Effects of Early Short-Course Corticosteroids on Immune-Related Adverse Events in Non-Small Cell Lung Cancer Patients Receiving Immune Checkpoint Inhibitors.

INTRODUCTION: In real-world practice, most non-small cell lung cancer (NSCLC) patients receiving combined immunochemotherapy are exposed to short-course corticosteroids following immune checkpoint inhibitor (ICI) infusion to prevent chemotherapy-related adverse events. However, whether this early short-course corticosteroid use prevents immune-related adverse events (irAEs) remains unknown. METHODS: Between January 1st, 2015, and December 31st, 2020, NSCLC patients who received at least one cycle of ICI with or without chemotherapy were enrolled. Early short-course corticosteroids were defined as corticosteroids administered following ICI injection and before chemotherapy on the same day and no longer than 3 days afterward. The patients were categorized as either "corticosteroid group" or "non-corticosteroid group" depending on their exposure to early short-course corticosteroid. The frequencies of irAEs requiring systemic corticosteroid use and irAEs leading to ICI discontinuation were compared between the two groups, and exploratory survival analyses were performed. RESULTS: Among 252 eligible patients, 137 patients were categorized as "corticosteroid group" and 115 patients as "non-corticosteroid group." The corticosteroid group enriched patients in the first-line setting (n = 75, 54.7%), compared to the non-corticosteroid group (n = 28, 24.3%). Thirty patients (21.9%) in the corticosteroid group and 35 patients (30.4%) in the non-corticosteroid group developed irAEs requiring systemic corticosteroid use (odds ratio [OR], 0.64; 95% confidence interval [CI], 0.35-1.18; p = 0.15). Eight patients (5.8%) in the corticosteroid group, as compared with 18 patients (15.7%) in the non-corticosteroid group, permanently discontinued ICI due to irAEs (OR, 0.34; 95% CI, 0.12-0.85; p = 0.013). CONCLUSION: Early short-course corticosteroids following each ICI injection may reduce the rate of irAEs that lead to ICIs discontinuation, warranting further investigation of its prophylactic use to mitigate clinically significant irAEs.

Sequential multimodal treatments with chemotherapy and surgery for advanced soft tissue sarcoma may be associated with better survival than chemotherapy.

BACKGROUND: In patients with advanced soft tissue sarcoma (STS), surgery had been reported to be associated with superior overall survival (OS). Chemotherapy details for such patients were less reported, and whether multimodal treatment with surgery and chemotherapy provides extra survival benefit remains unclear. METHODS: We retrospectively reviewed patients with newly diagnosed advanced STS treated at National Taiwan University Hospital from January 1, 2011, to December 31, 2017. OS was calculated from the day of diagnosis of advanced STS to the day of death or last follow-up. Baseline patient characteristics and details regarding surgery and chemotherapy were recorded. RESULTS: A total of 545 patients were diagnosed with STS from 2011 to 2017, of which 226 patients had advanced STS. The median age was 54.7 years, and 54% of patients were women. Approximately 38% of patients with advanced STS underwent surgery and exhibited a trend of longer OS compared with who did not (median = 18.6 vs. 11.9 months, p = 0.083). In the chemotherapy subgroup, the benefit of surgery was more prominent (median = 21.9 vs. 16.5 months, p = 0.037). Patients who received chemotherapy prior to surgery exhibited numerically longer OS than those who underwent surgery first (median = 33.9 vs. 18.3 months, p = 0.155). After adjusting other clinical factors, chemotherapy remained an independent factor associated with favourable OS. CONCLUSION: Surgery may be more beneficial for the patients who receive chemotherapy. Our results support evaluation of sequential multimodal treatments strategy including surgery and chemotherapy in patients with advanced STS.

PAK and PI3K pathway activation confers resistance to KRASG12C inhibitor sotorasib.

