Phase III, Randomized Study of Atezolizumab Plus Bevacizumab and Chemotherapy in Patients With EGFR- or ALK-Mutated Non-Small-Cell Lung Cancer (ATTLAS, KCSG-LU19-04).

PURPOSE: In the treatment of non-small-cell lung cancer (NSCLC) with a driver mutation, the role of anti-PD-(L)1 antibody after tyrosine kinase inhibitor (TKI) remains unclear. This randomized, open-label, multicenter, phase III study evaluates the efficacy of atezolizumab plus bevacizumab, paclitaxel, and carboplatin (ABCP ) in EGFR- or ALK-mutated NSCLC that progressed before TKI therapy. MATERIALS AND METHODS: We compared the clinical efficacy of ABCP followed by maintenance therapy with atezolizumab plus bevacizumab with pemetrexed plus carboplatin or cisplatin (PC) followed by pemetrexed maintenance. The primary end point was progression-free survival (PFS). RESULTS: A total of 228 patients with activating EGFR mutation (n = 215) or ALK translocation (n = 13) were enrolled from 16 sites in the Republic of Korea and randomly assigned at 2:1 ratio to either ABCP (n = 154) or PC arm (n = 74). The median follow-up duration was 26.1 months (95% CI, 24.7 to 28.2). Objective response rates (69.5% v 41.9%, P < .001) and median PFS (8.48 v 5.62 months, hazard ratio [HR], 0.62 [95% CI, 0.45 to 0.86]; P = .004) were significantly better in the ABCP than PC arm. PFS benefit increased as PD-L1 expression increased, with an HR of 0.47, 0.41, and 0.24 for PD-L1 ≥1%, ≥10%, and ≥50%, respectively. Overall survival was similar between ABCP and PC arm (20.63 v 20.27 months, HR, 1.01 [95% CI, 0.69 to 1.46]; P = .975). The safety profile of the ABCP arm was comparable with that previously reported, with no additional safety signals, but higher rates of treatment-related adverse events were observed compared with the PC arm. CONCLUSION: To our knowledge, this study is the first randomized phase III study to demonstrate the clinical benefit of anti-PD-L1 antibody in combination with bevacizumab and chemotherapy in patients with EGFR- or ALK-mutated NSCLC who have progressed on relevant targeted therapy.

Personalized Biomarker-Based Umbrella Trial for Patients With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: KCSG HN 15-16 TRIUMPH Trial.

PURPOSE: A precise oncologic approach for head and neck squamous cell carcinoma (HNSCC) is necessary. We performed a genomic profile-based umbrella trial for the patients with platinum-refractory recurrent and/or metastatic HNSCC. METHODS: In this multicenter, open-label, single-arm phase II trial, we performed targeted next-generation sequencing (NGS). Patients were assigned to each treatment arm on the basis of their matching genomic profiles: arm 1, alpelisib, a PIK3CA inhibitor; arm 2, poziotinib, an epidermal growth factor receptor/HER2 inhibitor; arm 3, nintedanib, an fibroblast growth factor receptor inhibitor; and arm 4, abemaciclib, a CDK4/6 inhibitor. If there was no matching target, patients were allocated to arm 5, duvalumab ± tremelimumab, anti-PD-L1/cytotoxic T-cell lymphocyte-4 inhibitor. When progressive disease (PD) occurred in arms 1-4, cross over to arm 5 was allowed. The primary end point was disease control rate (DCR) in arm 1 and overall response rate (ORR) in arms 2-5 by investigator assessment. RESULTS: Between October 2017 and August 2020, 203 patients were enrolled, including crossover. In arm 1, the ORR was 21.2% and DCR was 65.6%. The ORR was 0% for arm 2, 42.9% for arm 3, 0% for arm 4, and 15.6% for arm 5. In the case of PD with durvalumab, tremelimumab was added, and the ORR for durvalumab + tremelimumab was 2.2%. The median progression-free survival was 3.4, 3.2, 5.6, 1.6, and 1.7 months for each arm, respectively. The median overall survival was 12.4, 6.1, 11.1, 9.1, and 12.7 months, respectively. Overall, the toxicity profiles were manageable, and there were no treatment-related deaths. CONCLUSION: To our knowledge, this study is the first biomarker-driven umbrella trial for platinum-refractory HNSCC using matched molecular targeted agents. We found that NGS-based genomic phenotyping was methodologically feasible and applicable.

