Factors associated with engraftment success of patient-derived xenografts of breast cancer.

BACKGROUND: Patient-derived xenograft (PDX) models serve as a valuable tool for the preclinical evaluation of novel therapies. They closely replicate the genetic, phenotypic, and histopathological characteristics of primary breast tumors. Despite their promise, the rate of successful PDX engraftment is various in the literature. This study aimed to identify the key factors associated with successful PDX engraftment of primary breast cancer. METHODS: We integrated clinicopathological data with morphological attributes quantified using a trained artificial intelligence (AI) model to identify the principal factors affecting PDX engraftment. RESULTS: Multivariate logistic regression analyses demonstrated that several factors, including a high Ki-67 labeling index (Ki-67LI) (p < 0.001), younger age at diagnosis (p = 0.032), post neoadjuvant chemotherapy (NAC) (p = 0.006), higher histologic grade (p = 0.039), larger tumor size (p = 0.029), and AI-assessed higher intratumoral necrosis (p = 0.027) and intratumoral invasive carcinoma (p = 0.040) proportions, were significant factors for successful PDX engraftment (area under the curve [AUC] 0.905). In the NAC group, a higher Ki-67LI (p < 0.001), lower Miller-Payne grade (p < 0.001), and reduced proportion of intratumoral normal breast glands as assessed by AI (p = 0.06) collectively provided excellent prediction accuracy for successful PDX engraftment (AUC 0.89). CONCLUSIONS: We found that high Ki-67LI, younger age, post-NAC status, higher histologic grade, larger tumor size, and specific morphological attributes were significant factors for predicting successful PDX engraftment of primary breast cancer.

21-gene expression assay and clinical outcomes of premenopausal patients with hormone receptor-positive breast cancer.

The prognostic role of the recurrence score (RS) based on the 21-gene expression assay in premenopausal women is not well delineated, and we investigated the association of outcomes and the RS in premenopausal patients who had 21-gene expression assay at Asan Medical Center, Seoul, Korea, between June 2005 and July 2018. Invasive breast cancer-free survival (IBCFS) by STEEP version 2.0 was compared according to the RS and clinical risk factors. A total of 554 patients were included in our study and 116 patients (20.9%) had age <40 years, 238 patients (43.0%) had luminal B subtype (Ki67 ≥ 20%), and 83 patients (15.0%) had RS >25. All patients received adjuvant tamoxifen ± chemotherapy. Overall, patients with RS >25 showed trend toward worse IBCFS from multivariable analysis (adjusted HR 1.89 [95% CI: 0.95-3.73], P = .069). When comparing outcomes according to age and luminal subtypes, patients with luminal B subtype and age <40 years (n = 60) showed significantly worse outcomes compared to the others (luminal A or luminal B + age ≥40 years, n = 494; adjusted HR 2.95 [95% CI: 1.49-5.82], log-rank P < .001). Among patients with luminal B subtype and age <40 years, there was no significant association observed between IBCFS and the RS (log-rank P = .51). In conclusion, while RS >25 showed association with poor outcomes in premenopausal women, it may have less prognostic significance among those with luminal B subtype and age <40 years.

Adjuvant gemcitabine plus cisplatin versus capecitabine in node-positive extrahepatic cholangiocarcinoma: the STAMP randomized trial.

BACKGROUND AND AIMS: The effectiveness of gemcitabine-based adjuvant chemotherapy is unclear in cholangiocarcinoma. We investigated the role of adjuvant gemcitabine plus cisplatin (GemCis) in a homogeneous group of high-risk patients with resected, lymph node-positive extrahepatic cholangiocarcinoma. APPROACH AND RESULTS: Adenocarcinoma of perihilar or distal bile duct with regional lymph node metastasis who underwent curative-intent surgery (R0/R1) was eligible. Patients were randomized to receive GemCis (gemcitabine 1000 mg/m2, cisplatin 25 mg/m2 on days 1 and 8) or capecitabine (1250 mg/m2 twice daily on days 1-14) every 3 weeks for 8 cycles. Primary endpoint was disease-free survival. Secondary endpoints were overall survival and safety. All p values are 1 sided and were considered significant if <0.1. Between July 2017 and November 2020, 101 patients (50 in the GemCis and 51 in the capecitabine group) were included in the intention-to-treat population. Perihilar and distal bile ducts were the primary sites in 45 (44.6%) and 56 (55.4%) patients, respectively, and 32 (31.7%) had R1 resections. Median (1-sided 90% CI) follow-up duration was 33.4 (30.5-35.8) months. In the GemCis and capecitabine group, 2-year disease-free survival rates were 38.5% (29.5%-47.4%) and 25.1% (17.4%-33.5%) [HR=0.96 (CI, 0.71-1.30), p=0.430], and median overall survival was 35.7 months (29.5-not estimated) and 35.7 months (30.9-not estimated) [HR=1.08 (CI, 0.71-1.64), 1-sided p=0.404], respectively. Grade 3-4 adverse events occurred in 42 (84.0%) and 8 patients (16.0%) in the GemCis and capecitabine groups, respectively. No treatment-related deaths were reported. CONCLUSIONS: In resected lymph node-positive extrahepatic cholangiocarcinoma, adjuvant GemCis did not improve survival outcomes compared with capecitabine.

