safety in patients with baseline PS 2 versus those with PS 3-4. In the PS 2 (38 patients) and PS ≥3 (25 patients) groups, the overall response rate was 71.1% and 72.0%, median progression-free survival was 4.6 and 3.1 months, and overall survival was 7.7 and 5.1 months, respectively. PS improved to 0-1 post-treatment in 65.8% and 48.0% of the patients in the PS 2 and PS ≥3 groups, respectively. Patients with PS ≥3 showing improved PS had a progression-free survival of 6.1 months. A higher incidence of grade ≥3 decreased neutrophil counts, febrile neutropenia, and treatment-related death was observed in the PS ≥3 group. The progression-free survival of patients administered prophylactic granulocyte colony-stimulating factor (G-CSF) was 5.2 and 6.1 months in the PS2 and PS ≥3 groups. Overall, carboplatin plus etoposide therapy provided comparable tumor shrinkage, but shorter progression-free and overall survival in older ES-SCLC patients with PS ≥3 than in those with PS 2. Thus, supportive care, such as prophylactic G-CSF administration, may be necessary to ensure safety and survival.

Safety and efficacy of amrubicin with primary prophylactic pegfilgrastim as second-line chemotherapy in patients with small cell lung cancer.

BACKGROUND: Amrubicin (AMR) regimens have shown efficacy as second-line treatment in patients with small cell lung cancer (SCLC); however, adverse events such as febrile neutropenia (FN) sometimes preclude their use. Further, the safety and efficacy of AMR with primary prophylactic pegfilgrastim (P-PEG) have not been sufficiently evaluated. In this study, we evaluated the safety and efficacy of AMR with or without P-PEG as second-line chemotherapy for SCLC. METHODS: We retrospectively reviewed patients with SCLC who received AMR as second-line chemotherapy at Shizuoka Cancer Center, between December 2014 and November 2021. Based on presence/absence of P-PEG in their regimen, patients (n = 60) were divided into P-PEG (n = 21) and non-P-PEG groups, and their clinical outcomes were evaluated. RESULTS: Median of AMR treatment cycles was five (range: 1-39 cycles) in P-PEG group and four (range: 1-15 cycles) in non-P-PEG group. The incidence of FN (4.8% vs. 30.8%; p = 0.02) and AMR dose reduction because of adverse events (4.8% vs. 25.6%; p = 0.08) were lower in the P-PEG group than in the non-P-PEG group. The objective response rates were 52.4% and 30.8%, and median progression-free and overall survival were 4.7 and 3.0 months, and 9.6 and 6.8 months, in the P-PEG and non-P-PEG groups, respectively. CONCLUSIONS: AMR with P-PEG as second-line chemotherapy for SCLC reduced the incidence of FN at a maintained AMR dose intensity and was associated with favorable tumor responses and survival outcomes. P-PEG should be considered for patients treated with AMR for SCLC including refractory relapsed SCLC.

Clinical impact of tumour burden on the efficacy of PD-1/PD-L1 inhibitors plus chemotherapy in non-small-cell lung cancer.

BACKGROUND: Programmed cell death 1 (PD-1)/programmed cell death ligand (PD-L1) inhibitors plus chemotherapy (ICI + Chemo) is the standard treatment for advanced non-small-cell lung cancer (NSCLC). However, the impact of tumour burden on the efficacy of ICI + Chemo remains unknown. METHODS: We retrospectively evaluated 92 patients with advanced NSCLC treated with ICI + Chemo. Tumour burden was assessed as the sum of the longest diameter of the target lesion (BSLD) and number of metastatic lesions (BNMLs). We categorised the patients into three groups based on the combined BSLD and BNML values. RESULTS: Sixty-eight patients (74%) had progressive disease or died. Forty-four patients (48%) in the low-BSLD group had a median progression-free survival (PFS) of 9.5 months, whereas patients in the high-BSLD group had a median PFS of 4.6 months (hazard ratio [HR] = 0.54, p = 0012). Twenty-five patients (27%) in the low-BNML group had a median PFS of 9.6 months, whereas patients in the high-BNML group had a median PFS of 6.5 months (HR = 0.51, p = 0.029). Low-BSLD and low-BNML were associated independently with improved PFS in multivariate analysis. Analysis of the tumour burden combined with BSLD and BNML revealed a trend towards improved PFS as the tumour burden decreased, with median PFS of 22.3, 8.7, and 3.9 months in the low- (N = 13), medium- (N = 42) and high-burden (N = 37) groups respectively. CONCLUSIONS: Our findings demonstrated that a high tumour burden negatively impacts the efficacy of ICI + Chemo in patients with advanced NSCLC.