BACKGROUND: KRAS is a frequently mutated oncogene in human cancer. Clinical studies on the covalent inhibitors of the KRASG12C mutant have reported promising results. However, primary and acquired resistance may limit their clinical use. METHODS: Sotorasib-resistant cell lines were established. We explored the signalling pathways activated in these resistant cell lines and their roles in sotorasib resistance. RESULTS: The resistant cells exhibited increased cell-matrix adhesion with increased levels of stress fibres and focal adherens. p21-activated kinases (PAKs) were activated in resistant cells, which phosphorylate MEK at serine 298 of MEK and serine 338 of c-Raf to activate the mitogen-activated protein kinase pathway. The PAK inhibitors FRAX597 and FRAX486 in synergy with sotorasib reduced the viability of KRASG12C mutant cancer cells. Furthermore, the PI3K/AKT pathway was constitutively active in sotorasib-resistant cells. The overexpression of constitutively activated PI3K or the knockdown of PTEN resulted in resistance to sotorasib. PI3K inhibitor alpelisib was synergistic with sotorasib in compromising the viability of KRASG12C mutant cancer cells. Moreover, PI3K and PAK pathways formed a mutual positive regulatory loop that mediated sotorasib resistance. CONCLUSIONS: Our results indicate that the cell-matrix interaction-dependent activation of PAK mediates resistance to sotorasib through the activation of MAPK and PI3K pathways.

Monitoring of T790M in plasma ctDNA of advanced EGFR-mutant NSCLC patients on first- or second-generation tyrosine kinase inhibitors.

BACKGROUND: The T790M mutation is the major resistance mechanism to first- and second-generation TKIs in EGFR-mutant NSCLC. This study aimed to investigate the utility of droplet digital PCR (ddPCR) for detection of T790M in plasma circulating tumor DNA (ctDNA), and explore its impact on prognosis. METHODS: This prospective study enrolled 80 advanced lung adenocarcinoma patients treated with gefitinib, erlotinib, or afatinib for TKI-sensitizing mutations between 2015 and 2019. Plasma samples were collected before TKI therapy and at tri-monthly intervals thereafter. Genotyping of ctDNA for T790M was performed using a ddPCR EGFR Mutation Assay. Patients were followed up until the date of death or to the end of 2021. RESULTS: Seventy-five of 80 patients experienced progressive disease. Fifty-three (71%) of 75 patients underwent rebiopsy, and T790M mutation was identified in 53% (28/53) of samples. Meanwhile, plasma ddPCR detected T790M mutation in 23 (43%) of 53 patients. The concordance rate of T790M between ddPCR and rebiopsy was 76%, and ddPCR identified 4 additional T790M-positive patients. Ten (45%) of 22 patients who did not receive rebiopsy tested positive for T790M by ddPCR. Serial ddPCR analysis showed the time interval from detection of plasma T790M to objective progression was 1.1 (0-4.1) months. Compared to 28 patients with rebiopsy showing T790M, the overall survival of 14 patients with T790M detected solely by ddPCR was shorter(41.3 [95% CI, 36.6-46.0] vs. 26.6 months [95% CI, 9.9-43.3], respectively). CONCLUSION: Plasma ddPCR-based genotyping is a useful technology for detection and monitoring of the key actionable genomic alteration, namely, T790M, in patients treated with gefitinib, erlotinib, or afatinib for activating mutations, to achieve better patient care and outcome.

DNA replication stress and mitotic catastrophe mediate sotorasib addiction in KRASG12C-mutant cancer.

BACKGROUND: Sotorasib is the first KRASG12C inhibitor approved by the US Food and Drug Administration for treating KRASG12C-mutant non-small-cell lung cancer (NSCLC). Clinical trials on the therapeutic use of sotorasib for cancer have reported promising results. However, KRASG12C-mutant cancers can acquire resistance to sotorasib after treatment. We incidentally discovered that sotorasib-resistant (SR) cancer cells are addicted to this inhibitor. In this study, we investigated the mechanisms underlying sotorasib addiction. METHODS: Sotorasib-resistant cells were established using KRASG12C-mutant pancreatic cancer and NSCLC cell lines. Cell viability in the presence or absence of sotorasib and in combination with multiple inhibitors was assessed through proliferation assay and annexin V/propidium iodide (PI) flow cytometry assays. The mechanisms underlying drug addiction were elucidated through 5-bromo-2'-deoxyuridine (BrdU) incorporation assay, immunofluorescence staining, time-lapse microscopy, and comet assay. Furthermore, a subcutaneous xenograft model was used to demonstrate sotorasib addiction in vivo. RESULTS: In the absence of sotorasib, the sotorasib-resistant cells underwent p21Waf1/Cip1-mediated cell cycle arrest and caspase-dependent apoptosis. Sotorasib withdrawal resulted in robust activation of mitogen-activated protein kinase (MAPK) pathway, inducing severe DNA damage and replication stress, which activated the DNA damage response (DDR) pathway. Persistent MAPK pathway hyperactivation with DDR exhaustion led to premature mitotic entry and aberrant mitosis, followed by micronucleus and nucleoplasmic bridge formation. Pharmacologic activation of the MAPK pathway with a type I BRAF inhibitor could further enhance the effects of sotorasib withdrawal on sotorasib-resistant cancer cells both in vitro and in vivo. CONCLUSIONS: We elucidated the mechanisms underlying the sotorasib addiction of cancer cells. Sotorasib addiction appears to be mediated through MAPK pathway hyperactivity, DNA damage, replication stress, and mitotic catastrophe. Moreover, we devised a therapeutic strategy involving a type I BRAF inhibitor to strengthen the effects of sotorasib addiction; this strategy may provide clinical benefit for patients with cancer.

