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Gallbladder Cancer

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Latest Research Publications
Gastrointestinal System Cancers

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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Midorikawa R, Hisaka T, Sakai H, et al.
Clinical and Prognostic Significance of Neoplastic Spindle Cells in Gallbladder Cancer.
Anticancer Res. 2019; 39(8):4561-4568 [PubMed] Related Publications
BACKGROUND/AIM: Neoplastic spindle cells (NSCs) are believed to play a role in cancer invasion and metastasis, as well as in poor prognosis. The clinicopathological characteristics and prognostic relevance of NSCs was investigated in gallbladder cancer.
MATERIALS AND METHODS: Specimens were obtained from 62 patients with gallbladder cancer who underwent surgery. The emergence of NSCs and their correlation with clinicopathological factors, prognosis, and EMT markers was evaluated.
RESULTS: The NSC grade correlated with tumor size, preoperative CA19-9, surgical margin, the degree of differentiation, the depth of invasion, lymph node metastasis, lymphatic invasion, vascular invasion, and perineural invasion. Multivariate analysis of overall survival showed that NSCs were an independent prognostic factor. A correlation between NSCs and EMT was also suggested.
CONCLUSION: NSCs are an independent prognostic factor for patients with postoperative gallbladder cancer, which also suggests a correlation between NSCs and EMT.

Zhong H, Hao TT, Chen Y, Luo F
Unexpected Gallbladder Cancer during or after Laparoscopic Cholecystectomy: Risk Factors and Experience of Diagnosis and Treatment of 22 Cases.
Am Surg. 2019; 85(6):671-675 [PubMed] Related Publications
This study aims to provide some experience in diagnosis and treatment of unexpected gallbladder cancer (UGBC) and find the major risk factors. Retrospective data were collected and analyzed on 22 patients who were diagnosed with UGBC during or after laparoscopic cholecystectomy from January 2013 to January 2018 at our hospital. Average age of the patients was (60.2 ± 12.8) years (range, 42-83 years). Among them, there were 6 men and 16 women. Gallbladder stones, atrophic gallbladder, uneven thickened wall of the gallbladder, and choledocholithiasis were found to be the major risk factors. Eight patients (36.4%) were diagnosed intraoperatively. Seven cases (31.8%) were at the T1 stage; of these, three were treated with laparoscopic cholecystectomy; two were converted to cholecystectomy; and two underwent cholecystectomy, lymph node dissection, and liver resection. Eight (36.4%) T2 patients, five (22.7%) T3 patients, and one T4 patient had radical cholecystectomy. Partial cholecystectomy and cholecystotomy were carried out in another T4 patient. T1 patients did not receive chemotherapy or radiotherapy. Eleven had chemotherapy and four received chemoradiotherapy. The follow-up period ranged from six months to five years. The one-year survival rate for T1 to T4 patients was 100 per cent, 75 per cent, 40 per cent, and 0 per cent, respectively. A high index of clinical suspicion of UGBC is needed if one patient suffered from both gallbladder stones and choledocholithiasis with atrophic gallbladder or uneven thickened wall of the gallbladder preoperatively. To avoid more UGBC and reoperation, imaging examinations combined with tumor marker tests and intraoperative histopathologic examination are highly recommended.

Chun YJ, Jeung HC, Park HS, et al.
Significance of Metabolic Tumor Volume and Total Lesion Glycolysis Measured Using ¹⁸F-FDG PET/CT in Locally Advanced and Metastatic Gallbladder Carcinoma.
Yonsei Med J. 2019; 60(7):604-610 [PubMed] Free Access to Full Article Related Publications
PURPOSE: This study aimed to determine the prognostic value of new quantitative parameters of ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT), including metabolic tumor volume (MTV), in patients with locally advanced and metastatic gallbladder cancer (GBC).
MATERIALS AND METHODS: In total, 83 patients initially diagnosed with locally advanced and metastatic GBC and who underwent ¹⁸F-FDG PET/CT at the time of initial diagnosis were retrospectively reviewed. The metabolic volume-based PET parameters of primary tumors and metastatic lesions were measured, including maximum and average standardized uptake values (SUV), MTV, and total lesion glycolysis. An overall survival (OS) analysis was performed using the Kaplan-Meier method with PET and clinical parameters. A Cox proportional hazards regression analysis was performed to determine independent prognostic factors.
RESULTS: In univariate analysis, pathologic differentiation (
CONCLUSION: In locally advanced and metastatic GBC, volume-based PET/CT parameters of the total tumor burden of malignancy, such as MTV

Liu S, Li F, Pan L, et al.
BRD4 inhibitor and histone deacetylase inhibitor synergistically inhibit the proliferation of gallbladder cancer in vitro and in vivo.
Cancer Sci. 2019; 110(8):2493-2506 [PubMed] Free Access to Full Article Related Publications
Gallbladder cancer (GBC) is the most common malignancy of the bile duct and has a high mortality rate. Here, we demonstrated that BRD4 inhibitor JQ1 and histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) synergistically inhibited the GBC cells in vitro and in vivo. Our results showed that cotreatment with JQ1 and SAHA significantly inhibited proliferation, cell viability and metastasis, and induced apoptosis and G2/M arrest in GBC cells, with only minor effects in benign cells. In vivo, tumor volumes and weights of GBC xenograft models were significantly decreased after treatment with JQ1 or SAHA; meanwhile, the cotreatment showed the strongest effect. Further study indicated that the above anticancer effects was associated with the downregulation of BRD4 and suppression of PI3K/AKT and MAPK/ERK pathways. These findings highlight JQ1 and SAHA as potential therapeutic agents and their combination as a promising therapeutic strategy for GBC.