Incidence and Treatment Outcome of Radiation Pneumonitis in Patients With Limited-stage Small Cell Lung Cancer Treated With Concurrent Accelerated Hyperfractionated Radiation Therapy and Chemotherapy.

Purpose: This study aimed to clarify the characteristics of and evaluate the risk factors for radiation pneumonitis (RP) induced by chemoradiation therapy (CRT) using accelerated hyperfractionated (AHF) radiation therapy (RT) in patients with limited-stage small cell lung cancer (LS-SCLC). Methods and Materials: Between September 2002 and February 2018, 125 patients with LS-SCLC were treated with early concurrent CRT using AHF-RT. Chemotherapy was comprised of carboplatin/cisplatin with etoposide. RT was administered twice daily (45 Gy/30 fractions). We collected data regarding onset and treatment outcomes for RP, and analyzed the relationship between RP and total lung dose-volume histogram findings. Uni- and multivariate analyses were performed to assess patient- and treatment-related factors for grade ≥2 RP. Results: The median age of patients was 65 years, and 73.6% of participants were men. In addition, 20% and 80.0% of participants presented with disease stage II and III, respectively. The median follow-up time was 73.1 months. Grades 1, 2, and 3 RP were observed in 69, 17, and 12 patients, respectively. Grades 4 to 5 RP were not observed. RP was treated with corticosteroids in patients with grade ≥2 RP, without recurrence. The median time from initiation of RT to onset of RP was 147 days. Three patients developed RP within 59 days, 6 within 60 to 89 days, 16 within 90 to 119 days, 29 within 120 to 149 days, 24 within 150 to 179 days, and 20 within ≥180 days. Among the dose-volume histogram parameters, the percentage of lung volume receiving >30 Gy (V30) was most strongly related to the incidence of grade ≥2 RP, and the optimal threshold to predict RP incidence was V30 ≥20%. On multivariate analysis, V30 ≥20% was an independent risk factor for grade ≥2 RP. Conclusions: The incidence of grade ≥2 RP correlated strongly with a V30 of ≥20%. Contrarily, the onset of RP induced by concurrent CRT using AHF-RT may occur later. RP is manageable in patients with LS-SCLC.

Comprehensive genetic analysis of histological components of combined small cell carcinoma.

BACKGROUND: Combined small-cell lung cancer (cSCLC) is a rare type of small-cell lung cancer (SCLC) that includes both SCLC and non-small-cell lung cancer (NSCLC). The molecular biological mechanisms underlying the heterogeneity of histological types in combined or metachronously transformed SCLC (mtSCLC) remain unclear. This study aimed to investigate the relationship between genetic alterations and each histological component heterogeneously detected in cSCLC and mtSCLC. METHODS: This study included four cSCLC cases and one mtSCLC case. Formalin-fixed and paraffin-embedded sections of each histological component of these tumors were subjected to next-generation sequencing (NGS) and quantitative reverse transcription-polymerase chain reaction to investigate the genetic mutations and expression levels of neuroendocrine cell-specific transcription factors (achaete-scute homolog-1 [ASCL1], brain-2 [BRN2] also known as POU domain class 3 transcription factor 2, nuclear factor 1 B [NF1B], insulinoma-associated protein 1 [INSM1], and thyroid transcription factor-1 [TTF-1]). RESULTS: NGS analysis revealed that SCLC and NSCLC components share the same somatic mutations detected most frequently in TP53, and also in RB1 and EGFR. Gene expression analysis showed ASCL1 expression was significantly lower in the NSCLC component than in the SCLC component. CONCLUSION: We conclude that the morphological evolution of heterogeneous histological components in cSCLC may be associated with differences in ASCL1 expression levels, but not in acquired somatic gene mutations.

