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.

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.

Discontinuous Translocation of a Luciferase Protein beyond Graft Junction in Tobacco.

Transgrafting, a grafting technique that uses both genetically modified (GM) and non-GM plants, is a novel plant breeding technology that can be used to improve the efficiency of crop cultivation without introducing foreign genes into the edible parts of non-GM plants. This technique can facilitate the acquisition of disease resistance and/or increased yield. However, the translocation of low-molecular-weight compounds, ribonucleic acid (RNA), and proteins through graft junctions raises a potential safety risk for food crops. Here, we used a transgenic tobacco plant expressing a firefly luciferase gene (LUC) to examine the translocation of the LUC protein beyond the graft junction in grafted plants. We observed the bi-directional translocation of LUC proteins in transgrafted tobacco plants, i.e., from the rootstock to scion and vice versa. Transcriptomic analysis revealed that transcripts of the LUC gene were undetectable in non-GM plant bodies, indicating that the LUC protein itself was translocated. Moreover, the movement of the LUC protein is an episodic (i.e., non-continuous) event, since non-GM samples showing high LUC activity were flanked by non-GM samples showing no apparent LUC activity. Translocation from the GM to non-GM part depends on the characteristics of GM plant bodies; here, the enhanced translocation of the LUC protein into the non-GM scion was observed when LUC-expressing rootstocks with hairy roots were used. Moreover, the quantity of translocated LUC protein was far below the level that is generally required to induce an allergenic response. Finally, since the LUC protein levels of plants used for transgrafting are moderate and the LUC protein itself is relatively unstable, further investigation is necessary regarding whether the newly expressed protein in GM plants is highly stable, easily translocated, and/or highly expressed.

Discontinuous Translocation of a Luciferase Protein beyond Graft Junction in Tobacco.

Transgrafting, a grafting technique that uses both genetically modified (GM) and non-GM plants, is a novel plant breeding technology that can be used to improve the efficiency of crop cultivation without introducing foreign genes into the edible parts of non-GM plants. This technique can facilitate the acquisition of disease resistance and/or increased yield. However, the translocation of low-molecular-weight compounds, ribonucleic acid (RNA), and proteins through graft junctions raises a potential safety risk for food crops. Here, we used a transgenic tobacco plant expressing a firefly luciferase gene (LUC) to examine the translocation of the LUC protein beyond the graft junction in grafted plants. We observed the bi-directional translocation of LUC proteins in transgrafted tobacco plants, i.e., from the rootstock to scion and vice versa. Transcriptomic analysis revealed that transcripts of the LUC gene were undetectable in non-GM plant bodies, indicating that the LUC protein itself was translocated. Moreover, the movement of the LUC protein is an episodic (i.e., non-continuous) event, since non-GM samples showing high LUC activity were flanked by non-GM samples showing no apparent LUC activity. Translocation from the GM to non-GM part depends on the characteristics of GM plant bodies; here, the enhanced translocation of the LUC protein into the non-GM scion was observed when LUC-expressing rootstocks with hairy roots were used. Moreover, the quantity of translocated LUC protein was far below the level that is generally required to induce an allergenic response. Finally, since the LUC protein levels of plants used for transgrafting are moderate and the LUC protein itself is relatively unstable, further investigation is necessary regarding whether the newly expressed protein in GM plants is highly stable, easily translocated, and/or highly expressed.

Prophylactic pegfilgrastim reduces febrile neutropenia in ramucirumab plus docetaxel after chemoimmunotherapy in advanced NSCLC: post hoc analysis from NEJ051.