Precision Management of Advanced Non-Small Cell Lung Cancer.

The rapid evolution of treatment for advanced lung cancer is a story of how scientists have struggled to move from nonselective cytotoxic chemotherapy to personalized precision medicine. In this century, extraordinary advances have been made in the management of advanced and metastatic non-small cell lung cancer, especially in the development of small molecules targeting specific tyrosine kinase receptors and immune checkpoint inhibitors. These developments have led to a significant improvement in survival for lung cancer patients with metastatic disease. Now, the core guidelines to treat non-small cell lung cancer are based on the identification of targetable driver mutations and immune checkpoints. Continued investigations of newly identified druggable genetic alterations, explorations of biomarkers of immune checkpoint inhibitors, development of next-generation immunotherapy, and optimization of combination therapy are necessary to provide better treatment outcomes for lung cancer patients in the future.

Severe immune thrombocytopenia following COVID-19 vaccination (Moderna) and immune checkpoint inhibitor.

Safe and effective prophylactic vaccines are urgently needed to contain the coronavirus disease 2019 (COVID-19) pandemic. However, several vaccination-related adverse effects have been reported. Here, we report a rare case of severe immune thrombocytopenia occurring 3 days after receiving the mRNA-1273 (Moderna) COVID-19 vaccine in an Asian woman with a history of refractory lung adenocarcinoma treated with durvalumab, an immune checkpoint inhibitor. Treatment with platelet transfusion (12 units) and oral prednisolone (1 mg/kg per day) significantly improved her hemoptysis with thrombocytopenia. To the best of our knowledge, this is the first case of ITP following Moderna inoculation among Asians. This study highlights a potential adverse effect of mRNA-based COVID-19 vaccines in cancer patients receiving immune checkpoint inhibitors.

Dynamics of cellular immune responses in recipients of renal allografts positive for hepatitis B surface antigen.

BACKGROUND/PURPOSE: Hepatitis B surface antigen (HBsAg)-positive renal transplantation recipients must take lifelong immunosuppressants and nucleotide analogues (NAs). We investigated the cellular immune responses of HBsAg-positive renal transplantation recipients taking immunosuppressants and NAs. METHODS: Blood samples were collected from HBsAg-positive individuals with end-stage renal disease on the transplant waiting list (Group 1) and renal transplantation recipients taking immunosuppressants and NAs (Group 2) or immunosuppressants without NAs (Group 3). Hepatitis B virus (HBV)-specific pentamers were used to quantify circulating HBV-specific CD8+ T cells. RESULTS: Groups 2 and 3 had higher cellular immune responses, as indicated by significantly lower regulatory T (Treg)/CD8+ T cell ratios than Group 1. With undetectable viral loads under both immunosuppressant and NAs, the CD8+ T cell and HBV-specific CD8+ T cell frequencies were similar in Group 2 and Group 1. Patients in Group 3 did not use NAs and had an elevated viral load and higher HBV-specific CD8+ T cell and IFN-γ-producing HBV-specific CD8+ T cell frequencies, but lower a frequency of programmed death-1 (PD-1)+ HBV-specific CD8+ T cells than the other groups. Increased viral replication in Group 3 resulted in significantly higher CD8+ T cell and IFN-γ-producing CD8+ T cell frequencies than Group 1. CONCLUSION: Immunosuppressant therapy increases viral replication in HBsAg-positive renal transplant recipients due to disabling or dysregulation of virus-specific CD8+ T cells. The higher cellular immune responses due to lower Treg/CD8+ T cell ratios in HBsAg-positive renal transplant recipients may be one of the reasons to induce liver pathology because of uncontrolled viral replication.