Proteomic analysis of breast cancer based on immune subtypes.

BACKGROUND: Immunotherapy is applied to breast cancer to resolve the limitations of survival gain in existing treatment modalities. With immunotherapy, a tumor can be classified into immune-inflamed, excluded and desert based on the distribution of immune cells. We assessed the clinicopathological features, each subtype's prognostic value and differentially expressed proteins between immune subtypes. METHODS: Immune subtyping and proteomic analysis were performed on 56 breast cancer cases with neoadjuvant chemotherapy. The immune subtyping was based on the level of tumor-infiltrating lymphocytes (TILs) and Klintrup criteria. If the level of TILs was ≥ 10%, it was classified as immune-inflamed type without consideration of the Klintrup criteria. In cases of 1-9% TIL, Klintrup criteria 1-3 were classified as the immune-excluded subtype and Klintrup criteria not available (NA) was classified as NA. Cases of 1% TILs and Klintrup 0 were classified as the immune-desert subtype. Mass spectrometry was used to identify differentially expressed proteins in formalin-fixed paraffin-embedded biopsy tissues. RESULTS: Of the 56 cases, 31 (55%) were immune-inflamed, 21 (38%) were immune-excluded, 2 (4%) were immune-desert and 2 (4%) were NA. Welch's t-test revealed two differentially expressed proteins between immune-inflamed and immune-excluded/desert subtypes. Coronin-1A was upregulated in immune-inflamed tumors (adjusted p = 0.008) and α-1-antitrypsin was upregulated in immune-excluded/desert tumors (adjusted p = 0.008). Titin was upregulated in pathologic complete response (pCR) than non-pCR among immune-inflamed tumors (adjusted p = 0.036). CONCLUSIONS: Coronin-1A and α-1-antitrypsin were upregulated in immune-inflamed and immune-excluded/desert subtypes, respectively. Titin's elevated expression in pCR within the immune-inflamed subtype may indicate a favorable prognosis. Further studies involving large representative cohorts are necessary to validate these findings.

Abietane Diterpenoids Isolated from Torreya nucifera Disrupt Replication of Influenza Virus by Blocking the Phosphatidylinositol-3-Kinase (PI3K)-Akt and ERK Signaling Pathway.

Although vaccines and antiviral drugs are available, influenza viruses continue to pose a significant threat to vulnerable populations globally. With the emergence of drug-resistant strains, there is a growing need for novel antiviral therapeutic approaches. We found that 18-hydroxyferruginol (1) and 18-oxoferruginol (2) isolated from Torreya nucifera exhibited strong anti-influenza activity, with 50% inhibitory concentration values of 13.6 and 18.3 µM against H1N1, 12.8 and 10.8 µM against H9N2, and 29.2 µM (only compound 2) against H3N2 in the post-treatment assay, respectively. During the viral replication stages, the two compounds demonstrated stronger inhibition of viral RNA and protein in the late stages (12-18 h) than in the early stages (3-6 h). Moreover, both compounds inhibited PI3K-Akt signaling, which participates in viral replication during the later stages of infection. The ERK signaling pathway is also related to viral replication and was substantially inhibited by the two compounds. In particular, the inhibition of PI3K-Akt signaling by these compounds inhibited viral replication by sabotaging influenza ribonucleoprotein nucleus-to-cytoplasm export. These data indicate that compounds 1 and 2 could potentially reduce viral RNA and viral protein levels by inhibiting the PI3K-Akt signaling pathway. Our results suggest that abietane diterpenoids isolated from T. nucifera may be potent antiviral candidates for new influenza therapies.