Taskin OC, Akkas G, Memis B, et al.
Sarcomatoid carcinomas of the gallbladder: clinicopathologic characteristics.
Virchows Arch. 2019; 475(1):59-66 [PubMed] Related Publications
Sarcomatoid carcinomas recently came into the spotlight through genetic profiling studies and also as a distinct model of epithelial-mesenchymal transition. The literature on sarcomatoid carcinomas of gallbladder is limited. In this study, 656 gallbladder carcinomas (GBC) were reviewed. Eleven (1.7%) with a sarcomatoid component were identified and analyzed in comparison with ordinary GBC (O-GBC). Patients included 9 females and 2 males (F/M = 4.5 vs. 3.9) with a mean age-at-diagnosis of 71 (vs. 64). The median tumor size was 4.6 cm (vs. 2.5; P = 0.01). Nine patients (84%) presented with advanced stage (pT3/4) tumor (vs. 48%). An adenocarcinoma component constituting 1-75% of the tumor was present in nine, and eight had surface dysplasia/CIS; either in situ or invasive carcinoma was present in all cases. An intracholecystic papillary-tubular neoplasm was identified in one. Seven showed pleomorphic-sarcomatoid pattern, and four showed subtle/bland elongated spindle cells. Three had an angiosarcomatoid pattern. Two had heterologous elements. One showed few osteoclast-like giant cells, only adjacent to osteoid. Immunohistochemically, vimentin, was positive in six of six; P53 expression was > 60% in six of six, keratins in six of seven, and p63 in two of six. Actin, desmin, and S100 were negative. The median Ki67 index was 40%. In the follow-up, one died peri-operatively, eight died of disease within 3 to 8 months (vs. 26 months median survival for O-GBC), and two were alive at 9 and 15 months. The behavior overall was worse than ordinary adenocarcinomas in general but was not different when grade and stage were matched. In summary, sarcomatoid component is identified in < 2% of GBC. Unlike sarcomatoid carcinomas in the remainder of pancreatobiliary tract, these are seldom of the "osteoclastic" type and patients present with large/advanced stage tumors. Limited data suggests that these tumors are aggressive with rapid mortality unlike pancreatic osteoclastic ones which often have indolent behavior.

Bisello S, Buwenge M, Palloni A, et al.
Radiotherapy or Chemoradiation in Unresectable Biliary Cancer: A Retrospective Study.
Anticancer Res. 2019; 39(6):3095-3100 [PubMed] Related Publications
BACKGROUND/AIM: To retrospectively evaluate the outcome of patients with unresectable biliary cholangiocarcinoma (CC) treated with radiotherapy (RT) plus/minus chemotherapy (CHT).
MATERIALS AND METHODS: Data of patients with intrahepatic CC (ICC), Klatskin's tumor (KT), distal extrahepatic CC (ECC), and gallbladder cancer (GBC) diagnosed from 1991 to 2017 were retrospectively analyzed. The treatment was mainly based on RT plus concurrent CHT +/- brachytherapy (BRT) boost. The Kaplan-Meier method was used to calculate survival curves that were compared using the log-rank test.
RESULTS: Seventy-six patients were included in this analysis (males: 59%; females: 41%; median age: 66.5 years). A minority of patients (7.9%) were treated for disease recurrence after surgery. According to TNM, 78.5% of patients had T stage >3 and 77.6% of patients were treated with concurrent CHT-RT while 22.3% received RT followed by sequential CHT. Median RT dose was 50 Gy (range: 16-75 Gy) delivered with conventional fractionation. CHT was based on Gemcitabine or 5-fluorouracil. BRT was prescribed to 51.3% of patient with a median dose of 14 Gy. Reported Grade ≥3 acute GI and hematological toxicity were 13.2% and 8.1%, respectively. No other severe acute toxicities were reported. One- and 2-year overall survival (OS) were 58.1% and 25.8%, respectively (median: 13.5 months), while 1- and 2-year progression-free survival (PFS) were 43.4% and 9.4%, respectively. None of the following variables had a significant impact on OS and PFS: BRT boost, tumor site, concurrent CHT, and the drugs used in concurrent CHT. In contrast, patients receiving RT with 2D technique showed a PFS significantly higher compared to patients treated with the 3D technique (median: 15.5 vs. 8.5 months; p=0.02).
CONCLUSION: Combined modality treatment (RT+CHT±BRT) in unresectable biliary cancer was associated with acceptable toxicity and OS comparable to the actual standard treatment (CHT). The significantly improved PFS in patients undergoing 2D-RT raises doubts regarding the adequacy of target delineation in these neoplasms.

Dušek L, Mužík J, Krejčí D
Epidemiology of gallbladder and bile duct malignancies in the Czech Republic.
Cas Lek Cesk. 2019; 158(2):52-56 [PubMed] Related Publications
Overview of epidemiology focused on tumors of the bile ducts and gallbladder is based on data of the National Cancer Registry and its newly validated and published data from 2016. In most recent period 2012-2016, 1013 patients were annually (in average) diagnosed with tumors of the bile ducts and gallbladder in the Czech Republic. In the same time, average annual mortality of this disease reached value 836. Prevalence of bile ducts and gallbladder cancer reached 1723 in 2016 and in comparison, with the value measured in 2006, it increased by 28 %. More than 50 % of bile ducts and gallbladder cancers are diagnosed in advanced clinical stages (stage III+) which makes prognosis of patients worse and limits reachable results of therapy.

Pandey S, Garg RK, Malhotra HS, et al.
Atypical frontal lobe seizure as the first manifestation of gall-bladder cancer: a case report.
BMC Neurol. 2019; 19(1):95 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Gall bladder cancer (GBC) is associated with abdominal pain, lump, nausea, vomiting, and jaundice due to either gall bladder mass or the involved adjacent peritoneal structures. Gall bladder cancer presenting as refractory epilepsy is rare. Here we report a young female GBC patient who presented with an atypical and refractory frontal lobe seizures as the first manifestation of gall bladder cancer.
CASE PRESENTATION: A 46 years young female presented first time to the hospital with uncontrolled seizures and headache in 5 months duration. Seizures were very atypical in semiology with ptosis and mydriasis to either side along with ipsilateral ocular deviation. The episodes were bilateral but right eyelid ptosis, mydriasis and right horizontal conjugate deviation were frequent. MRI brain showed encephalomalacia in the left frontal region on axial T2 and coronal T1 weighted images without any enhancement on gadolinium contrast. CECT abdomen revealed a heterogeneously enhancing gall bladder mass with the evidence of lung metastasis from chest CT scan. CSF for malignant cytology was negative. Seizures were refractory to the treatment.
CONCLUSION: Though CNS involvement is uncommon but it can be the only presentation in gall bladder cancer.