Methylmercury Induces Mitochondria- and Endoplasmic Reticulum Stress-Dependent Pancreatic ß-Cell Apoptosis via an Oxidative Stress-Mediated JNK Signaling Pathway.

Methylmercury (MeHg), a long-lasting organic pollutant, is known to induce cytotoxic effects in mammalian cells. Epidemiological studies have suggested that environmental exposure to MeHg is linked to the development of diabetes mellitus (DM). The exact molecular mechanism of MeHg-induced pancreatic ß-cell cytotoxicity is still unclear. Here, we found that MeHg (1-4 µM) significantly decreased insulin secretion and cell viability in pancreatic ß-cell-derived RIN-m5F cells. A concomitant elevation of mitochondrial-dependent apoptotic events was observed, including decreased mitochondrial membrane potential and increased proapoptotic (Bax, Bak, p53)/antiapoptotic (Bcl-2) mRNA ratio, cytochrome c release, annexin V-Cy3 binding, caspase-3 activity, and caspase-3/-7/-9 activation. Exposure of RIN-m5F cells to MeHg (2 µM) also induced protein expression of endoplasmic reticulum (ER) stress-related signaling molecules, including C/EBP homologous protein (CHOP), X-box binding protein (XBP-1), and caspase-12. Pretreatment with 4-phenylbutyric acid (4-PBA; an ER stress inhibitor) and specific siRNAs for CHOP and XBP-1 significantly inhibited their expression and caspase-3/-12 activation in MeHg-exposed RIN-mF cells. MeHg could also evoke c-Jun N-terminal kinase (JNK) activation and reactive oxygen species (ROS) generation. Antioxidant N-acetylcysteine (NAC; 1mM) or 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (trolox; 100 µM) markedly prevented MeH-induced ROS generation and decreased cell viability in RIN-m5F cells. Furthermore, pretreatment of cells with SP600125 (JNK inhibitor; 10 µM) or NAC (1 mM) or transfection with JNK-specific siRNA obviously attenuated the MeHg-induced JNK phosphorylation, CHOP and XBP-1 protein expression, apoptotic events, and insulin secretion dysfunction. NAC significantly inhibited MeHg-activated JNK signaling, but SP600125 could not effectively reduce MeHg-induced ROS generation. Collectively, these findings demonstrate that the induction of ROS-activated JNK signaling is a crucial mechanism underlying MeHg-induced mitochondria- and ER stress-dependent apoptosis, ultimately leading to ß-cell death.

Two-year protocol biopsy after kidney transplantation in clinically stable recipients - a retrospective study.

The idea of protocol biopsy is to detect subclinical pathologies, including rejection, recurrent disease, or infection for early intervention and adjustment of immunosuppressants. Nevertheless, it is not adopted by most clinicians because of its low yield rate and uncertain long-term benefits. This retrospective study evaluated the impact of protocol biopsy on renal function and allograft survival. A two-year protocol biopsy was proposed for 190 stable patients; 68 of them accepted [protocol biopsy (PB) group], while 122 did not [nonprotocol biopsy (NPB) group]. The rejection diagnosis was made in 13 patients by protocol biopsy, and 11 of them had borderline rejection. In the following 5 years, graft survival was better in the PB group than in the NPB group (P = 0.0143). A total of 4 and 17 patients in the PB and NPB groups, respectively, had rejection events proven by indication biopsy. Renal function was better preserved in the PB group than in the NPB group (P = 0.0107) for patients with rejection events. Nevertheless, the survival benefit disappeared by a longer follow-up period (12-year, P = 0.2886). In conclusion, 2-year protocol biopsy detects subclinical pathological changes in rejection and preserves renal function by early intervention so as to prolong graft survival within 5 years.

4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene, a Major Active Metabolite of Bisphenol A, Triggers Pancreatic ß-Cell Death via a JNK/AMPKα Activation-Regulated Endoplasmic Reticulum Stress-Mediated Apoptotic Pathway.