Expression of Three Clones of PD-L1 in Lung Cancer: A Single-center Experience.

BACKGROUND/AIM: Programmed cell death ligand 1 (PD-L1) is an immune checkpoint protein involved in immune evasion of malignant tumors. Confirmation of PD-L1 expression in non-small cell lung cancer (NSCLC) is necessary for the determination of immunotherapy using immune checkpoint inhibitors (ICIs). PDL-1 expression is currently analyzed by immunohistochemistry and is the only available biomarker that can guide the treatment of NSCLC using ICIs. The present study was conducted to compare the expression of three different commercial clones of PD-L1 in order for immunohistochemistry (IHC) for these clones to become more reliable for surgical pathologists. MATERIALS AND METHODS: This study examined the expression of PD-L1 in 76 cases of resected lung cancer using IHC. Three clones were examined: SP263, SP142, and 22C3PharmDx, which are commercially approved for quantifying PD-L1 expression in lung cancer. RESULTS: Of the 76 patients whose samples were evaluated for PD-L1 using the IHC 22C3pharmDx assay, 19 (25.0%) had a tumor proportion score (TPS) of ≥50% and 41 (53.9%) had a PD-L1 TPS of ≥1%. Furthermore, using the SP263, 48.7% had a TPS of ≥1% and 18.4% of >50%. The SP142 assay was used to evaluate tumor cells (TCs) and immune cells (ICs). Twenty (26.3%) cases were positive for TCs and 25 (32.9%) were reactive for ICs. CONCLUSION: These three commercial PD-L1 clones are comparable for detecting primary targets for anti-tumor immunotherapies. Careful evaluation by a pathologist is necessary to minimize misinterpretation errors.

Case mistaken for leukemia after mRNA COVID-19 vaccine administration: A case report.

BACKGROUND: Following the global outbreak of coronavirus disease 2019 (COVID-19), unlike other vaccines, COVID-19 vaccines were developed and commercialized in a relatively short period of time. The large-scale administration of this vaccine in a short time-period led to various unexpected side effects, including severe cytopenia and thrombosis with thrombocytopenia syndrome. Despite many reports on adverse reactions, vaccination was necessary to prevent the spread of COVID-19; thus, it is essential to understand and discuss various cases of adverse reactions after vaccination. CASE SUMMARY: A 77-year-old woman was administered the second dose of Pfizer mRNA COVID-19 vaccine. After vaccination she experienced fever, myalgia, and weakness. Antibiotics were subsequently administered for several days, but there was no improvement in the symptoms. The patient showed severe thrombocytopenia and leukocytosis. Thoracic and abdominopelvic computed tomography showed no infection related findings, but splenomegaly and cirrhotic liver features were observed. A large number of immature cells were observed in the peripheral blood smear; thus, bone marrow examination was performed for acute leukemia. However, there were no abnormalities. The patient recovered after administration of hepatotoxins and transfusion treatment for cytopenia and was diagnosed with an adverse reaction to COVID-19 vaccination. CONCLUSION: Adverse reactions of vaccination could be mistaken for hematologic malignancies including leukemia. We report a patient with leukocytosis following COVID-19 vaccination.

Non-secretory multiple myeloma expressed as multiple extramedullary plasmacytoma with an endobronchial lesion mimicking metastatic cancer: A case report.

BACKGROUND: Non-secretory multiple myeloma (MM) is a rare condition that accounts for only 3% of MM cases and is defined by normal serum and urine immunofixation and a normal serum free light chain ratio. Non-secretory MM with multiple extramedullary plasmacytomas derived from endobronchial lesions is extremely rare and can be misdiagnosed as metastasis of solid cancer. CASE SUMMARY: A 36-year-old man presented with progressive facial swelling and nasal congestion with cough. Various imaging studies revealed an endobronchial mass in the left bronchus and a large left maxillary mass with multiple destructive bone metastatic lesions. He initially presented with lung cancer and multiple metastases. However, pathologic reports showed multiple extramedullary plasmacytomas in the left maxilla and the left bronchus. There was no change in the serum and urine monoclonal protein levels, and no abnormalities were observed in laboratory examinations, including hemoglobin, calcium, and creatinine levels. The bone marrow was hypercellular, with 13.49% plasma cells. The patient was diagnosed with non-secretory MM expressed as multiple extramedullary plasmacytomas with endobronchial lesions in a rare location. Radiation therapy for symptomatic lesions with high-dose dexamethasone was started, and the size of the left maxillary sinus lesion dramatically decreased. In the future, chemotherapy will be administered to control lesions in other areas. CONCLUSION: We present a rare case of non-secretory MM with multiple extramedullary plasmacytoma with an endobronchial lesion.