Wang W, Hu Z, Huang Y, et al.
Pretreatment with Gemcitabine/5-Fluorouracil Enhances the Cytotoxicity of Trastuzumab to HER2-Negative Human Gallbladder Cancer Cells In Vitro and In Vivo.
Biomed Res Int. 2019; 2019:9205851 [PubMed] Free Access to Full Article Related Publications
The effects of standard clinical therapies including surgery and chemotherapy are poor in advanced gallbladder cancer (GBC). There are a few reported cases of human epidermal growth factor receptor 2 (HER2)-positive GBC that responded well to trastuzumab. But trastuzumab has not yet been used to treat HER2-negative GBC. In this study, we investigated the cytotoxic effects of different combined therapies with trastuzumab and gemcitabine and/or 5-fluorouracil on HER2-negative GBC cell lines in vitro and in vivo. Trastuzumab alone showed almost no cytotoxicity to GBC cells with originally low HER2 gene amplification. Sequential therapy with chemotherapy followed by trastuzumab showed superiority over reverse sequential chemotherapy (

Bae JS, Kim SH, Kang HJ, et al.
Quantitative contrast-enhanced US helps differentiating neoplastic vs non-neoplastic gallbladder polyps.
Eur Radiol. 2019; 29(7):3772-3781 [PubMed] Related Publications
OBJECTIVES: To differentiate between large (≥ 1 cm in diameter) gallbladder (GB) non-neoplastic and neoplastic polyps using quantitative analysis of contrast-enhanced ultrasound (CEUS) findings.
METHODS: From September 2017 to May 2018, 29 patients (10 males; median age, 63 years) with GB polyps of ≥ 1 cm in diameter who were undergoing cholecystectomy were consecutively enrolled. All patients underwent preoperative conventional US and CEUS examinations. Quantitative analysis of CEUS findings using time-intensity curves between the two groups was independently performed by two radiologists. The interobserver agreement for the quantitative analysis of the CEUS results was measured using the intraclass correlation coefficient. Receiver operating characteristic analysis was performed to evaluate the diagnostic performance of CEUS examination.
RESULTS: After the cholecystectomy, the patients were classified into the non-neoplastic polyp group (n = 12) and the neoplastic polyp group (n = 17) according to the pathological results. The interobserver agreement for quantitative assessment between the two radiologists was near perfect to substantial. Quantitative assessment of the CEUS findings revealed that the rise time, mean transit time, time to peak, and fall time of non-neoplastic GB polyps were significantly shorter than those of neoplastic polyps (p < 0.001, p = 0.008, p = 0.013, and p = 0.002, respectively). The sensitivity and specificity of the quantitative CEUS parameters for the differentiation between the two groups were 76.5-100% and 75%, respectively, with an area under the curve of 0.765-0.887.
CONCLUSIONS: Quantitative analysis of CEUS findings could be valuable in differentiating GB neoplastic polyps from non-neoplastic polyps.
KEY POINTS: • Quantitative analysis of CEUS findings could be valuable in differentiating gallbladder neoplastic polyps from non-neoplastic polyps. • Quantitative analysis of CEUS findings in gallbladder polyps provides cut-off values for differentiation between neoplastic polyps and non-neoplastic polyps with near-perfect to substantial interobserver agreement.

Cai Q, Wang S, Jin L, et al.
Long non-coding RNA GBCDRlnc1 induces chemoresistance of gallbladder cancer cells by activating autophagy.
Mol Cancer. 2019; 18(1):82 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Gallbladder cancer is the most common biliary tract malignancy and not sensitive to chemotherapy. Autophagy is an important factor prolonging the survival of cancer cells under chemotherapeutic stress. We aimed to investigate the role of long non-coding RNAs (lncRNAs) in autophagy and chemoresistance of gallbladder cancer cells.
METHODS: We established doxorubicin (Dox)-resistant gallbladder cancer cells and used microarray analysis to compare the expression profiles of lncRNAs in Dox-resistant gallbladder cancer cells and their parental cells. Knockdown or exogenous expression of lncRNA combined with in vitro and in vivo assays were performed to prove the functional significance of lncRNA. The effects of lncRNA on autophagy were assessed by stubRFP-sensGFP-LC3 and western blot. We used RNA pull-down and mass spectrometry analysis to identify the target proteins of lncRNA.
RESULTS: The drug-resistant property of gallbladder cancer cells is related to their enhanced autophagic activity. And we found a lncRNA ENST00000425894 termed gallbladder cancer drug resistance-associated lncRNA1 (GBCDRlnc1) that serves as a critical regulator in gallbladder cancer chemoresistance. Furthermore, we discovered that GBCDRlnc1 is upregulated in gallbladder cancer tissues. Knockdown of GBCDRlnc1, via inhibiting autophagy at initial stage, enhanced the sensitivity of Dox-resistant gallbladder cancer cells to Dox in vitro and in vivo. Mechanically, we identified that GBCDRlnc1 interacts with phosphoglycerate kinase 1 and inhibits its ubiquitination in Dox-resistant gallbladder cancer cells, which leads to the down-regulation of autophagy initiator ATG5-ATG12 conjugate.
CONCLUSIONS: Our findings established that the chemoresistant driver GBCDRlnc1 might be a candidate therapeutic target for the treatment of advanced gallbladder cancer.