4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP), a major active metabolite of bisphenol A (BPA), is generated in the mammalian liver. Some studies have suggested that MBP exerts greater toxicity than BPA. However, the mechanism underlying MBP-induced pancreatic ß-cell cytotoxicity remains largely unclear. This study demonstrated the cytotoxicity of MBP in pancreatic ß-cells and elucidated the cellular mechanism involved in MBP-induced ß-cell death. Our results showed that MBP exposure significantly reduced cell viability, caused insulin secretion dysfunction, and induced apoptotic events including increased caspase-3 activity and the expression of active forms of caspase-3/-7/-9 and PARP protein. In addition, MBP triggered endoplasmic reticulum (ER) stress, as indicated by the upregulation of GRP 78, CHOP, and cleaved caspase-12 proteins. Pretreatment with 4-phenylbutyric acid (4-PBA; a pharmacological inhibitor of ER stress) markedly reversed MBP-induced ER stress and apoptosis-related signals. Furthermore, exposure to MBP significantly induced the protein phosphorylation of JNK and AMP-activated protein kinase (AMPK)α. Pretreatment of ß-cells with pharmacological inhibitors for JNK (SP600125) and AMPK (compound C), respectively, effectively abrogated the MBP-induced apoptosis-related signals. Both JNK and AMPK inhibitors also suppressed the MBP-induced activation of JNK and AMPKα and of each other. In conclusion, these findings suggest that MBP exposure exerts cytotoxicity on ß-cells via the interdependent activation of JNK and AMPKα, which regulates the downstream apoptotic signaling pathway.

Pancreatic neck transection using a harmonic scalpel increases risk of biochemical leak but not postoperative pancreatic fistula after pancreaticoduodenectomy.

BACKGROUND: The effect of a harmonic scalpel on postoperative pancreatic fistula (POPF) has not been addressed. This study assessed the effect of pancreatic neck transection using a harmonic scalpel on rate and severity of POPF after pancreaticoduodenectomy (PD). METHODS: This retrospective analysis included patients who underwent PD at National Taiwan University Hospital between July 2015 and March 2019. We compared rate and severity of POPF between patients who underwent pancreatic neck transection using a harmonic scalpel versus electrosurgical unit. RESULTS: Of 422 consecutive PDs, the pancreatic neck was transected using a harmonic scalpel or electrosurgical unit in 144 and 278 patients, respectively. Use of a harmonic scalpel significantly increased risk of biochemical leak (25.7% versus [vs] 10.8%; P < 0.05) but not clinically relevant POPF (CR-POPF; 30.2% vs 26.4%; P = 0.41). Harmonic transection was an independent predictor of biochemical leak (odds ratio [OR] = 2.93; P < 0.05) but not CR-POPF (OR = 0.83; P = 0.41) or other major complications (OR = 0.72; P = 0.27). There was no significant intergroup difference in postoperative hospital stay. CONCLUSION: Pancreatic neck transection using a harmonic scalpel increased risk of biochemical leak but not CR-POPF or other major complications.

Association of Programmed Death-Ligand 1 Expression with Fusion Variants and Clinical Outcomes in Patients with Anaplastic Lymphoma Kinase-Positive Lung Adenocarcinoma Receiving Crizotinib.

BACKGROUND: Programmed death-ligand 1 (PD-L1) expression is associated with clinical outcomes of epidermal growth factor receptor (EGFR) mutant lung adenocarcinoma (ADC) treated with tyrosine kinase inhibitors (TKIs). However, whether PD-L1 expression plays a role in anaplastic lymphoma kinase (ALK)-positive lung ADC is unknown. We aimed to evaluate the impact of PD-L1 in patients with ALK-positive lung ADC receiving crizotinib. MATERIALS AND METHODS: PD-L1 expression was identified by immunohistochemistry (IHC). Reverse transcriptase-polymerase chain reaction was used for ALK variant detection, and immunofluorescence-based multiplex staining was applied for exploring immune cells in tumor microenvironments. RESULTS: A total of 78 patients with ALK-positive advanced ADC were enrolled in our study, of whom 52 received crizotinib. Compared with EGFR/ALK wild-type tumors, PD-L1 expression was lower in ALK-positive ADC. ALK fusion variants were identified in 32 patients, and those with variant 3 and 5 (short variants) had higher PD-L1 expression than those with other variants. The crizotinib objective response rate (ORR) and progression-free survival (PFS) was better in tumors with negative PD-L1 expression (ORR/PFS in PD-L1 0% vs. 1%-49% vs. 50%-100%: 60.7%/11.8 months vs. 38.5%/6.5 months vs. 36.4%/4.0 months, p = .007/.022). The multivariate Cox proportional hazards model revealed that PD-L1 0% (vs. ≥1%) was an independent factor for longer PFS (adjusted hazard ratio 0.322, 95% confidence interval 0.160-0.650, p = .002). Multiplex IHC in three cases showed a varied extent of immune cell infiltrations in tumors with different PD-L1 expression. CONCLUSION: Positive PD-L1 expression was associated with unfavorable clinical outcomes in patients with ALK-positive lung ADC receiving crizotinib. IMPLICATIONS FOR PRACTICE: Not all lung adenocarcinoma with sensitizing driver mutations experienced durable responses to small-molecule tyrosine kinase inhibitors (TKIs). Similar to the negative impact of programmed death-ligand 1 (PD-L1) in epidermal growth factor receptor mutant tumors treated with TKIs, this study demonstrated that positive PD-L1 expression was also associated with worse response rate and shorter progression-free survival of anaplastic lymphoma kinase (ALK)-positive adenocarcinoma treated with crizotinib. Among different ALK fusion partners, tumors with short variants (V3 and V5) had higher PD-L1 compared with long variants (V1, V2, and V6). Testing PD-L1 before initiating crizotinib for ALK-positive lung cancer could be a simple method to provide important prognostic information.