Randomized phase III trial of a neoadjuvant regimen of four cycles of adriamycin plus cyclophosphamide followed by four cycles of docetaxel (AC4-D4) versus a shorter treatment of three cycles of FEC followed by three cycles of docetaxel (FEC3-D3) in node-positive breast cancer (Neo-shorter; NCT02001506).

PURPOSE: To determine whether six cycles of FEC3-D3 has a comparable efficacy to eight of AC4-D4. METHODS: The enrolled patients (pts) were clinically diagnosed with stage II or III breast cancer. The primary endpoint was a pathologic complete response (pCR), and the secondary endpoints were 3 year disease-free survival (3Y DFS), toxicities, and health-related quality of life (HRQoL). We calculated that 252 pts were needed in each treatment group to enable the detection of non-inferiority (non-inferiority margin of 10%). RESULTS: In terms of ITT analysis, 248 pts were finally enrolled. The 218 pts who completed the surgery were included in the current analysis. The baseline characteristics of these subjects were well balanced between the two arms. By ITT analysis, pCR was achieved in 15/121 (12.4%) pts in the FEC3-D3 arm and 18/126 (14.3%) in the AC4-D4 arm. With a median follow up of 64.1 months, the 3Y DFS was comparable between the two arms (75.8% in FEC3-D3 vs. 75.6% in AC4-D4). The most common adverse event (AE) was Grade 3/4 neutropenia, which arose in 27/126 (21.4%) AC4-D4 arm pts vs 23/121 (19.0%) FEC3-D3 arm cases. The primary HRQoL domains were similar between the two groups (FACT-B scores at baseline, P = 0.35; at the midpoint of NACT, P = 0.20; at the completion of NACT, P = 0.44). CONCLUSION: Six cycles of FEC3-D3 could be an alternative to eight of AC4-D4. Trial registration ClinicalTrials.gov NCT02001506. Registered December 5,2013. https://clinicaltrials.gov/ct2/show/NCT02001506.

Analysis of random mutations in Salmonella Gallinarum dihydropteroate synthase conferring sulfonamide resistance.

In bacteria and primitive eukaryotes, sulfonamide antibiotics block the folate pathway by inhibiting dihydropteroate synthase (FolP) that combines para-aminobenzoic acid (pABA) and dihydropterin pyrophosphate (DHPP) to form dihydropteroic acid (DHP), a precursor for tetrahydrofolate synthesis. However, the emergence of resistant strains has severely compromised the use of pABA mimetics as sulfonamide drugs. Salmonella enterica serovar Gallinarum (S. Gallinarum) is a significant source of antibiotic-resistant infections in poultry. Here, a sulfonamide-resistant FolP mutant library of S. Gallinarum was generated through random mutagenesis. Among resistant strains, substitution of amino acid Arginine 171 with Proline (R171P) in the FolP protein conferred the highest resistance against sulfonamide. Substitution of Phe28 with Leu or Ile (F28L/I) led to modest sulfonamide resistance. Structural modeling indicates that R171P and Phenylalanine 28 with leucine or isoleucine (F28L/I) substitution mutations are located far from the substrate-binding site and cause insignificant conformational changes in the FolP protein. Rather, in silico studies suggest that the mutations altered the stability of the protein, potentially resulting in sulfonamide resistance. Identification of specific mutations in FolP that confer resistance to sulfonamide would contribute to our understanding of the molecular mechanisms of antibiotic resistance.

Anti-obesity activity of human gut microbiota Bacteroides stercoris KGMB02265.

Obesity is a global health threat that causes various complications such as type 2 diabetes and nonalcoholic fatty liver disease. Gut microbiota is closely related to obesity. In particular, a higher Firmicutes to Bacteroidetes ratio has been reported as a biomarker of obesity, suggesting that the phylum Bacteroidetes may play a role in inhibiting obesity. Indeed, the genus Bacteroides was enriched in the healthy subjects based on metagenome analysis. In this study, we determined the effects of Bacteroides stercoris KGMB02265, a species belonging to the phylum Bacteroidetes, on obesity both in vitro and in vivo. The cell-free supernatant of B. stercoris KGMB02265 inhibited lipid accumulation in 3T3-L1 preadipocytes, in which the expression of adipogenic marker genes was repressed. In vivo study showed that the oral administration of B. stercoris KGMB02265 substantially reduced body weight and fat weight in high-fat diet induced obesity in mice. Furthermore, obese mice orally administered with B. stercoris KGMB02265 restored glucose sensitivity and reduced leptin and triglyceride levels. Taken together, our study reveals that B. stercoris KGMB02265 has anti-obesity activity and suggests that it may be a promising candidate for treating obesity.