HspBP1 is a dual function regulatory protein that controls both DNA repair and apoptosis in breast cancer cells.

The Hsp70-binding protein 1 (HspBP1) belongs to a family of co-chaperones that regulate Hsp70 activity and whose biological significance is not well understood. In the present study, we show that when HspBP1 is either knocked down or overexpressed in BRCA1-proficient breast cancer cells, there were profound changes in tumorigenesis, including anchorage-independent cell growth in vitro and in tumor formation in xenograft models. However, HspBP1 did not affect tumorigenic properties in BRCA1-deficient breast cancer cells. The mechanisms underlying HspBP1-induced tumor suppression were found to include interactions with BRCA1 and promotion of BRCA1-mediated homologous recombination DNA repair, suggesting that HspBP1 contributes to the suppression of breast cancer by regulating BRCA1 function and thereby maintaining genomic stability. Interestingly, independent of BRCA1 status, HspBP1 facilitates cell survival in response to ionizing radiation (IR) by interfering with the association of Hsp70 and apoptotic protease-activating factor-1. These findings suggest that decreased HspBP1 expression, a common occurrence in high-grade and metastatic breast cancers, leads to genomic instability and enables resistance to IR treatment.

The association of genetic alterations with response rate in newly diagnosed chronic myeloid leukemia patients.

Genetic differences may be associated with the response to tyrosine kinase inhibitor (TKI) in patients with chronic myeloid leukemia (CML). In this study, we identified genetic alterations between rapid and slow responders (BCR/ABL1 International Scale at 6 months: ≤0.1 % vs. > 0.1 %) of TKI treatment in chronic phase CML patients. Our analyses involved single nucleotide polymorphism (SNP), a Genome Wide Association Study and a Network-wide Association Study (NetWAS). Seventy-two patients from 16 institutions were enrolled and treated with a TKI, nilotinib. Gene Set Analysis identified genetic alterations in pathways related to the differentiation, proliferation, and activity of various innate immune cells. The NetWAS analysis found that genes associated with natural killer (NK) cells (PTPRCAP, BLNK, HCK, ARHGEF11, GPR183, TRPV2, SHKBP1, CD2) showed significant differences between rapid and slow responders of nilotinib. However, we found no significantly different genetic alterations according to the response in the SNP analysis. In conclusion, we found that rapidity of response to TKI was associated with pathway-associated genetic alterations in immune cells, particularly with respect to NK cell activity. These results suggested that the innate immune system at initial diagnosis had an important role in treatment response in patients with CML.

Ultra-deep sequencing mutation analysis of the BCR/ABL1 kinase domain in newly diagnosed chronic myeloid leukemia patients.

Ultra-deep sequencing detects low-frequency genetic mutations with high sensitivity. We used this approach to prospectively examine mutations in the BCR/ABL1 tyrosine kinase from patients with newly diagnosed, chronic-phase chronic myeloid leukemia (CML) treated with the tyrosine kinase inhibitor nilotinib. Between May 2013 and November 2014, 50 patients from 18 institutions were enrolled in the study. We screened 103 somatic mutations and found that mutations in the P-loop domain were the most frequent (173/454 mutations in the P-loop) and noted the presence of the V299 L mutation (dasatinib-resistant/nilotinib-sensitive) in 98 % of patients (49/50). No patients had Y253H, E255 V, or F359 V/C/I mutations, which would recommend dasatinib rather than nilotinib treatment. The S417Y mutation was associated with lower achievement of a major molecular response (MMR) at 6 months, and the V371A mutation was associated with reduced MMR and MR4.5 durations (MMR for 2 years: 100 % for no mutation vs. 75 % for mutation, P=0.039; MR4.5 for 15 months: 94.1 % vs. 25 %, P=0.002). Patients with known nilotinib-resistant mutations had lower rates of MR4.5 achievement. In conclusion, ultra-deep sequencing is a sensitive method for genetic-based treatment decisions. Based on the results of these mutational analyses, nilotinib treatment is a promising option for Korean patients with CML.