Telbivudine for renal transplant recipients with chronic hepatitis B infection: a randomized controlled trial with early termination.

BACKGROUND: The aim of this study was to analyze changes in renal function in HBsAg-positive renal transplant recipients receiving lamivudine who did or did not switch to telbivudine. METHODS: In this prospective randomized clinical trial (RCT), HBsAg-positive renal transplant recipients who had received lamivudine prophylaxis for at least 6 months were 1:2 randomized to receive either lamivudine or telbivudine for another 24 months. Renal function was evaluated by creatinine level and estimated glomerular filtration rate (eGFR) at the time of randomization (baseline), 6, 12, 18, and 24 months respectively. RESULTS: This RCT was prematurely terminated after recruiting only 17 patients due to a high incidence (61.5%; 8/13) of clinical myalgia in the telbivudine group. Cox's proportional hazards model revealed that there was no independent predictor of myalgia. Based on intention-to-treat and per protocol analyses using generalized estimating equations, the patients in the randomized telbivudine group had a significantly increased eGFR and the patients in the lamivudine group had a significantly decreased eGFR at the end of follow-up compared to the values at study enrollment. However, there was no significant difference between the lamivudine and telbivudine groups. CONCLUSIONS: The renal protective effect of telbivudine for HBsAg positive renal transplant recipients was uncertain for high incidence of myalgia and only patients who were on telbivudine for 24 months had renal function maintenance.

Prognostic factors for renal transplant graft survival in a retrospective cohort of 1000 cases: The role of desensitization therapy.

BACKGROUND: To review the results of renal transplantation after promulgation of the Human Organ Transplant Act in Taiwan in 1987, we conducted a retrospective study in the first 1000 cases performed in our hospital. Prognostic factors for graft survival were assessed with emphasis on the impact of donor-specific antibody (DSA). METHODS: Between January 1988 and April 2014, there were 1000 cases of renal transplantation performed in our hospital. Excluding 30 patients of ABO-incompatible transplantation, we reviewed 970 cases of ABO-compatible renal transplantation to analyze the prognostic factors for graft survival. The patients were grouped according to the dates of operations before (the Early group: 503 cases) and after (the Late group: 467 cases) the introduction of detection and desensitization of alloantibody in our hospital in 2004. RESULTS: The overall 5-year graft survival rate were 82.6%, which was significantly lower in the Early group (79.2%) than the Late group (86.3%) (p = 0.0012). The 1-year rejection-free survival was significantly lower in the Early group (78.3%) than the Late group (91.2%) (p = 0.0165). The difference between the two groups became insignificant when the time of observation extended beyond 12 months. In a multivariate regression model, we identified significant factors for poor graft survival, including HLA mismatches, delayed graft function with or without recovery, and antibody-mediate rejection (AMR). CONCLUSION: HLA mismatches, delayed graft function with or without recovery, and AMR were significant factors for poor graft survival. Detection and desensitization of DSA currently might be inadequate to improve the long-term outcome of renal transplantation.

The effect of performing two pancreatoduodenectomies by a single surgical team in one day on surgeons and patient outcomes.