Mononostril Endoscopic Approach for Bilateral Sphenoid Sinus Lesions.

INTRODUCTION: A mononostril endoscopic approach was attempted for bilateral sphenoid sinus lesions. The objective of this study was to introduce the surgical method along with treatment results for patients. METHODS: We retrospectively analyzed 16 patients who underwent a mononostril endoscopic surgery for bilateral sphenoid lesions from 2018 to 2022. RESULTS: Endoscopic mononostril surgery for bilateral sphenoid lesions was performed for 13 cases under general anesthesia and 3 cases under local anesthesia. The surgical approach to the sphenoid sinus was transnasal approach in 8 cases and transethmoidal in 8 cases. Among those with bilateral sphenoid sinuses lesions, fungal ball and sinusitis were the most common. After surgery, the size of the sphenoid sinus opening remained almost the same in 14 patients. It decreased but maintained in 2 patients. There was no recurrence of sphenoid lesions. CONCLUSION: The mononostril endoscopic approach for bilateral sphenoid lesions is a feasible, safe, effective, and minimally invasive surgical technique.

Oncologic outcomes of immediate breast reconstruction in young women with breast cancer receiving neoadjuvant chemotherapy.

BACKGROUND: Oncologic safety of postmastectomy breast reconstruction in young women with breast cancer is not well-defined, especially in the setting of neoadjuvant chemotherapy (NACT). We retrospectively compared the oncologic outcomes following nipple-sparing (NSM)/skin-sparing mastectomy (SSM) with immediate breast reconstruction (IBR) and conventional mastectomy (CM) alone in young breast cancer patients after NACT. METHODS: A total of 1266 women with primary breast cancer who underwent NACT followed by total mastectomy with or without IBR were reviewed. Of these, only young patients (age ≤ 40 years at diagnosis) were included in the outcome analysis (n = 375). After propensity score-matching by clinical T and N stage, molecular subtype, response to NACT, and adjuvant radiotherapy status, 228 patients were 1:1 matched, comprising balanced IBR group (with NSM/SSM) and CM-alone group. RESULTS: The 5-year locoregional recurrence-free, disease-free, distant metastasis (DM)-free, and breast cancer-specific survival (BCSS) rates for the entire cohort of young patients were 83.4%, 65.3%, 71.7%, and 85.4%, respectively. Locoregional recurrence rates between the matched groups were similar (14% vs. 15.8%; p = 0.710); however, IBR group had significantly lower DM rate (27.2% vs. 40.4%; p = 0.036) and breast cancer mortality (14.9% vs. 27.2%; p = 0.023) than CM-alone group. IBR group showed significantly improved 5-year DM-free survival (74.1% vs. 62.6%; p = 0.043) and BCSS (89.1% vs. 77.6%; p = 0.048) rates than CM-alone group. CONCLUSIONS: Our results indicated that IBR with NSM/SSM does not negatively affect long-term oncologic outcomes compared to CM alone in young women with breast cancer receiving NACT.

Breast cancer outcomes following immediate breast reconstruction with implants versus autologous flaps: a propensity score-matched study.

PURPOSE: A large proportion of patients with breast cancer who had mastectomy had undergone breast reconstruction with implants or autologous flaps. However, only a few studies have compared the breast cancer outcomes between the implant-based reconstruction (IBR) and autologous flap reconstruction (AFR). In this study, we retrospectively compared the local recurrence rates, distant metastasis rates, and survival outcomes between immediate IBR and AFR. METHODS: A total of 1530 patients with primary breast cancer who underwent IBR or AFR with nipple-/skin-sparing mastectomy were included. Patients who underwent neoadjuvant systemic therapy were excluded from the study. After propensity score matching by age at diagnosis, T stage, N stage, molecular subtype, mastectomy type, adjuvant radiotherapy status, and follow-up period, 938 patients were 1:1 matched, comprising the well-balanced IBR and AFR groups. Locoregional recurrence-free survival (LRRFS), disease-free survival (DFS), distant metastasis-free survival (DMFS), and breast cancer-specific survival (BCSS) were compared between the matched groups. RESULTS: After matching, the median follow-up periods were 68 months and 71 months for the IBR and AFR groups, respectively. No significant differences were observed between the IBR and AFR groups regarding the local recurrence (7.2% vs. 5.1%; P = 0.175), regional recurrence (2.1% vs. 1.5%; P = 0.463), or distant metastasis (3.2% vs. 3.2%; P = 1.000) rates. Moreover, no significant difference was observed between the IBR and AFR groups in the LRRFS (hazard ratio, 0.691; 95% CI, 0.433-1.102; P = 0.118), DFS (hazard ratio, 0.709; 95% CI, 0.468-1.076; P = 0.104), DMFS (hazard ratio, 1.006; 95% CI, 0.491-2.059; P = 0.987), or BCSS (hazard ratio, 0.445; 95% CI, 0.111-1.786; P = 0.659). CONCLUSION: In this propensity score-matched analysis of oncologic outcomes in patients with primary breast cancer who underwent immediate breast reconstruction with nipple-/skin-sparing mastectomy, no significant differences were observed between the IBR and AFR groups.