Impact of losing adipose tissue on outcomes from PD-1/PD-L1 inhibitor monotherapy in non-small cell lung cancer.

BACKGROUND: Adipose tissue induces inflammation, which desensitizes the efficacy of immunotherapy. However, several reports show that the therapeutic effect of programed cell death 1 (PD-1)/programed death-ligand 1 (PD-L1) inhibitor(s) monotherapy is significantly better in obese patients. Therefore, the effect of adipose tissue on immunotherapy is unclear. METHODS: In this study, we retrospectively reviewed patients with advanced non-small cell lung cancer (NSCLC) who received PD-1/PD-L1 inhibitor monotherapy between May 2016 and December 2018. We classified patients into total adipose tissue maintenance or loss groups according to adipose tissue change during the 6 months before treatment and compared the therapeutic effect of PD-1/PD-L1 inhibitors between these groups along with the presence or absence of cachexia, a poor prognostic factor. RESULTS: Of the 74 patients, 40 (54.1%) were cachexic. Among cachexic patients, we found no clear difference in the overall response rate (ORR) and progression-free survival (PFS) between the total adipose tissue maintenance and loss group. However, among noncachexic patients, the total adipose tissue loss group had a higher ORR (64.7% vs. 23.5%, p < 0.05) and longer PFS (18.5 months vs. 2.86 months, p = 0.037) than the maintenance group. CONCLUSIONS: This study showed that decreasing adipose tissue without cachexia might favor the therapeutic effects of immunotherapy.

Predicting the efficacy of first-line immunotherapy by combining cancer cachexia and tumor burden in advanced non-small cell lung cancer.

BACKGROUND: Cancer cachexia and tumor burden predict efficacies of programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors and chemotherapy or pembrolizumab in non-small cell lung cancer (NSCLC). There are no predictive models that simultaneously assess cancer cachexia and tumor burden. METHODS: In the present retrospective study, we reviewed the medical records of patients with advanced NSCLC who received cancer immunotherapy as first-line systemic therapy. Clinical immune predictive scores were defined according to multivariate analysis of progression-free survival (PFS) and overall survival (OS). RESULTS: A total of 157 patients were included in the present study (75 treated with PD-1/PD-L1 inhibitors + chemotherapy; 82, pembrolizumab monotherapy). Multivariate analysis for PFS revealed that PD-L1 tumor proportion scores <50%, a total target lesion diameter ≥76 mm, and cancer cachexia were independently associated with poor PFS. Multivariate analysis for OS revealed that ≥4 metastases and cancer cachexia were significantly associated with poor OS. In the immune predictive model, the median PFS was 21.7 months in the low-risk group (N = 41); 7.6 in the medium-risk group (N = 64); and 3.0 in the high-risk group (N = 47). The median OS were not reached, 22.4 and 9.1 months respectively. Our immune predictive model was significantly associated with PFS (p < 0.001) and OS (p < 0.001). CONCLUSION: We proposed the immune predictive model, including tumor burden and cancer cachexia, which may predict the efficacy and survival outcome of first-line immunotherapy in advanced NSCLC.

Genomic analysis between idiopathic pulmonary fibrosis and associated lung cancer using laser-assisted microdissection: A case report.

Lung cancer (LC) is the most fatal complication of idiopathic pulmonary fibrosis (IPF). However, the molecular pathogenesis of the development of LC from IPF is still unclear. Here, we report a case of IPF-associated LC for which we investigated the genetic alterations between IPF and LC. We extracted formalin-fixed paraffin-embedded DNA from each part of the surgical lung tissue using a laser-assisted microdissection technique. The mutations in each part were detected by next-generation sequencing (NGS) using 72 lung cancer-related mutation panels. Five mutations were found in IPF and four in LC. Almost all somatic mutations did not overlap between the IPF and LC regions. These findings suggest that IPF-associated LC may not be a result of the accumulation of somatic mutations in the regenerated epithelium of the honeycomb lung in the IPF region.