BACKGROUND: The centralization of pancreatoduodenectomy (PD) has been shown to improve patient outcomes. The scheduling of two PDs in one day is one option to shorten the waiting time for patients referred to high volume centers. The effect on the surgical team or patient outcomes of such an approach have not previously been explored. This study aimed to investigate the effect of scheduling two PDs in one day on the surgeon's workload and patient outcomes. METHODS: A retrospective review of patients undergoing PD by a single surgeon between 2007 and 2018 was performed. Patients were allocated into: first PD (FIRSTPD group) or second PD (SECONDPD group) according to the position on the surgical operating list. The intraoperative, postoperative outcomes, and workload (the Surgery Task Load Index; SURG-TLX) were assessed between two groups. RESULTS: A total of 967 (91%) and 101 (9%) patients were included in the FIRSTPD and SECONDPD group, respectively. There were no differences in the duration of surgery (coefficient = -9.65; 95% confidence interval: -29.26 to 9.94; P = 0.334), incidence of major complications (odds ratio = 1.08; 95% confidence interval: 0.67-1.73; P = 0.739), or 90-day mortality (odds ratio = 1.03; 95% confidence interval: 0.12-8.53; P = 0.978) for those patients in the SECONDPD group as compared to the FIRSTPD group. The mean scores of two (physical and temporal demand) of the six SURG-TLX subscales of surgical workload were recorded as significantly higher by surgeons following two PD's as compared to one PD. CONCLUSIONS: Although scheduling a second PD in one day shows no association with adverse patient outcomes, there is an increase in the physical and temporal subscales of surgical workload and consideration should be given to how this could be minimized.

Clinical outcomes and secondary epidermal growth factor receptor (EGFR) T790M mutation among first-line gefitinib, erlotinib and afatinib-treated non-small cell lung cancer patients with activating EGFR mutations.

Gefitinib, erlotinib and afatinib are approved for first-line treatment of advanced non-small cell lung cancer (NSCLC) bearing an activating epidermal growth factor receptor (EGFR) mutation. However, the clinical outcomes among the three EGFR tyrosine kinase inhibitors (TKIs) are still controversial. We aimed to evaluate clinical outcomes and secondary EGFR T790M mutation among the three EGFR TKIs. From May 2014 to January 2016, a total of 301 patients received treatment with gefitinib, erlotinib or afatinib, for first-line treatment of advanced NSCLC with an activating EGFR mutation, based on their clinicians' choice. The median overall survival (OS) was 37.0 months. Although the baseline characteristics of patients were unequal, progression-free survival and OS did not differ among the 3 groups. Multivariate analysis found that gefitinib (adjusted odds ratio [aOR] 3.29, 95% confidence interval [CI], 1.15-9.46, p = 0.027), EGFR TKI treatment duration more than 13 months (aOR 3.16, 95% CI, 1.20-8.33, p = 0.020), male (aOR 3.25, 95% CI, 1.10-9.66, p = 0.034), initial liver metastasis (aOR 4.97, 95% CI 1.18-20.96, p = 0.029) and uncommon EGFR mutation (aOR 0.14, 95% CI, 0.02-0.97, compared to EGFR deletion 19, p = 0.047) were independent factors for secondary T790M mutation. In real-world practice, choosing first line EGFR TKI based on the patients' clinical characteristics yielded good clinical outcomes. First-line gefitinib, longer EGFR TKI treatment duration, male, initial liver metastasis and uncommon EGFR mutations may be independent factors for secondary EGFR T790M mutation.

Targeted next-generation sequencing identifies distinct clinicopathologic and molecular entities of intraductal papillary neoplasms of the bile duct.

Intraductal papillary neoplasm of the bile duct (IPNB) is a mass-forming neoplasm in the bile duct considered to be the biliary counterpart of pancreatic intraductal papillary mucinous neoplasm (IPMN). By its cell lineage, IPNB can be classified into gastric, intestinal, pancreatobiliary, and oncocytic types. Recently, a group of Japanese and Korean pathologists proposed that IPNB be classified into two types, with type 1, being the histological counterpart of IPMN and type 2, having a more complex histological architecture. We used targeted next-generation sequencing to study the molecular change of 37 IPNBs and identified frequent mutations of KRAS (49%), GNAS (32%), RNF43 (24%), APC (24%), TP53 (24%), and CTNNB1 (11%) in IPNBs. Intestinal-type IPNB was associated with KRAS, GNAS, and RNF43 mutations. Japan-Korea consensus type 1 was associated with KRAS and GNAS mutations. All four IPNBs with CTNNB1 mutations were of pancreatobiliary type and located in the extrahepatic bile duct. A hierarchical analysis identified three distinct groups within IPNB: group 1 was Japan-Korea consensus type 1 tumors with macroscopic mucin, old age, and frequent KRAS, GNAS, and RNF43 mutations. Group 2 was Japan-Korea consensus type 2 with intestinal differentiation and frequent KRAS mutation but rare GNAS mutation, MUC2 expression, and macroscopic mucin. Group 3 was characterized by CTNNB1 mutation, extrahepatic location, lack of expression of intestinal markers, Japan-Korea consensus type 2, and lack of mutations in KRAS, APC, RNF43, and GNAS. Our results indicated that IPNB is a heterogeneous disease and that the activation of Ras-mitogen-activated protein kinase (MAPK), Wnt/ß-catenin, and G-protein-coupled receptor (GPCR)-cAMP signaling is the main oncogenic mechanism of IPNB.