Ramucirumab plus docetaxel (RD) can cause febrile neutropenia (FN), which frequently requires the prophylactic administration of pegfilgrastim. However, the effects of prophylactic pegfilgrastim on FN prevention, therapeutic efficacy, and prognosis after RD have not been fully evaluated in patients with advanced non-small-cell lung cancer (NSCLC). Two hundred and eighty-eight patients with advanced NSCLC who received RD as second-line therapy after platinum-based chemotherapy plus PD-1 blockade were included. Patients were divided into groups with and without prophylactic pegfilgrastim, and adverse events, efficacy, and prognosis were compared between both groups. Of the 288 patients, 247 received prophylactic pegfilgrastim and 41 did not. The frequency of grade 3/4 neutropenia was 62 patients (25.1%) in the pegfilgrastim group and 28 (68.3%) in the control group (p < 0.001). The frequency of FN was 25 patients (10.1%) in the pegfilgrastim group and 10 (24.4%) in the control group (p = 0.018). The objective response rate was 31.2% and 14.6% in the pegfilgrastim and control groups (p = 0.039), respectively. The disease control rate was 72.9% in the pegfilgrastim group and 51.2% in the control group (p = 0.009). Median progression free survival was 4.3 months in the pegfilgrastim group and 2.5 months in the control group (p = 0.002). The median overall survival was 12.8 and 8.1 months in the pegfilgrastim and control groups (p = 0.004), respectively. Prophylactic pegfilgrastim for RD reduced the frequency of grade 3/4 neutropenia and febrile neutropenia and did not appear to be detrimental to patient outcome RD.Clinical Trial Registration Number: UMIN000042333.

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.

Effectiveness and Safety of Immune Checkpoint Inhibitors Alone or in Combination With Chemotherapy in Pulmonary Sarcomatoid Carcinoma.

Introduction: Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of lung cancer associated with poor prognosis and resistance to conventional chemotherapy. Immune checkpoint inhibitors (ICIs), alone or in combination with chemotherapy, were found to have clinical benefits in PSC in recent studies. Nevertheless, because these studies included a small number of patients owing to disease rarity, larger studies are needed to evaluate the effectiveness and safety of ICI-based therapy for PSC. Methods: This multicenter retrospective study evaluated patients with ICI-naive advanced or metastatic PSC who were treated with ICI-based therapy at 25 hospitals in Japan. Results: A total of 124 patients were evaluated. The overall response rate, median progression-free survival (PFS), and median overall survival (OS) were 59.0%, 10.5 months, and 32.8 months, respectively. The PFS and OS rates at 24 months were 35.3% and 51.5%, respectively. Programmed death-ligand 1 expression, concomitant chemotherapy, and the treatment line were not significantly associated with PFS or OS. Immune-related adverse events (irAEs) were observed in 70 patients (56.5%), including 30 (24.2%) with grade 3 to 5 events. Patients with mild irAEs (grades 1-2) had longer PFS and OS than did those with severe (grades 3-5) or no irAEs. In a multivariate analysis, any-grade irAEs and the absence of liver metastases were independently associated with PFS, whereas any-grade irAEs and Eastern Cooperative Oncology Group performance status less than or equal to 1 were independently associated with OS. Conclusions: ICI-based therapy was found to have promising effectiveness in patients with advanced or metastatic PSC, regardless of programmed death-ligand 1 expression, concomitant chemotherapy, or treatment line.

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.

A Thermophile-Fermented Compost Modulates Intestinal Cations and the Expression of a Juvenile Hormone-Binding Protein Gene in the Female Larvae of Hercules Beetle Dynastes hercules (Coleoptera: Scarabaeidae).

The Hercules beetle larvae grow by feeding on humus, and adding a thermophile-fermented compost to the humus can upregulate the growth of female larvae. In this study, the effects of compost on the intestinal environment, including pH, cation concentrations, and organic acid concentrations of intestinal fluids, were investigated, and the RNA profile of the fat body was determined. Although the total intestinal potassium ions were similar between the larvae grown without compost (control larvae) and those with compost (compost larvae), the proportion of potassium ions in the midgut of the compost larvae drastically increased. In the midgut, an unidentified organic acid was the most abundant, and its concentration increased in the compost larvae. Transcriptome analysis showed that a gene encoding hemolymph juvenile-binding protein (JHBP) was expressed in the compost female larvae and not in the control female larvae. Expression of many genes involved in the defensive system was decreased in the compost female larvae. These results suggest that the female-specific enhancement of larval growth by compost was associated with the increased JHBP expression under conditions in which the availability of nutrition from the humus was improved by an increase in potassium ions in the midgut.