Jagged-1 Expression Level Is Correlated With Recurrence of Stage III Colorectal Cancer in Patients Receiving Adjuvant Chemotherapy.

BACKGROUND/AIM: Previous reports have indicated that increased expression of Jagged-1 (JAG1) may predict chemotherapy response and poor prognosis for patients with recurrent or metastatic colorectal cancer (CRC). This study aimed to investigate the clinical impact of JAG1 expression level in patients with CRC, including recurrence, especially in those diagnosed with lymph node-positive stage III CRC who underwent complete resection and appropriate adjuvant chemotherapy. PATIENTS AND METHODS: All patients were enrolled through a retrospective chart review, and only those for whom the clinical course and all clinical information were adequately determined according to the inclusion criteria were selected for retrospective review through medical records. Immunohistochemical staining of JAG1 was performed using paraffin-embedded tissue. JAG1 expression was determined by scoring for staining intensity and percentage of positively stained cells; the final JAG1 score was determined as the sum of both scores. RESULTS: Sixteen patients who experienced relapse and 15 without (for over 3 years) were selected. The protein expression level of JAG1 showed a tendency for being lower in the group without recurrence, although not statistically significantly (p=0.083); however, the mean JAG1 expression score was significantly lower in the group without recurrence (1.53 vs. 3.19; p=0.004). The patients were divided into two groups with low and high JAG1 expression. The results showed that high JAG1 expression was significantly associated with recurrence of stage III CRC (p=0.029). CONCLUSION: The expression of JAG1 may be a potential novel biomarker for predicting CRC recurrence.

Modified FOLFIRINOX versus S-1 as second-line chemotherapy in gemcitabine-failed metastatic pancreatic cancer patients: A randomised controlled trial (MPACA-3).

BACKGROUND: The efficacy of modified FOLFIRINOX (mFOLFIRINOX) as a second-line chemotherapy treatment for metastatic pancreatic adenocarcinoma (mPAC), remains unclear. This multi-center randomised phase III trial aimed to elucidate the efficacy of mFOLFIRINOX as a second-line chemotherapy treatment for mPAC patients with good performance status. PATIENTS AND METHODS: Eighty mPAC patients (age, 19-75 years) refractory to first-line gemcitabine-based chemotherapy were randomly selected to receive mFOLFIRINOX or S-1. mFOLFIRINOX comprised oxaliplatin (65 mg/m2), irinotecan (135 mg/m2), and leucovorin (400 mg/m2) on day 1 and continuous 5-FU infusion (1000 mg/m2) over 24 h on days 1-2 every 2 weeks. S-1 comprised body surface area-dependent oral S-1, divided into two doses per day on days 1-28 every 6 weeks. RESULTS: Overall survival was the primary endpoint. The objective response and disease control rates were higher in the mFOLFIRINOX than in the S-1 group (15% versus 2%; p = .04 and 67% versus 37%; p = .007). The median progression-free survival rates were 5.2 and 2.2 months in the mFOLFIRINOX and S-1 groups, respectively (adjusted hazard ratio [HR]: .4; 95% confidence interval [CI]: .2-.6; p < .001). The median overall survival rates were 9.2 and 4.9 months in the mFOLFIRINOX and S-1 groups, respectively (adjusted HR: .4; 95% CI: .2-.7; p = .002). Grade 3-4 adverse events occurred in 56% and 17% of the patients in the mFOLFIRINOX and S-1 groups, respectively (p < .001). CONCLUSION: Administration of mFOLFIRINOX as a second-line chemotherapy treatment for mPAC patients refractory to gemcitabine-based chemotherapy resulted in increased survival rates than S-1 treatment alone.

Interstitial lung disease induced by the roots of Achyranthes japonica Nakai: Three case reports.