Skalický A, Vištejnová L, Dubová M, et al.
Mixed neuroendocrine-non-neuroendocrine carcinoma of gallbladder: case report.
World J Surg Oncol. 2019; 17(1):55 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Mixed neuroendocrine-non-neuroendocrine tumors (MINEN) of the gallbladder are extremely rare; indeed, the English expert literature reports a mere handful of case reports and case series on this topic. According to the WHO classification of 2010, MINEN are considered to be tumors consisting of two major components, neuroendocrine and non-neuroendocrine, each of which hosts at least 30% of the total cellular population. To date, the etiology and pathogenesis of MINEN have not been precisely determined and the non-specific symptoms generally result in late diagnosis (mainly in the terminal stages of the condition) and contribute to the generally poor prognosis. As far as the management of the disease is concerned, radical surgery plays a crucial role; however, the significance of surgical debulking and biological therapy applying somatostatin analogues has not yet been determined.
CASE PRESENTATION: A 56-year-old female was referred to our department for a rapidly progressing tumor in the subhepatic area along with the infiltration of S5 and S6 liver segments. With regard to preoperative findings, the tumor appeared as operable, although, during the surgery, an extensive involvement of the hepatoduodenal ligament by the tumor through the lymph nodes was revealed. Due to acute perioperative bleeding from the necrotic tumor, we decided to perform modified resection. Histologically, the tumor was confirmed as MINEN of gallbladder, where the neuroendocrine component was dominant over the non-neuroendocrine component. Six weeks after the discharge, the patient underwent a follow-up CT revealing large recurrence of the disease. Thereafter, the patient was started on systemic therapy with etoposide and carboplatin in combination with somatostatin analogues. Thirteen months after the surgery, the patient is in good clinical condition, and while a recently performed PET/MRI scan revealed a hepatic lesion and hilar lymphadenopathy in full regression, there was a spread of small peritoneal and pleural metastases. The patient remains in the follow-up care.
CONCLUSIONS: The occurrence of mixed neuroendocrine-non-neuroendocrine neoplasms is extremely rare. Radical surgery remains the only potentially effective approach to the cure of this disease. The role of biological therapy and debulking in the management of the disease has not yet been precisely defined. In our experience, both of these methods have the potential to positively influence overall survival rates and the postoperational quality of life of patients.

Heitz L, Kratzer W, Gräter T, et al.
Gallbladder polyps - a follow-up study after 11 years.
BMC Gastroenterol. 2019; 19(1):42 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The aim of our study was to investigate the prevalence and natural long-term progression of gallbladder polyps in a random sample of the general population.
METHODS: Four hundred and thirteen subjects (190 women, 223 men; aged 29-75 years) were studied first in 2002 and again eleven years later in 2013. All subjects were interviewed using a standardised questionnaire, anthropometric data were recorded, and an abdominal ultrasound scan was carried out.
RESULTS: The prevalence of gallbladder polyps was 6.1% (115/1880) in the 2002 study and 12.1% (50/413) in the 2013 follow-up study. After eleven years, 36 subjects (8.7%, 36/413) had developed new polyps, thirteen subjects (48.1%, 13/27) no longer had gallbladder polyps, and 14 subjects (51.9%, 14/27) still had polyps. The number of polyps had increased in six of these subjects (43%, 6/14), decreased in a further six (43%, 6/14), and remained unchanged in two (14%, 2/14). The mean polyp size was 4.7 mm (± 2.2 mm, range 2-20 mm) in 2002 and 4.0 mm (± 1.9 mm, range 0.5-11 mm) at follow-up. A decrease in polyp size was noted in seven (50%) of the 14 subjects, an increase in size in five subjects (35.7%), and no change in two subjects (14.3%). The shape of the polyps had changed from pedunculated to sessile in two subjects (14.3%, 2/14) and from sessile to pedunculated in one subject (7.1%, 1/14).
CONCLUSIONS: In long-term follow-up, the prevalence of gallbladder polyps increased, with new lesions developing in 8.7% of the population. Polyps persisted in 51.9% of the subjects who had them in the original study and disappeared in the other 48.1%.

Bhattacharjee PK, Nanda D
Prospective observational study on cholelithiasis in patients with carcinoma gall bladder in a tertiary referral hospital of Eastern India.
J Cancer Res Ther. 2019 Jan-Mar; 15(1):153-156 [PubMed] Related Publications
Context: Gallbladder carcinoma (GBCA) is the fifth most common types of gastrointestinal malignancy and is the most common malignancy of the biliary tract. Cholelithiasis, gallbladder polyps, porcelain gall, and choledochal cysts are common known associations with GBCA. Because of the better understanding of the etiopathogenesis, the traditional nihilistic attitude toward the prognosis has, over the years, given way to greater interest and hope for treating the disease. Long-term survival has been reported in patients with resectable lesions in the hands of expert hepatobiliary surgeons.
Objective: This prospective observational study was conducted at a tertiary referral hospital of Eastern India on patients with the diagnosis of GBCA. The main objective was to assess the incidence of gallstones in patients with GBCA, and the relationship, if any, between the size and number of stones and GBCA in our patient cohort.
Materials and Methods: This prospective observational study was conducted, over a period of 2 years, at a tertiary referral hospital of Eastern India which caters to patients from all the neighboring districts. A total of 54 patients with the diagnosis of GBCA were included in the study. Data on their demographic and clinical profile, the incidence of associated gallstones, their size (<3 or ≥3cm), and number (solitary or multiple) were collected. Known predisposing factors of GBCA, if any, in those presenting without stones were noted.
Results: GBCA was found to afflict females 2.4 times as frequently as males. Patients, irrespective of their sex, were mostly in their sixth decade. Approximately three-fourth of the cases had associated cholelithiasis. The number of stones had no correlation with the disease. However, contrary to available published data, stones <3 cm were significantly more common in our study cohort.
Conclusion: The results of this study reaffirm that cholelithiasis is a strong predisposing factor for GBCA and females with gallstones in their sixth decade, are more at risk. Although number of stones was not found to be an independent risk factor, patients with stones <3 cm (mostly multiple) were found to be more at risk in our study.