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.

Multi-omics Analyses of Non-GM Tomato Scion Engrafted on GM Rootstocks.

Grafting has been widely applied in agricultural production in order to utilize agriculturally valuable traits. The use of genetically modified (GM) plants for grafting with non-GM crops will soon be implemented to generate chimeric plants (transgrafting)*, and the non-GM edible portions thus obtained could fall outside of the current legal regulations. A number of metabolites and macromolecules are reciprocally exchanged between scion and rootstock, affecting the crop properties as food. Accordingly, the potential risks associated with grafting, particularly those related to transgrafting with GM plants, should be carefully evaluated based on scientific evidence. In this study, we prepared a hetero-transgraft line composed of non-GM tomato scion and GM-tobacco rootstock expressing firefly luciferase. We also prepared a homograft line (both rootstock and scion are from non-GM tomato) and a heterograft line (non-GM tobacco rootstock and non-GM tomato scion). The non-GM tomato fruits were harvested from these grafted lines and subjected to comprehensive characterization by multi-omics analysis. Proteomic analysis detected tobacco-derived proteins from both heterograft and hetero-transgraft lines, suggesting protein transfer from the tobacco rootstock to the tomato fruits. No allergenicity information is available for these two tobacco-derived proteins. The transcript levels of the genes encoding two allergenic tomato intrinsic proteins (Sola l 4.0101 and Sola l 4.0201) decreased in the heterograft and hetero-transgraft lines. Several differences were observed in the metabolic profiles, including α-tomatine and nicotine. The accumulation of tobacco-derived nicotine in the tomato fruits of both heterograft and hetero-transgraft lines indicated that the transfer of unfavorable metabolites from rootstock to scion should be assessed as a food safety concern. Further investigations are needed to clarify whether variable environmental conditions and growth periods may influence the qualities of the non-GM edible parts produced by such transgrafted plants.

Multicentre real-world data of ramucirumab plus docetaxel after combined platinum-based chemotherapy with programmed death-1 blockade in advanced non-small cell lung cancer: NEJ051 (REACTIVE study).

BACKGROUND: Ramucirumab plus docetaxel (RD) is a promising treatment for previously treated advanced non-small cell lung cancer (NSCLC). However, its clinical significance after platinum-based chemotherapy plus programmed death-1 (PD-1) blockade remains unclear. RESEARCH QUESTION: What is the clinical significance of RD as a second-line treatment after the failure of chemo-immunotherapy in NSCLC? STUDY DESIGN AND METHODS: In this multicentre retrospective study, 288 patients with advanced NSCLC who received RDas second-line therapy after platinum-based chemotherapy plus PD-1 blockade, at 62 Japanese institutions from January 2017 to August 2020, were included. Prognostic analyses were performed using the log-rank test. Prognostic factor analyses were performed using a Cox regression analysis. RESULTS: A total of 288 patients were enrolled: 222 were men (77.1%), 262 were aged <75 years (91.0%), 237 (82.3%) had smoking history and 269 (93.4%) had a performance status (PS) of 0-1. One hundred ninety-nine patients (69.1%) were classified as adenocarcinoma (AC) and 89 (30.9%) as non-AC. The types of PD-1 blockade used in the first-line treatment were anti-PD-1 antibody and anti-programmed death-ligand 1 antibody in 236 (81.9%) and 52 (18.1%) patients, respectively. The objective response rate for RD was 28.8% (95% confidence interval [CI], 23.7-34.4). The disease control rate was 69.8% (95% CI, 64.1-75.0).The median progression free survival and overall survival were 4.1 months (95% CI, 3.5-4.6) and 11.6 months (95% CI, 9.9-13.9), respectively. In a multivariate analysis, non-AC and PS 2-3 were independent prognostic factors for worse progression free survival , while bone metastasis on diagnosis, PS 2-3 and non-AC were identified as independent prognostic factors for poor overall survival. INTERPRETATION: RD is a feasible second-line treatment in patients with advanced NSCLC who had received combined chemo-immunotherapy with PD-1 blockade. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000042333.