BACKGROUND: The roots of Achyranthes japonica Nakai (AJN), called "Useul-puli," has been traditionally used to control pain and improve dysfunction in osteoarthritis patients in South Korea. CASE SUMMARY: We described 3 patients diagnosed with herbal medicine induced interstitial lung disease after consuming boiled the roots of AJN. They were referred to our hospital because of the modified Medical Research Council grade 4 dyspnea. Chest computed tomography showed bilateral ground-glass opacities with patchy consolidation. After treatment with systemic glucocorticoid therapy and discontinuation of the roots of AJN, their symptoms improved, and almost all ground-glass opacities and patchy consolidations on chest radiography and chest computed tomography resolved. CONCLUSION: We present three cases of interstitial lung disease induced by the roots of AJN.

Successful treatment of relapsed acute promyelocytic leukemia with arsenic trioxide in a hemodialysis-dependent patient: A case report.

BACKGROUND: Arsenic trioxide (ATO) is recommended for patients who do not achieve molecular remission or who have molecular or morphologic relapse. However, there are no guidelines for adjusting ATO dosage in patients with severe renal failure or on dialysis. Herein, we report the successful treatment of relapsed acute promyelocytic leukemia (APL) in a patient on hemodialysis with ATO single agent and review the cases in literature. CASE SUMMARY: A 46-year-old woman who has been on hemodialysis to chronic glomerulone-phritis for 15 years visited our hospital for pancytopenia. She had been seen for pancytopenia 3 years ago and had been diagnosed with APL. She also received chemotherapy for APL but unfortunately was lost to follow-up after her second consolidation chemotherapy. She was noted to have pancytopenia by her nephrologist during hemodialysis 1 mo ago. Bone marrow biopsy and reverse transcriptase-polymerase chain reaction (RT-PCR) tests revealed a diagnosis of relapsed APL. Treatment for relapsed APL with ATO single agent was started and she achieved molecular remission after administering 24 doses of ATO. Thus far, four consolidation therapies have been performed with the ATO single agent, and, to date, the molecular remission has been maintained as negative promyelocytic leukemia/retinoic acid receptor-α fusion gene as confirmed by RT-PCR testing for two years. CONCLUSION: This is a rare case of relapsed APL successfully treated with the single agent ATO in a patient on hemodialysis.

Extremely rare case of successful treatment of metastatic ovarian undifferentiated carcinoma with high-dose combination cytotoxic chemotherapy: A case report.

BACKGROUND: Ovarian undifferentiated carcinomas are significantly rare and have an aggressive clinical course. Surgical resection is the only curative treatment in early-stage ovarian undifferentiated carcinomas that has a favorable prognosis. In case of recurrent and metastatic disease, palliative chemotherapy is the only available treatment. However, the effectiveness of standard chemotherapy regimen is not well-known, specifically in the case of extra-ovarian spread. We report an ovarian undifferentiated carcinoma of recurrent and inoperable advanced stage that was successfully treated with high-dose combination chemotherapy. CASE SUMMARY: A 52-year-old woman presented with a 1-mo history of right lower quadrant and epigastric pain. A computed tomography (CT) scan of the abdomen revealed a multicystic mass with extensive internal necrosis of the right ovary without evidence of metastatic disease. A total hysterectomy with bilateral salpingo-oophorectomy and omentectomy was performed, but the surgery had a positive resection margin. Pathologically, it was diagnosed as ovarian undifferentiated carcinoma with sarcomatoid change. Although adjuvant chemotherapy was planned, it was delayed for 6 wk because of postoperative recovery, and the patient complained of abdominal pain. A CT scan and positron emission tomography-CT revealed a huge mass with multiple nodules in the pelvic cavity and para-aortic lymph node metastasis. Instead of standard therapy such as paclitaxel and platinum, combined chemotherapy with etoposide, ifosfamide, and cisplatin was administered. The patient experienced no recurrence for 5 years. CONCLUSION: This is a case of metastatic ovarian undifferentiated carcinoma with sarcomatoid change that was successfully treated with high-dose combination cytotoxic chemotherapy.

Acute myelomonocytic leukemia during pembrolizumab treatment for non-small cell lung cancer: A case report.