The Differences in Clinicopathologic and Prognostic Characteristics Between Surgically Resected Peripheral and Central Lung Squamous Cell Carcinoma.

BACKGROUND: Pulmonary peripheral-type squamous cell carcinoma (p-SqCC) has been increasing in incidence. However, little is known about the clinicopathologic features of p-SqCC. This study aimed to investigate the clinicopathologic characteristics and clinical outcomes of p-SqCC compared with central-type SqCC (c-SqCC) in a large cohort of surgically resected lung SqCC patients with long-term follow-up results. METHODS: The study included 268 patients with SqCC who underwent surgical resection at the authors' institute from January 1990 to September 2013. The mean follow-up period was 67.1 months. The clinicopathologic and genetic characteristics were investigated in relation to their association with progression-free survival (PFS) and overall survival (OS) based on tumor location. RESULTS: The study cohort included 120 patients with p-SqCC and 148 patients with c-SqCC. Compared with c-SqCC, p-SqCC was correlated with older age (p = 0.002), female sex (p = 0.033), better performance status (p < 0.001), smaller tumor (p = 0.004), less lymph node metastasis (p < 0.001), and an earlier pathologic stage (p < 0.001). Despite the clinicopathologic differences, tumor location was not significantly correlated with clinical outcomes. For the p-SqCC patients, the multivariate analysis showed a significant correlation of lymphovascular invasion (PFS, p < 0.001; OS, p < 0.001) and lymph node metastasis (p = 0.007; OS, p = 0.022) with poor PFS and OS, but a significant correlation of incomplete tumor resection (PFS, p = 0.009) only with poor PFS. CONCLUSIONS: The clinicopathologic features differed between the p-SqCC and c-SqCC patients. Lymphovascular invasion and lymph node metastasis were independent prognostic factors of p-SqCC. These prognostic factors may be potentially used as indicators for adjuvant therapies to be used with patients who have p-SqCC.

Endoscopic Retrograde Biliary Drainage Causes Intra-Abdominal Abscess in Pancreaticoduodenectomy Patients: An Important But Neglected Risk Factor.

BACKGROUND: Patients with periampullary cancer frequently suffer obstructive jaundice and commonly require preoperative biliary drainage (PBD) for relief and to avoid related complications. Although research has established a correlation between PBD and surgical wound infection, the impact of PBD on major infectious complications (intra-abdominal abscess [IAA]) and overall mortality remains debatable. We hypothesized that PBD could lead to IAA and mortality, and evaluated their correlation in patients undergoing pancreaticoduodenectomy (PD). METHODS: We enrolled patients undergoing PD at an Asian academic medical center between 2007 and 2016. The types of PBD included endoscopic retrograde biliary drainage (ERBD) and percutaneous transhepatic cholangiography and drainage (PTCD). The primary outcome was IAA, defined as the presence of pus or infected fluid inside the abdominal cavity and with documented infectious pathogens. RESULTS: There was one (0.1%) 30-day mortality and eight (0.9%) 90-day mortalities among 899 consecutive patients examined. More than one-quarter of patients had PBD (n = 237, 26.4%; 165 ERBD, 72 PTCD). In the ERBD, PTCD, and non-PBD groups, the IAA rates were 37.0%, 16.7%, and 10.6%, respectively. On multivariate analysis, ERBD (odds ratio 3.67; 95% confidence interval 2.22-6.06; p < 0.001) was the only significant factor associated with IAA. No significant factor was found to analyze variables associated with mortality. CONCLUSIONS: ERBD, but not PTCD, is associated with an increased risk of IAA in patients undergoing PD, which suggests that ERBD should be avoided whenever possible to prevent IAA. Further randomized clinical trials should be conducted to validate this relationship.