Omics Profiles of Non-GM Tubers from Transgrafted Potato with a GM Scion.

"Transgrafting" is a grafting procedure whereby a transgenic plant body is grafted to a non-transgenic plant body. It is a novel plant breeding technology that allows non-transgenic plants to obtain benefits usually conferred to transgenic plants. Many plants regulate flowering by perceiving the day-length cycle via expression of FLOWERING LOCUS T (FT) in the leaves. The resulting FT protein is translocated to the shoot apical meristem via the phloem. In potato plants, FT is involved in the promotion of tuber formation. Here we investigated the effects of a genetically modified (GM) scion on the edible parts of the non-GM rootstock by using potato plants transformed with StSP6A, a novel potato homolog of the FT gene. Scions prepared from GM or control (wild-type) potato plants were grafted to non-GM potato rootstocks; these were designated as TN and NN plants, respectively. After tuber harvest, we observed no significant differences in potato yield between TN and NN plants. Transcriptomic analysis revealed that only one gene-with unknown function-was differentially expressed between TN and NN plants. Subsequent proteomic analysis indicated that several members of protease inhibitor families, known as anti-nutritional factors in potato, were slightly more abundant in TN plants. Metabolomic analysis revealed a slight increase in metabolite abundance in NN plants, but we observed no difference in the accumulation of steroid glycoalkaloids, toxic metabolites found in potato. Finally, we found that TN and NN plants did not differ in nutrient composition. Taken together, these results indicate that FT expression in scions had a limited effect on the metabolism of non-transgenic potato tubers.

An agroecological structure model of compost-soil-plant interactions for sustainable organic farming.

Compost is used worldwide as a soil conditioner for crops, but its functions have still been explored. Here, the omics profiles of carrots were investigated, as a root vegetable plant model, in a field amended with compost fermented with thermophilic Bacillaceae for growth and quality indices. Exposure to compost significantly increased the productivity, antioxidant activity, color, and taste of the carrot root and altered the soil bacterial composition with the levels of characteristic metabolites of the leaf, root, and soil. Based on the data, structural equation modeling (SEM) estimated that amino acids, antioxidant activity, flavonoids and/or carotenoids in plants were optimally linked by exposure to compost. The SEM of the soil estimated that the genus Paenibacillus and nitrogen compounds were optimally involved during exposure. These estimates did not show a contradiction between the whole genomic analysis of compost-derived Paenibacillus isolates and the bioactivity data, inferring the presence of a complex cascade of plant growth-promoting effects and modulation of the nitrogen cycle by the compost itself. These observations have provided information on the qualitative indicators of compost in complex soil-plant interactions and offer a new perspective for chemically independent sustainable agriculture through the efficient use of natural nitrogen.

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.

Amendment of a thermophile-fermented compost to humus improves the growth of female larvae of the Hercules beetle Dynastes hercules (Coleoptera: scarabaeidae).

AIMS: Hercules beetle is a popular pet and large adult individuals are considered valuable. Incorporating compost prepared from marine animals and fermented by thermophilic bacteria into the humus benefits the gut microflora of several livestock. Here, we evaluated whether this compost improves the growth of the Hercules beetle (Dynastes hercules hercules) larvae. METHODS AND RESULTS: We mixed the compost grains with the humus at a final concentration of 1% (w/w) and transferred ∼90 days old Hercules beetle larvae to fresh humus with or without the compost. After 72 days rearing period, only the female larvae reared in the humus with compost exhibited superior growth, compared with those grown in compost-free humus. The gut bacterial composition was determined at 0 and 46 day after transferring the larvae to humus with or without compost. Improved growth of the female larvae was associated with increased abundance of Mollicutes and decreased abundance of Gammaproteobacteria. CONCLUSION: The thermophile-fermented compost has a probiotic effect on the female Hercules beetle larvae that is mediated by altered gut microflora.