BACKGROUND: Pembrolizumab is a highly selective IgG4 kappa isotype monoclonal antibody against the programmed cell death-1 (PD-1) molecule. In the treatment of non-small cell lung cancer (NSCLC), pembrolizumab has demonstrated significant efficacy, significant survival outcomes, long-lasting responses, and a good safety profile compared with cytotoxic chemotherapy. CASE SUMMARY: A 79-year-old Korean male presented with a left side palpable neck mass. An ultrasound-guided core-needle biopsy of the largest neck mass was performed, and squamous cell carcinoma was confirmed based on the histological and immunohistochemical findings. He was diagnosed with squamous cell carcinoma of the lung with multiple lymph nodes and rib metastases (T1N3M1b, Stage IVA) using enhanced chest computed tomography and 18F-fluorodeoxyglucose positron emission/computed tomography. After 4 cycles of gemcitabine and carboplatin, we clinically judged the disease as progressive. Owing to the high PD-1 expression demonstrated by the patient, pembrolizumab was initiated (200 mg every 3 wk). After 3 cycles of pembrolizumab, a complete response was achieved. At the 4th cycle of pembrolizumab, the white blood cell count was markedly elevated. Peripheral blood smear analysis and bone marrow biopsy were performed. The patient was diagnosed with acute myelomonocytic leukemia. CONCLUSION: We present the first report of acute myelomonocytic leukemia during pembrolizumab treatment in an NSCLC patient; the mechanism remains unknown.

Clinical Significance of Jagged-1 Activated by APEX1 as a Chemoresistance Factor in Advanced Gastric Cancer.

BACKGROUND/AIM: We investigated the clinical role of the molecular targets, APEX1 and Jagged-1, and the Apex1 - Jagged-1 cascade in gastric cancer cells. MATERIALS AND METHODS: We used 6 human gastric cancer cell lines (SNU-1, SNU-5, SNU-16, NCI-N87, KATO- III and AGS), and demonstrated the chemosensitivity of APEX1 and Jagged-1 through the MTT assay and immunoblotting. Tumor growth was assayed following cisplatin and 5-FU treatment using a xenograft model injected with KATO-III cells. Moreover, gastric tumor samples from 9 patients, divided in 2 groups according to chemotherapy response, were examined by immunocytochemical (IHC) staining, and protein expression levels were scored. RESULTS: Following APEX1 knockdown, the MTT assay revealed that the IC50 of cisplatin and 5-FU in AGS cells was decreased approximately 7% and 15%, respectively, however, their decrease in chemoresistant KATO-III cells was decreased by approximately 21% and 67% for cisplatin and 5-FU, respectively. The tumor volume of KATO-III/sicontrol mice treated with cisplatin and 5-FU was affected less, compared with KATO-III/siAPEX1 mice treated with cisplatin and 5-FU. Also, the expression levels of APEX1, Jagged-1 and CD133, assayed by IHC staining, were higher in the chemorefractory group than in the chemoresponsive group. CONCLUSION: Jagged-1-activated signaling by APEX1 plays a role in advanced gastric cancer.

Evaluation and Clinical Significance of Jagged-1-activated Notch Signaling by APEX1 in Colorectal Cancer.

BACKGROUND/AIM: Colorectal cancer (CRC) is one of the most common in the world and its prevalence is rapidly increasing. Jagged-1-activated Notch signaling by apurinic/apyrimidinic endodeoxyribonuclease 1 (APEX1) promotes CRC, and high expression of Jagged-1 is associated with poor prognosis. However, its clinical implication is unknown. The aim of this study was to investigate the clinical role of Jagged-1-activated Notch signaling by APEX1. MATERIALS AND METHODS: The 5-dimethylthiazol-2-yl) 2, 5-diphenyltetrazolium bromide (MTT) assay was used to evaluate the anti-cancer efficacy of 5-fluorouracil (5-FU), oxaliplatin, and irinotecan. Tissue from CRC patients was analyzed to assess the clinical specificity of Jagged-1 activated by APEX1. RESULTS: The half-maximal inhibitory concentration (IC50) in cells co-expressing APEX1 and Jagged-1 cells was higher than that in cells expressing only APEX1. These results indicated that the simultaneous expression of APEX1 and Jagged-1 might be associated with chemoresistance toward 5-FU, oxaliplatin, and irinotecan. Analysis of tissue from CRC patients revealed that high expression of Jagged-1 was associated with a statistically significantly low response to chemotherapy. CONCLUSION: Overexpression of Jagged-1 by APEX1 might serve as a predictor of response to chemotherapy and of poor prognosis, and moreover may be a therapeutic target for chemotherapy of advanced CRC.