Zhou D, Wang J, Quan Z, et al.
Improvement in the diagnosis and treatment of T2 gallbladder carcinoma is pivotal to improvement in the overall prognosis for this disease.
Biosci Trends. 2019; 13(1):1-9 [PubMed] Related Publications
Since the American Joint Committee on Cancer (AJCC) subdivided the T2 stage of gallbladder carcinoma (GBC) into T2a and T2b, the diagnosis and treatment of those stages have been a subject of heated discussion and controversy. T2 is a stage of GBC that might be treatable. Based on the extent of lymph node metastasis and distant metastasis, T2 GBC can be classified into various pathological stages such as IIA, IIB, IIIB, and IVB, leading to controversy in clinical settings. This review aims to discuss the effectiveness of and controversies concerning S4b+5 resection, the acceptable extent of lymph node dissection, the timing for treatment of incidental gallbladder cancer, and adjuvant therapy. This review also aims to suggest directions for and recommendations regarding clinical research in the future.

Tsilimigras DI, Hyer JM, Paredes AZ, et al.
The optimal number of lymph nodes to evaluate among patients undergoing surgery for gallbladder cancer: Correlating the number of nodes removed with survival in 6531 patients.
J Surg Oncol. 2019; 119(8):1099-1107 [PubMed] Related Publications
BACKGROUND: The aim of the current study was to identify the minimum number and the optimal range of lymph nodes (LNs) to be examined among patients with gallbladder cancer (GBC).
METHODS: Between January 1, 2004, and December 31, 2015, patients with a diagnosis of GBC were identified in the National Cancer Database. A machine-based learning approach was used to identify the minimum number and range of LNs to evaluate relative to long-term outcomes.
RESULTS: Among 6531 patients with GBC, median number of LNs evaluated was 2 (IQR:1-5); only 21.1% (n = 1376) of patients had 6 or more LNs evaluated. The median number of metastatic LNs was 0 (IQR: 0-1). On multivariable analysis, evaluation of < 4 LNs was associated with a higher hazard of death (referent 4-7 LNs: < 4 LNs, HR = 1.27, 95% CI, 1.16-1.40; P < 0.001), whereas, patients who had 4 to 7 LNs and > 7 LNs evaluated had comparable long-term mortality risk (HR = 1.10, 95%CI, 0.98-1.24; P = 0.11). There was no difference in the proportion of patients who had at least one metastatic LN identified per T category based on total number of nodes resected (all P > 0.05).
CONCLUSION: The overwhelming majority of patients did not have the American Joint Committee on Cancer (AJCC) recommended 6 total LN count . A machine-based learning approach identified evaluation of 4 to 7 LNs as the LN number associated with optimal staging and survival. While obtaining 6 LNs may be challenging, evaluation of at least 4 LNs may be a more appropriate threshold as this cut-off value was associated with optimal patient outcomes and staging.

Vega EA, Sanhueza M, Viñuela E
Minimally Invasive Surgery for Gallbladder Cancer.
Surg Oncol Clin N Am. 2019; 28(2):243-253 [PubMed] Related Publications
There is consensus that oncologic extended resection should be performed for resectable incidental and nonincidental gallbladder cancer. The safety and feasibility of a minimally invasive approach to oncologic extended resection of gallbladder cancer has been demonstrated and is performed in centers of expertise worldwide. In this article, a systematic approach to the indications and techniques for a minimally invasive approach to extended resection for gallbladder cancer is detailed.

Hickman L, Contreras C
Gallbladder Cancer: Diagnosis, Surgical Management, and Adjuvant Therapies.
Surg Clin North Am. 2019; 99(2):337-355 [PubMed] Related Publications
Gallbladder cancer (GBC) is an often lethal disease, but surgical resection is potentially curative. Symptoms may be misdiagnosed as biliary colic; over half of new diagnoses are made after laparoscopic cholecystectomy for presumed benign disease. Gallbladder polyps >1 cm should prompt additional imaging and cholecystectomy. For GBC diagnosed after cholecystectomy, tumors T1b and greater necessitate radical cholecystectomy. Radical cholecystectomy includes staging laparoscopy, hepatic resection, and locoregional lymph node clearance to achieve R0 resection. Patients with locally advanced disease (T3 or T4), hepatic-sided T2 tumors, node positivity, or R1 resection may benefit from adjuvant chemotherapy. Chemotherapy increases survival in unresectable disease.

Fu Z, Chen X, Yang X, Li Q
Cholesterol Granuloma Masquerading as Gallbladder Carcinoma on 18F-FDG PET/CT.
Clin Nucl Med. 2019; 44(6):489-490 [PubMed] Related Publications
F-FDG PET/CT was performed on a 70-year-old man to stage the newly diagnosed multiple myeloma. A hypermetabolic lesion in the gallbladder fundus was revealed incidentally and suspected for gallbladder carcinoma, but was finally proven to be a cholesterol granuloma by the pathology of cholecystectomy.

Chen J, Yu Y, Li H, et al.
Long non-coding RNA PVT1 promotes tumor progression by regulating the miR-143/HK2 axis in gallbladder cancer.
Mol Cancer. 2019; 18(1):33 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The long non-coding RNA PVT1 (lncRNA PVT1) has been reported to act as an oncogenic regulator of several cancers. However, its expression and function in gallbladder cancer (GBC) remain largely unknown.
METHODS: In situ hybridization (ISH) and quantitative real-time PCR (qPCR) were performed to detect the expression of PVT1 and miR-143 in GBC tissues and cell lines. Immunohistochemistry (IHC) assays were performed to assess the expression of the hexokinase 2 (HK2) protein. The relationships among PVT1, miR-143 and HK2 were evaluated using dual-luciferase reporter, RNA immunoprecipitation (RIP) and biotin pull-down assays. The biological functions of PVT1, miR-143 and HK2 in GBC cells were explored with cell counting kit 8 (CCK-8), 5-ethynyl-20-deoxyuridine (EdU), colony formation, transwell, wound healing and glucose metabolism assays in vitro. For in vivo experiments, a xenograft model was used to investigate the effects of PVT1 and HK2 on GBC.
RESULTS: PVT1 was upregulated in GBC tissues and cells and was positively associated with malignancies and worse overall survival. PVT1 knockdown inhibited cell proliferation, migration, and invasion in vitro and restrained tumor growth in vivo. Further studies demonstrated that PVT1 positively regulated HK2 expression via its competing endogenous RNA (ceRNA) activity on miR-143. Additionally, HK2 expression and function were positively correlated with PVT1. Furthermore, we observed that the PVT1/miR-143/HK2 axis promoted cell proliferation and metastasis by regulating aerobic glucose metabolism in GBC cells.
CONCLUSIONS: The results of our study reveal a potential ceRNA regulatory pathway in which PVT1 modulates HK2 expression by competitively binding to endogenous miR-143 in GBC cells, which may provide new insights into novel molecular therapeutic targets for GBC.