Liposomal irinotecan plus fluorouracil and leucovorin versus fluorouracil and leucovorin for metastatic biliary tract cancer after progression on gemcitabine plus cisplatin (NIFTY): a multicentre, open-label, randomised, phase 2b study.

BACKGROUND: The prognosis of patients with advanced biliary tract cancer who have progressed on gemcitabine plus cisplatin is dismal. We aimed to investigate the efficacy and safety of second-line liposomal irinotecan plus fluorouracil and leucovorin in patients with metastatic biliary tract cancer that has progressed on gemcitabine plus cisplatin. METHODS: This multicentre, open-label, randomised, phase 2b (NIFTY) study was done at five academic institutions in South Korea and included patients aged 19 years or older with histologically or cytologically confirmed metastatic biliary tract cancer that had progressed on first-line gemcitabine plus cisplatin and an Eastern Cooperative Oncology Group performance status of 0 or 1. By use of an interactive web-based response system integrated with an electronic data capture system, patients were randomly assigned (1:1) using permuted blocks (block size 4) to receive either intravenous liposomal irinotecan (70 mg/m2 for 90 min) plus intravenous leucovorin (400 mg/m2 for 30 min) and intravenous fluorouracil (2400 mg/m2 for 46 h) every 2 weeks or leucovorin and fluorouracil only every 2 weeks, and were stratified by primary tumour site, previous surgery with curative intent, and participating centre. Study treatment was continued until the patient had disease progression or unacceptable toxicities, or withdrew consent. The primary endpoint was blinded independent central review (BICR)-assessed progression-free survival. The primary endpoint and safety were assessed in the full analysis set and the safety analysis set, respectively, both of which comprised all randomly assigned patients who received at least one dose of the study treatment. This trial is registered with ClinicalTrials.gov, NCT03524508, and enrolment is complete. FINDINGS: Between Sept 5, 2018, and Feb 18, 2020, 193 patients were screened for eligibility, of whom 174 (88 in the liposomal irinotecan plus fluorouracil and leucovorin group and 86 in the fluorouracil plus leucovorin group) were enrolled and included in the full analysis and safety analysis sets. At a median follow-up of 11·8 months (IQR 7·7-18·7), the median BICR-assessed progression-free survival was significantly longer in the liposomal irinotecan plus fluorouracil and leucovorin group (7·1 months, 95% CI 3·6-8·8) than in the fluorouracil and leucovorin group (1·4 months, 1·2-1·5; hazard ratio 0·56, 95% CI 0·39-0·81; p=0·0019). The most common grade 3-4 adverse events were neutropenia (21 [24%] of 88 in the liposomal irinotecan plus fluorouracil and leucovorin group vs one [1%] of 86 in the fluorouracil and leucovorin group) and fatigue or asthenia (11 [13%] vs three [3%]). Serious adverse events occurred in 37 (42%) patients receiving liposomal irinotecan plus fluorouracil and leucovorin and 21 (24%) patients receiving fluorouracil and leucovorin. There were no treatment-related deaths. INTERPRETATION: Adding liposomal irinotecan to fluorouracil and leucovorin significantly improved BICR-assessed progression-free survival in patients with advanced biliary tract cancer. Liposomal irinotecan plus fluorouracil and leucovorin could be considered a standard-of-care second-line therapy for advanced biliary tract cancer. FUNDING: Servier and HK inno. N TRANSLATION: For the Korean translation of the abstract see Supplementary Materials section.

Final results of the randomized phase 2 LEO trial and bone protective effects of everolimus for premenopausal hormone receptor-positive, HER2-negative metastatic breast cancer.