Bronchobiliary fistula after ramucirumab treatment for advanced gastric cancer: A case report.

BACKGROUND: Bronchobiliary fistula (BBF) is a rare disease characterized by an abnormal connection between the biliary system and bronchi. Traditional causes of BBF include trauma and infections, and more recent causes include malignancies and certain cancer treatments. Ramucirumab is an antivascular endothelial growth factor receptor 2 monoclonal antibody, currently used as a second-line treatment for gastric cancer. CASE SUMMARY: A 43-year-old man visited our hospital with the complaint of jaundice. He was diagnosed with inoperable advanced gastric cancer owing to invasion of the hepatic hilum by the tumor. After percutaneous transhepatic biliary drainage (PTBD) and stent placement, capecitabine and oxaliplatin were administered as first-line palliative chemotherapy. The tumor progressed, and paclitaxel and ramucirumab were administered as second-line chemotherapy. However, on the first day of the second cycle, the patient suddenly developed dyspnea and pneumonia. BBF was diagnosed on the basis of the presence of bilious sputum and the results of computed tomography, and PTBD was repeated. CONCLUSION: This is the first report of BBF after administration of the new antiangiogenic agent ramucirumab.

Use of Droplet Digital Polymerase Chain Reaction for Detecting Minimal Residual Disease: A Prospective Multi-Institutional Study.

BACKGROUND/AIM: Droplet digital polymerase chain reaction (ddPCR) is an exact method of measuring nucleic acids. The aim of this prospective study was to evaluate minimal residual disease (MRD) using ddPCR in chronic myeloid leukemia (CML) patients. PATIENTS AND METHODS: Between May 2013 and November 2014, CML patients treated with nilotinib were enrolled in our study. BCR/ABL1 transcripts levels were evaluated using ddPCR at the first time of complete molecular response (CMR). We enrolled 15 patients from 7 Institutions. The treatment period and median follow-up period were 45 months and 47 months, respectively. RESULTS: Patients with a high level of BCR/ABL1 transcript had a greater tendency to lose the CMR during the follow-up period (p=0.095). In addition, patients with a low level of BCR/ABL1 transcript showed a longer duration of CMR compared to those with a high level (p=0.032). CONCLUSION: We found that ddPCR is a sensitive method for detecting MRD and that MRD could affect the duration of the treatment response.

Inhibitory Effect of Sestrin 2 on Hepatic Stellate Cell Activation and Liver Fibrosis.

Aims: Hepatic fibrosis results from chronic liver injury and inflammatory responses. Sestrin 2 (Sesn2), an evolutionarily conserved antioxidant enzyme, reduces the severities of acute hepatitis and metabolic liver diseases. However, the role of Sesn2 in the pathogenesis of liver fibrosis remains obscure. Here, we used cultured hepatic stellate cells (HSCs) and chronic carbon tetrachloride (CCl4) and bile duct ligation (BDL) murine models to investigate the effects of Sesn2 on fibrogenesis. Results: Sesn2 protein and mRNA levels were upregulated in activated primary HSCs, and by increasing transcription, transforming growth factor-ß (TGF-ß) also increased Sesn2 expression in HSCs. Furthermore, Smad activation was primarily initiated by TGF-ß signaling, and Smad3 activation increased Sesn2 luciferase activity. In silico analysis of the 5' upstream region of the Sesn2 gene revealed a putative Smad-binding element (SBE), and its deletion demonstrated that the SBE between -964 and -956 bp within human Sesn2 promoter was critically required for TGF-ß-mediated response. Moreover, ectopic expression of Sesn2 reduced gene expressions associated with HSC activation, and this was accompanied by marked decreases in SBE luciferase activity and Smad phosphorylation. Infection of recombinant adenovirus Sesn2 reduced hepatic injury severity, as evidenced by reductions in CCl4- or BDL-induced alanine aminotransferase and aspartate aminotransferase, and inhibited collagen accumulation. Furthermore, HSC-specific lentiviral delivery of Sesn2 prevented CCl4-induced liver fibrosis. Finally, Sesn2 expression was downregulated in the livers of patients with liver cirrhosis and in mouse models of hepatic fibrosis. Innovation and Conclusion: Our findings suggest that Sesn2 has the potential to inhibit HSC activation and hepatic fibrosis.