Fujii M, Fujimoto K, Yabe S, et al.
Impact of Body Mass Index of Japanese Gallbladder Cancer Patients on their Postoperative Outcomes.
Acta Med Okayama. 2019; 73(1):51-59 [PubMed] Related Publications
 We investigated the relationship between body mass index (BMI) and postoperative outcomes in 450 gallbladder cancer patients in Japan. We collected patient information, including sex, age, underlying disease, BMI, stage, surgery method, postoperative time to discharge, and postoperative Medicare fees, from the Japanese administrative database associated with the Diagnosis Procedure Combination system. We classified patient BMIs as underweight (BMI<18.5 kg/m2), normal (BMI≥18.5 kg/m2 and <25 kg/m2) or overweight/obese (BMI≥25 kg/m2), then investigated the relationship between these categories and two postoperative outcomes: time to discharge and postoperative Medicare fees. The median postoperative time to discharge was 12 days in all patients, and 12 days in each of the three weight groups (p=0.62, n.s.). The median postoperative Medicare fees from surgery until discharge were (USD): all patients, $5,002; underweight, $5,875; normal weight, $4,797; and overweight/obese, $5,179 (p=0.146, n.s.). A multivariate analysis with adjustment for competing risk factors revealed that BMI was not associated with increased risk of longer postoperative time to discharge (normal weight: HR 1.17, p=0.29; overweight/obese: HR 1.17, p=0.37) or higher postoperative Medicare fees (OR 0.99, p=0.86, n.s.). Thus, high BMI was not found to be a factor for poor postoperative outcomes in Japanese patients with gallbladder cancer.

Liu F, Hu HJ, Ma WJ, et al.
Prognostic significance of neutrophil-lymphocyte ratio and carbohydrate antigen 19-9 in patients with gallbladder carcinoma.
Medicine (Baltimore). 2019; 98(8):e14550 [PubMed] Free Access to Full Article Related Publications
The neutrophil-lymphocyte ratio (NLR) is an immune response-related indicator and it is associated with poor prognosis of various cancers. The carbohydrate antigen19-9 (CA19-9) is a tumor-associated antigen and it has prognostic relevance in gallbladder carcinoma (GBC). We aimed to analyze whether preoperative NLR and serum CA19-9 were associated with outcomes of GBC patients after surgery with curative intent.Between January 2010 and May 2015, 90 resectable GBC patients who underwent curative surgery in our institution were included. All final diagnoses were confirmed by pathologic examination. The demographics, clinical, and histopathology data were analyzed. The Cox regression proportional hazard model and Kaplan-Meier method were used to assess prognostic factors.The cutoff values of 4.33 and 250.90 U/mL were defined as high NLR and high CA19-9, respectively. The univariate analyses showed that TNM stage, lymph node metastasis, the degree of tumor differentiation, margin status, combined hepatectomy, CA19-9, NLR, and PNI were all associated with overall survival (P < .05). According to the multivariable analysis, NLR (hazard ratio (HR) 3.840, 95% confidence interval (95% CI): 2.122-6.947, P < .001), CA19-9 (HR 2.230, 95% CI: 1.297-3.835, P = .004), TNM stage (HR 3.864, 95% CI: 1.819-8.207, P < .001), lymph node metastasis (HR 1.679, 95% CI: 1.005-2.805, P = .048), and margin status (HR 1.873, 95% CI: 1.063-3.300, P = .030) were independent prognostic factors. The median survival time in low NLR and CA19-9 group was better than high NLR and CA19-9 group (P < .05).The preoperative NLR and serum CA19-9 are associated with prognosis of patients with GBC. High NLR and high CA19-9 were predictors of poor long-term outcome among patients with GBC undergoing curative surgery.

Goel M, Khobragade K, Patkar S, et al.
Robotic surgery for gallbladder cancer: Operative technique and early outcomes.
J Surg Oncol. 2019; 119(7):958-963 [PubMed] Related Publications
BACKGROUND: The objective was to elucidate the operative technique of robotic radical cholecystectomy (RRC) and to compare the early outcomes of RRC with open radical cholecystectomy (ORC) for gallbladder cancer (GBC).
METHODS: Patients who underwent RRC for suspected or incidental GBC between July 2015 and August 2018 were analyzed. Patients who underwent ORC during the same period and fulfilled the study criteria formed the control group.
RESULTS: During the study period, 27 patients who underwent RRC formed the study group (group A) and 70 matched patients who underwent ORC formed the control group (group B). Median surgical time was higher in group A (295 vs 200 minutes, P < 0.001). However, median blood loss (200 vs 600 mL, P < 0.001), postoperative hospital stay (4 vs 5 days, P = 0.046) and postoperative morbidity (1 vs 15 patients, P = 0.035) were lower in group A. Median lymph node yield was 10 (range = 2-21) for group A and 9 (range = 2-25) for group B, and was comparable (P = 0.408). During a median follow up of 9 (1-46) months, two patients in group A developed recurrence (no port site recurrence).
CONCLUSION: RRC is safe and feasible and the short-term results are compared with ORC.