The phase 2 LEO study showed that everolimus (EVE) plus letrozole (LET) with ovarian suppression increased progression-free survival (PFS) in tamoxifen-exposed premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer with visceral metastases. Here we report final survival outcomes from the LEO study, and the results of exploratory analyses of bone turnover marker changes and bone-specific progressive disease. Patients who were exposed to or progressed on tamoxifen as adjuvant/palliative treatments were randomly assigned (2:1) to the EVE (leuprorelin + LET + EVE, n = 92) or LET (leuprorelin + LET, n = 45) arm. In a median 51-months of follow-up, the median PFS was 17.5 and 13.8 months in the EVE and LET arms, respectively (P = .245). Patients in the EVE arm with baseline visceral (median PFS 16.4 vs 9.5 months, P = .040) and bone (median PFS 17.1 vs 10.9, P = .003) metastases had greater PFS compared to the LET arm. No differences in overall survival (OS) were observed (median OS, 48.3 vs 50.8 months, P = .948). The 1-year cumulative incidences of bone-specific disease progression were 6.0% and 23.4% in the EVE and LET arms, respectively (hazard ratio 0.26, P < .001). Bone turnover markers at 6 and 12 weeks after treatment decreased in the EVE arm but were increased or stationary in the LET arm. Skeletal-related events occurred in 6.5% and 11.1% of patients in the EVE and LET arms, respectively. EVE + LET with ovarian suppression prolonged PFS in patients with baseline visceral or bone metastases and offered bone-protective effects in the overall study population. However, these clinical benefits did not translate into an OS benefit.

Prognostic value of the 21-gene recurrence score for regional recurrence in patients with estrogen receptor-positive breast cancer.

PURPOSE: To evaluate the prognostic value of the 21-gene recurrence score (RS) for regional recurrence (RR) in patients with estrogen receptor-positive breast cancer. METHODS: We reviewed the medical records of 446 patients who underwent 21-gene RS assay after breast-conserving surgery or mastectomy. The high-RS group was defined as patients who were (1) older than 50 years with an RS of 26 or higher, or (2) 50 years or younger with an RS of 16 or higher. RESULTS: The 5-year rates of local recurrence (LR), RR, and distant metastasis (DM) were 2.2%, 2.7%, and 4.7%, respectively. The 5-year overall survival (OS) rate was 99.1%. Of the patients, 269 (60.3%) had low-RS, while 177 (39.7%) had high-RS. The 5-year OS rate of the high-RS group was significantly lower than that of the low-RS. The 5-year rates of RR and DM in the high-RS group were significantly higher than those in the low-RS group, while the LR rates did not differ significantly. In multivariable analysis, the high-RS group had a significant relationship with increased RR rate (p = 0.037). Patients who had both high-RS and clinical high-risk features had a significantly higher 5-year RR rate (7.9%) compared with other groups. CONCLUSIONS: High-RS was an independent risk factor for RR. The significantly higher RR rate of patients with both high-RS and clinical high-risk features compared with other groups suggests that this patient group can be a potential candidate for regional nodal irradiation.

Metabolic activity by FDG-PET/CT after neoadjuvant chemotherapy in borderline resectable and locally advanced pancreatic cancer and association with survival.

BACKGROUND: The optimal prognostic markers for neoadjuvant chemotherapy in patients with borderline resectable or locally advanced pancreatic cancer are not yet established. METHOD: Patients who received neoadjuvant chemotherapy prior to surgery and underwent FDG-PET/CT between July 2012 and December 2017 were included. Metabolic parameters including standardized uptake value (SUV), metabolic tumour volume (MTV), and total lesion glycolysis (TLG) on PET/CT, and response evaluations using PERCIST criteria, were investigated for its impact on survival and recurrence. Cox proportional hazards model was performed. Differences in risk were expressed as hazard ratio (HR) with 95 per cent confidence interval. RESULTS: The patients with borderline resectable (N = 106) or locally advanced pancreatic cancer (N = 82) were identified. The median survival was 33.6 months. Decreased metabolic parameters of PET/CT after neoadjuvant chemotherapy were associated with positive impacts on survival and recurrence such as SUVmax (HR 1.16, 95 per cent c.i. 1.01 to 1.32, P = 0.025), SUVpeak (HR 1.26, 95 per cent c.i. 1.05 to 1.51, P = 0.011), and MTV (HR 1.15, 95 per cent c.i. 1.04 to 1.26, P = 0.005). Large delta values were related to a positive impact on recurrence such as SUVmax (HR 1.21, 95 per cent c.i. 1.06 to 1.38, P = 0.005). Post-neoadjuvant chemotherapy SUVmax ≥3 (HR 3.46, 95 per cent c.i. 1.21 to 9.91; P = 0.036) was an independent prognostic factor for negative impact on survival. Patients with post-neoadjuvant chemotherapy SUVmax <3 showed more chemotherapy cycles (8.7 versus 6.2, P = 0.001), more frequent complete metabolic response (25 versus 2.2 per cent, P = 0.002), smaller tumour size (2.1 versus 3.1 cm, P = 0.002), and less frequent lymphovascular invasion (23.7 versus 51.1 per cent, P = 0.020) than patients with SUVmax ≥3. CONCLUSION: Reduction in metabolic tumour parameters of FDG- PET/CT after neoadjuvant chemotherapy indicates improved overall survival and recurrence-free survival.