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.

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.

Artificial Intelligence-Powered Prediction of ALK Gene Rearrangement in Patients With Non-Small-Cell Lung Cancer.

PURPOSE: Several studies reported the possibility of predicting genetic abnormalities in non-small-cell lung cancer by deep learning (DL). However, there are no data of predicting ALK gene rearrangement (ALKr) using DL. We evaluated the ALKr predictability using the DL platform. MATERIALS AND METHODS: We selected 66 ALKr-positive cases and 142 ALKr-negative cases, which were diagnosed by ALKr immunohistochemical staining in our institution from January 2009 to March 2019. We generated virtual slide of 300 slides (150 ALKr-positive slides and 150 ALKr-negative slides) using NanoZoomer. HALO-AI was used to analyze the whole-slide imaging data, and the DenseNet network was used to build the learning model. Of the 300 slides, we randomly assigned 172 slides to the training cohort and 128 slides to the test cohort to ensure no duplication of cases. In four resolutions (16.0/4.0/1.0/0.25 µm/pix), ALKr prediction models were built in the training cohort and ALKr prediction performance was evaluated in the test cohort. We evaluated the diagnostic probability of ALKr by receiver operating characteristic analysis in each ALKr probability threshold (50%, 60%, 70%, 80%, 90%, and 95%). We expected the area under the curve to be 0.64-0.85 in the model of a previous study. Furthermore, in the test cohort data, an expert pathologist also evaluated the presence of ALKr by hematoxylin and eosin staining on whole-slide imaging. RESULTS: The maximum area under the curve was 0.73 (50% threshold: 95% CI, 0.65 to 0.82) in the resolution of 1.0 µm/pix. In this resolution, with an ALKr probability of 50% threshold, the sensitivity and specificity were 73% and 73%, respectively. The expert pathologist's sensitivity and specificity in the same test cohort were 13% and 94%. CONCLUSION: The ALKr prediction by DL was feasible. Further study should be addressed to improve accuracy of ALKr prediction.

Noninvasive fecal metabolic profiling for the evaluation of characteristics of thermostable lactic acid bacteria, Weizmannia coagulans SANK70258, for broiler chickens.

Weizmannia coagulans SANK70258 is a spore-forming thermostable lactic acid bacterium and an effective probiotic for the growth of livestock animals, but its growth-promoting mechanism remains unclear. Here, the composition of fecal metabolites in broilers continuously administered with W. coagulans SANK70258 was assessed under a regular program with antibiotics, which was transiently given for 6 days after birth. Oral administration of W. coagulans to broiler chicks tended to increase the average daily gain of body weights thereafter. The composition of fecal metabolites in the early chick stage (day 10 after birth) was dramatically altered by the continuous exposure. The levels of short-chain fatty acids (SCFAs) propionate and butyrate markedly increased, while those of acetate, one of the SCFAs, and lactate were reduced. Simultaneously, arabitol, fructose, mannitol, and erythritol, which are carbohydrates as substrates for gut microbes to produce SCFAs, also increased along with altered correlation. Correlation network analyses classified the modularity clusters (|r| > 0.7) among carbohydrates, SCFAs, lactate, amino acids, and the other metabolites under the two conditions. The characteristic diversities by the exposure were visualized beyond the perspective associated with differences in metabolite concentrations. Further, enrichment pathway analyses showed that metabolic composition related to biosynthesis and/or metabolism for SCFAs, amino acids, and energy were activated. Thus, these observations suggest that W. coagulans SANK70258 dramatically modulates the gut metabolism of the broiler chicks, and the metabolomics profiles during the early chick stages may be associated with growth promotion.