Liu W, Chen W, Chen J, et al.
Neuroendocrine carcinoma of gallbladder: a case series and literature review.
Eur J Med Res. 2019; 24(1):8 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Neuroendocrine carcinoma (NEC) of gallbladder is a rare tumor. The clinical manifestation, treatment, and prognosis of gallbladder NEC are rarely reported.
CASE PRESENTATION: Eight gallbladder NEC patients were admitted into our hospital. The major complaint was right upper quadrant pain. Two patients underwent a radical resection of gallbladder and liver quadrate lobe. One of them underwent chemotherapies and had no recurrence of NEC during a 25-month followed-up period. The other patient did not undergo chemotherapies, and the NEC recurred in the patient 15 months afterwards. Two patients underwent a radical resection of gallbladder. One of them underwent chemotherapies and had an NEC recurrence 12 months afterwards. The other patient did not undergo chemotherapies and died due to the NEC recurrence 5 months after surgery. Three patients underwent a laparoscopic cholecystectomy and pathologic result showed gallbladder NEC. They did not undergo further treatment and no NEC recurrence was found. One patient underwent tumor biopsy and died due to obstructive jaundice 3 months afterwards. Pathologic results showed that all cases had positive chromogranin A and synaptophysin staining.
CONCLUSIONS: Gallbladder NEC showed no noticeably specific features, and the diagnosis relied on the pathological and immunohistochemistrical results. For T1N0M0 gallbladder NEC, cholecystectomy might be enough. For patients in a late stage, the management of combined therapies might be optimal.

Liang C, Yang P, Han T, et al.
Long non-coding RNA DILC promotes the progression of gallbladder carcinoma.
Gene. 2019; 694:102-110 [PubMed] Related Publications
Increasing evidence has demonstrated that long non-coding RNAs (lncRNAs) contribute to tumorigenesis, progression and recurrence of various malignancies including Gallbladder carcinoma (GBC). Lnc-DILC is reported to be the tumor suppressor gene to play an important role in liver cancer stem cells (CSCs). However, the role of lnc-DILC in GBC remains to be elucidated. Herein, we show that lnc-DILC is upregulated in gallbladder CSCs and GBC patients' tissues. Knockdown of lnc-DILC attenuates the self-renewal, tumorigenicity, proliferation and metastasis of gallbladder CSCs. Mechanistically, lnc-DILC promotes gallbladder CSCs expansion via Wnt/β-catenin pathway. Special Wnt/β-catenin inhibitor FH535 diminishes the discrepancy of self-renewal, growth and metastasis between lnc-DILC interference GBC cells and their control cells. In conclusion, lnc-DILC drives gallbladder CSCs self-renewal, tumorigenicity, proliferation and metastasis by activating Wnt/β-catenin signaling, and may therefore prove to be a potential therapeutic target for GBC patients.

Vidaurre T, Casavilca S, Montenegro P, et al.
Tumor Protein p53 and K-ras Gene Mutations in Peruvian Patients with Gallbladder Cancer
Asian Pac J Cancer Prev. 2019; 20(1):289-294 [PubMed] Free Access to Full Article Related Publications
Background: Recent studies have shown that genetic alterations are associated with the effect of patient geographic location on gallbladder cancer development. Peru has a high incidence of gallbladder cancer, but causative factors have not yet been identified. We examined the frequency of mutations in TP53 and K-ras genes in Peruvian patients with gallbladder cancer, and compared this with data from Bolivia, Hungary, Chile, and Japan, which have a high gallbladder cancer incidence. Methods: DNA was extracted from formalin-fixed paraffin-embedded gallbladder tissue sections of 30 gallbladder cancer patients (9 men and 21 women) obtained using microdissection. Mutations in exons 5 to 8 of TP53 and codons 12, 13, and 61 of K-ras were examined using direct sequencing. Results: TP53 mutations were observed in 10 (33.3%) of patients, but K-ras mutations were absent. Nine (90%) TP53 mutations were point mutations (7 missense and 2 silent mutations), and the most frequent substitution was a G:C to A:T transition. G:C to A:T transitions at the CpG site or G:C to T:A transversions were found in one patient each. No significant differences were found in the frequency of TP53 and K-ras mutations among patients in the 5 countries. Conclusions: Our findings suggest that endogenous mechanisms and exogenous carcinogens may affect the carcinogenic process in Peruvian gallbladder cancer patients, similar to that in Bolivian patients. Further studies with a larger sample size are needed to clarify these findings.

Graur F, Mois E, Margarit S, et al.
Gallbladder carcinoma. Surgical management of gallblad-der carcinoma. An analysis of 37 cases.
Ann Ital Chir. 2018; 89:501-506 [PubMed] Related Publications
BACKGROUND & AIMS: Gallbladder carcinoma is a rare yet very aggressive cancer. In this study we evaluate the presentation, staging, procedures, complications and survival of patients with gallbladder carcinoma.
MATERIAL AND METHODS: Data at presentation, operative findings, postoperative evolution, complications and survival data were analyzed for 37 patients with gallbladder carcinoma (as cohort study) confirmed at histopathology between January 2005 and December 2011 in Surgical Department of Regional Institute of Gastroenterology And Hepatology "Octavian Fodor" Cluj-Napoca, Romania.
RESULTS: In 12 cases we had the suspicion of GBC (gallbladder carcinoma) before surgery, in 6 cases GBC was suspected intraoperatory and in 19 cases only after the histopathology exam. Radical cholecystectomy was considered in 9 cases (24.32%): 4 cases with cholecystectomy alone (patients with Tis-T1) and in 5 cases liver resection was associated.
CONCLUSION: The GBC has a low incidence (0.35% out of all cholecystectomies), the females being more affected (F:B=4.3:1). GBC was associated with low resecability rate (24.32%) and having a bad prognosis (survival under a year in stages T3 and T4). In most cases the diagnosis was hidden by an acute inflammatory process (acute cholecystitis) and the diagnosis was made after surgical intervention, therefore, the histopathology is crucial in these situations.
KEY WORDS: Gallbladder carcinoma, Jaundice, Palliative treatment, Resection, Survival.