Faecalicatena faecalis sp. nov., a moderately alkaliphilic bacterial strain isolated from swine faeces.

An obligately anaerobic, Gram-stain-positive, non-motile, non-spore-forming and rod-shaped strain AGMB00832T was isolated from swine faeces. Phylogenetic analysis based on the 16S rRNA gene, together with the housekeeping genes, gyrB and rpoD, revealed that strain AGMB00832T belonged to the genus Faecalicatena and was most closely related to Faecalicatena orotica KCTC 15331T. In biochemical analysis, strain AGMB00832T was shown to be negative for catalase, oxidase and urease. Furthermore, the isolate was positive for ß-glucosidase, ß-glucuronidase, glutamic acid decarboxylase, proline arylamidase, acid phosphatase and naphthol-AS-BI-phosphohydrolase. The major cellular fatty acids (> 10%) of the isolate were C14:0, C16:0 and C18:1ω11t DMA. Based on the whole genome sequence analysis, the DNA G + C content of strain AGMB00832T was 44.2 mol%, and the genome size and numbers of rRNA and tRNA genes were 5,175,159 bp, 11 and 53, respectively. The average nucleotide identity and digital DNA-DNA hybridization values between strain AGMB00832T and related strains were ≤ 77.4 and 22.5%, respectively. Furthermore, the genome analysis revealed the presence of genes for alkaline shock protein 23 and cation/proton antiporters, which may facilitate growth of strain AGMB00832T in alkaline culture condition. On the basis of polyphasic taxonomic approach, strain AGMB00832T represents a novel species within the genus Faecalicatena, for which the name Faecalicatena faecalis sp. nov. is proposed. The type strain is AGMB00832T (= KCTC 15946T = NBRC 114613T).

Neoadjuvant modified FOLFIRINOX followed by postoperative gemcitabine in borderline resectable pancreatic adenocarcinoma: a Phase 2 study for clinical and biomarker analysis.

BACKGROUND: Patients with borderline resectable pancreatic cancer (BRPC) have poor prognosis with upfront surgery. METHODS: This was a single-arm Phase 2 trial for clinical and biomarker analysis. The primary endpoint is 1-year progression-free survival (PFS) rate. Patients received 8 cycles of neoadjuvant modified (m) FOLFIRINOX. Up to 6 cycles of gemcitabine were given for patients who underwent surgery. Plasma immune cell subsets were measured for analysing correlations with overall survival (OS). RESULTS: Between May 2016 and March 2018, 44 chemotherapy- and radiotherapy-naïve patients with BRPC were included. With neoadjuvant mFOLFIRINOX, the objective response rate was 34.1%, and curative-intent surgery was done in 27 (61.4%) patients. With a median follow-up duration of 20.6 months (95% confidence interval [CI], 19.7-21.6 months), the median PFS and OS were 12.2 months (95% CI, 8.9-15.5 months) and 24.7 months (95% CI, 12.6-36.9), respectively. The 1-year PFS rate was 52.3% (95% CI, 37.6-67.0%). Higher CD14+ monocyte (quartile 4 vs 1-3) and lower CD69+ γδ T cell (γδ TCR+/CD69+) levels (quartiles 1-3 vs 4) were significantly associated with poor OS (p = 0.045 and p = 0.043, respectively). CONCLUSIONS: Neoadjuvant mFOLFIRINOX followed by postoperative gemcitabine were feasible and effective in BRPC patients. Monocyte and γδ T cells may have prognostic implications for patients with pancreatic cancer. ClinicalTrials.gov identifier: NCT02749136.

Transcriptional regulation of Salmochelin glucosyltransferase by Fur in Salmonella.

Pathogenic bacteria acquire the acquisition of iron from the host to ensure their survival. Salmonella spp. utilizes siderophores, including salmochelin, for high affinity aggressive import of iron. Although the iroBCDEN operon is reportedly responsible for the production and the transport of salmochelin, the molecular mechanisms underlying the regulation of its gene expression have not yet been characterized. Here, we analyzed the expression pattern of iroB using the lacZY transcriptional reporter system and determined the transcription start site in response to iron availability using primer extension analysis. We further examined the regulation of iroB expression by the ferric uptake regulator (Fur), a key regulatory protein involved in the maintenance of iron homeostasis in various bacteria, including Salmonella. Using sequence analysis followed by a gel shift assay, we verified that the Fur box lies within the promoter region of iroBCDE. The Fur box contained the consensus sequence (GATATTGGTAATTATTATC) and overlapped with the -10-element region. The expression of iroB was repressed by Fur in the presence of iron, as determined using an in vitro transcription assay. Therefore, we found that the iron acquisition system is regulated in a Fur-dependent manner in Salmonella.

A pilot study on intermittent every other days of 5-dose Filgrastim compared with single Pegfilgrastim in breast Cancer patients receiving adjuvant Docetaxel, doxorubicin, and cyclophosphamide (TAC) chemotherapy.

Aim To compare the efficacy and safety of intermittent every other days 5-dose filgrastim with single pegfilgrastim in patients with breast cancer receiving adjuvant docetaxel, doxorubicin, and cyclophosphamide (TAC) chemotherapy. Methods In this pilot study, Korean patients who had undergone complete resection for breast cancer and scheduled for adjuvant TAC chemotherapy were enrolled. Patients were randomized to receive either intermittent 5 doses of filgrastim (5 mcg/kg/day) or once-a-cycle pegfilgrastim (6 mg) as primary prophylaxis during the first three cycles of the TAC chemotherapy. Absolute neutrophil count (ANC) was analyzed as well. Results A total of 22 patients were randomly and equally divided into filgrastim or pegfilgrastim arms. Febrile neutropenia (FN) occurred in 1 patient in the pegfilgrastim arm (1 of 33 cycles) and none in the filgrastim arm. G3 neutropenia occurred in 1 patient (1 of 33 cycles) in the filgrastim arm and 2 patients (4 of 33 cycles) in the pegfilgrastim arm (P = 0.476). G4 neutropenia occurred in 11 patients (28 of 33 cycles) in the filgrastim arm and 9 patients (18 of 33 cycles) in the pegfilgrastim arm (P = 0.476). Except for on day 9 in cycle 3, there was no significant difference between the two groups in terms of ANC. Conclusion We observed no significant differences between the two methods of prophylaxis in terms of FN and G3/4 neutropenia incidence in patients receiving adjuvant TAC chemotherapy. Intermittent every other days 5-dose filgrastim may be available alternative to pegfilgrastim.

Prognostic factors in patients with metastatic or recurrent pancreatic cancer treated with first-line nab-paclitaxel plus gemcitabine: implication of inflammation-based scores.

Background Nab-paclitaxel plus gemcitabine (AG) is standard first-line chemotherapy for patients with metastatic pancreatic cancer (mPC). However, prognostic factors for patients with mPC treated with AG, are largely unknown. We retrospectively identified prognostic factors, including inflammation-based prognostic scores, in patients with mPC, and recurrent pancreatic cancer treated with AG as first-line treatment. Method A total of 203 patients with histologically-confirmed recurrent or metastatic pancreatic cancer who were treated with first-line AG in Asan Medical Center, Seoul, Korea, between February 2016 and December 2016 were included in this analysis. As inflammation-based scores, baseline neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and modified Glasgow prognostic scores (mGPS) were tested. Result Median age was 62 years and 116 patients (57%) were male. With median follow-up duration of 21.5 months, median progression-free survival (PFS) was 7.1 (95% CI 6.2-7.9) months, and overall survival (OS) was 15.1 (95% CI 12.6-17.6) months. In the multivariate analysis, PFS was significantly associated with liver metastasis (HR 1.43), distant lymph node metastasis (HR 1.48), and elevated CA19-9 (HR 1.56). In multivariate analysis for OS, elevated CA19-9 (HR 1.75), liver metastasis (HR 1.76), distant lymph node metastasis (HR 1.41), and high mGPS (mGPS ≥1 vs.0: HR 1.64) were independent prognostic factors. NLR and PLR were not significantly associated with PFS and OS. Conclusion Among the inflammation based prognostic scores, mGPS was a reliable prognostic indicator that could stratify survival outcomes in patients with recurrent or mPC who received AG as first-line chemotherapy.