Menon S, Mathew R
Association between metabolic syndrome and hepatobiliary cancers: A case-control study.
Indian J Gastroenterol. 2019; 38(1):61-68 [PubMed] Related Publications
BACKGROUND: The incidence of hepatobiliary cancer is steadily increasing. It is unclear if this rise is related to increasing trends in obesity, metabolic syndrome, and lifestyle changes.
METHODS: A case-control study was performed using the Health Improvement Network (THIN) database. Cases with a diagnosis of liver, bile duct, and gallbladder cancers were matched in a 1:2 fashion with controls and analyzed for potential associations between hepatobiliary cancer and obesity/metabolic syndrome.
RESULTS: Four thousand two hundred and eighty-seven patients (62% male, 38% female) with hepatobiliary cancers were matched with 8574 controls. On univariate analysis, body mass index (BMI), smoking, diabetes, alcohol consumption, ischemic heart disease, and hypertension were associated with hepatobiliary cancer. Statin use and non-smoking status had an inverse association. On multivariate analysis, BMI, diabetes, hypertension, ischemic heart disease, and insulin use were associated with the risk of hepatobiliary cancer. Statin use and non-smoking status were protective. On modeling BMI, each of diabetes and hypertension as a single covariate, there was a significant association with hepatobiliary cancer (1.59 [1.49-1.69], p < 0.001) which persisted despite adjusting for increasing age (1.006 [1005-1.006], p < 0.001) and background liver cirrhosis (1.037 [1.03-1.044], p < 0.001).
CONCLUSIONS: Obesity and metabolic syndrome are associated with the risk of hepatobiliary cancer. Statin use seems to be protective.

Cho JK, Lee W, Jang JY, et al.
Validation of the oncologic effect of hepatic resection for T2 gallbladder cancer: a retrospective study.
World J Surg Oncol. 2019; 17(1):8 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: While extended cholecystectomy is recommended for T2 gallbladder cancer (GBC), the role of hepatic resection for T2 GBC is unclear. This study aimed to identify the necessity of hepatic resection in patients with T2 GBC.
METHODS: Data of 81 patients with histopathologically proven T2 GBC who underwent surgical resection between January 1999 and December 2017 were enrolled from a retrospective database. Of these, 36 patients had peritoneal-side (T2a) tumors and 45 had hepatic-side (T2b) tumors. To identify the optimal surgical management method, T2 GBC patients were classified into the hepatic resection group (n = 44, T2a/T2b = 20/24) and non-hepatic resection group (n = 37, T2a/T2b = 16/21). The recurrence pattern and role of hepatic resection for T2 GBC were then investigated.
RESULTS: Mean age of the patients was 69 (range 36-88) years, and the male-to-female ratio was 42:39 (male, 51.9%; female, 48.1%). Hepatic-side GBC had a higher rate of recurrence than peritoneal-side GBC (44.4% vs. 8.3%, p = 0.006). The most common type of recurrence in T2a GBC was para-aortic lymph node recurrence (n = 2, 5.6%); the most common types of recurrence in T2b GBC were para-aortic lymph node recurrence (n = 7, 15.6%) and intrahepatic metastasis (n = 6, 13.3%). Hepatic-side GBC patients had worse survival outcomes than peritoneal-side GBC patients (76.0% vs. 96.6%, p = 0.041). Hepatic resection had no significant treatment effect in T2 GBC patients (p = 0.272). Multivariate analysis showed that lymph node metastasis was the only significant prognostic factor (p = 0.002).
CONCLUSIONS: Hepatic resection is not essential for curative treatment in T2 GBC, and more systemic treatments are needed for GBC patients, particularly for those with T2b GBC.

You MS, Ryu JK, Choi YH, et al.
Therapeutic outcomes and prognostic factors in unresectable gallbladder cancer treated with gemcitabine plus cisplatin.
BMC Cancer. 2019; 19(1):10 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Gallbladder cancer (GBC) is likely to be diagnosed at progressive stages and shows a very poor prognosis. Combination therapy with gemcitabine and cisplatin (GEMCIS) has been widely used as first-line palliative chemotherapy for advanced GBC. This study was designed to investigate the efficacy of GEMCIS and identify prognostic factors in patients with unresectable GBC.
METHODS: Patients with GBC who were treated with GEMCIS from January 2008 to June 2017 in a single tertiary hospital were included. All cases of GBC were diagnosed by pathologic findings and extent of the tumour was assessed by imaging tests. Combination chemotherapy consisted of cisplatin 25 mg/m
RESULTS: A total of 173 patients received a median of 5.3 ± 4.4 cycles of chemotherapy over 3.8 ± 3.9 months. Most of the patients (94.8%) were stage IVB at the time of diagnosis and the most common site of metastasis was the liver (42.8%). Disease control rate was 59.5%: 2 (1.2%) patients with complete response, 26 (15.0%) patients with partial response and 75 (43.4%) patients with stable disease. Overall survival (OS) and progression-free survival were 8.1 (95% confidence interval [CI], 7.1-10.2) and 5.6 (95% CI 4.5-6.8) months, respectively. Multivariable regression model indicated that metastasis to liver (hazard ratio [HR] = 1.63, 95% CI 1.11-2.40; P = 0.013), neutrophil-to-lymphocyte ratio (NLR) ≥3 (HR 1.65, 95% CI 1.09-2.49; P = 0.017), CEA ≥ 5 ng/mL (HR 1.50, 95% CI 1.02-2.19; P = 0.038), and CA19-9 ≥ 500 U/mL (HR 1.59, 95% CI 1.01-2.50; P = 0.043) were significantly associated with OS.
CONCLUSIONS: GEMCIS demonstrated a high disease control rate in patients with unresectable GBC. Factors independently related to OS were metastasis to liver, NLR ≥ 3, CEA ≥ 5 ng/mL and CA19-9 ≥ 500 U/mL.

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