TLK1 Inhibition Enhances the Anticancer Effect of Deep UV Irradiation Through CHK1 Activation.

BACKGROUND/AIM: A deep ultraviolet (DUV) light-emitting diode (LED) is a device that can irradiate electromagnetic waves from 250 nm to 350 nm. Tousled-like kinase 1 (TLK1) encodes a nuclear serine/threonine kinase, which is thought to influence the effects of DUV irradiation in cancer. The aim of this study was to clarify the interaction of TLK1 with DUV irradiation-induced DNA damage in cancer cells. MATERIALS AND METHODS: Pancreatic cancer cell lines were treated with or without DUV. TLK1 expression and phosphorylation in the two groups were examined. Then, these cancer cell lines were treated with thioridazine (THD), DUV or both. Thereafter, cytomorphology and apoptosis were assessed. Several proteins related to DNA damage, were analyzed in cancer cells treated with DUV and THD. Tumors in a subcutaneous xenograft model were treated with THD, DUV, or both for six weeks. RESULTS: DUV irradiation induced the phosphorylation of TLK1 in pancreatic cancer cell lines. Cytomorphology was significantly changed in pancreatic cancer cells treated with DUV and THD. TLK1 inhibition enhanced DUV irradiation-induced apoptosis in cancer cells. Interestingly, CHK1 and pCHK1 expression was suppressed after TLK1 inhibition. In addition, inhibition of MRE11 led to a decrease in the expression of CHK1 and pCHK1, accompanied by a notable increase in apoptosis. In the subcutaneous xenograft models, the tumor volume in the DUV and THD groups was lower than that in the other groups. CONCLUSION: TLK1 phosphorylation is an important event in DUV irradiation. DUV irradiation combined with TLK1 inhibition has therapeutic potential in pancreatic cancer cells.

A clinical assessment of three-dimensional-printed liver model navigation for thrice or more repeated hepatectomy based on a conversation analysis.

PURPOSES: We performed a conversation analysis of the speech conducted among the surgical team during three-dimensional (3D)-printed liver model navigation for thrice or more repeated hepatectomy (TMRH). METHODS: Seventeen patients underwent 3D-printed liver navigation surgery for TMRH. After transcription of the utterances recorded during surgery, the transcribed utterances were coded by the utterer, utterance object, utterance content, sensor, and surgical process during conversation. We then analyzed the utterances and clarified the association between the surgical process and conversation through the intraoperative reference of the 3D-printed liver. RESULTS: In total, 130 conversations including 1648 segments were recorded. Utterance coding showed that the operator/assistant, 3D-printed liver/real liver, fact check (F)/plan check (Pc), visual check/tactile check, and confirmation of planned resection or preservation target (T)/confirmation of planned or ongoing resection line (L) accounted for 791/857, 885/763, 1148/500, 1208/440, and 1304/344 segments, respectively. The utterance's proportions of assistants, F, F of T on 3D-printed liver, F of T on real liver, and Pc of L on 3D-printed liver were significantly higher during non-expert surgeries than during expert surgeries. Confirming the surgical process with both 3D-printed liver and real liver and performing planning using a 3D-printed liver facilitates the safe implementation of TMRH, regardless of the surgeon's experience. CONCLUSIONS: The present study, using a unique conversation analysis, provided the first evidence for the clinical value of 3D-printed liver for TMRH for anatomical guidance of non-expert surgeons.

Utility of modified pancreaticoduodenectomy (Hi-cut PD) for middle-third cholangiocarcinoma: an alternative to hepatopancreaticoduodenectomy.

BACKGROUND: The standard procedure for middle-third cholangiocarcinoma (MCC) is pancreaticoduodenectomy (PD); hepatopancreaticoduodenectomy (HPD) is often performed despite its high risk. There is no clear selection guidance for these procedures. METHODS: Patients with MCC who underwent HPD or PD were retrospectively evaluated. The conventional PD was modified (mPD) to transect the bile duct beyond or close to the cranial level of the portal bifurcation. RESULTS: The mPD group (n = 55) was characterized by older age, shorter operation time, less blood loss, and less frequent complications than were observed in the HPD group (n = 34). The median grossly tumor-free margin of the proximal bile duct (GM) was 13 mm vs 20 mm (P = 0.006). Overall survival did not differ significantly between groups (48% vs 53% at 5 years, P = 0.399). Multivariate analysis identified positive surgical margin as a sole independent prognostic factor (hazard ratio, 1.89; P = 0.043), which was statistically associated with GM length. Five-year survival for mPD patients with GM ≥15 mm was significantly better than that for those who had GM <15 mm (69% vs 33%, P = 0.011) and comparable to that of HPD patients (53%, P = 0.450). CONCLUSION: The mPD may be recommended in patients with MCC, provided that GM ≥15 mm is expected from the preoperative radiological imaging. Otherwise, HPD should be considered.

Development of real-time navigation system for laparoscopic hepatectomy using magnetic micro sensor.

BACKGROUND: We report a new real-time navigation system for laparoscopic hepatectomy (LH), which resembles a car navigation system. MATERIAL AND METHODS: Virtual three-dimensional liver and body images were reconstructed using the "New-VES" system, which worked as roadmap during surgery. Several points of the patient's body were registered in virtual images using a magnetic position sensor (MPS). A magnetic transmitter, corresponding to an artificial satellite, was placed about 40 cm above the patient's body. Another MPS, corresponding to a GPS antenna, was fixed on the handling part of the laparoscope. Fiducial registration error (FRE, an error between real and virtual lengths) was utilized to evaluate the accuracy of this system. RESULTS: Twenty-one patients underwent LH with this system. Mean FRE of the initial five patients was 17.7 mm. Mean FRE of eight patients in whom MDCT was taken using radiological markers for registration of body parts as first improvement, was reduced to 10.2 mm (p = .014). As second improvement, a new MPS as an intraoperative body position sensor was fixed on the right-sided chest wall for automatic correction of postural gap. The preoperative and postoperative mean FREs of 8 patients with both improvements were 11.1 mm and 10.1 mm (p = .250). CONCLUSIONS: Our system may provide a promising option that virtually guides LH.

Clinical value of fluorescent cholangiography for the infraportal type of right posterior bile duct.

BACKGROUND: The infraportal type of the right posterior bile duct (infraportal RPBD) is a well-known anatomical variation that increases the potential risk of intraoperative biliary injury. The aim of this study is to clarify the clinical value of fluorescent cholangiography during single-incision laparoscopic cholecystectomy (SILC) for patients with infraportal RPBD. MATERIAL AND METHODS: Our procedure for SILC utilized the SILS-Port, and another 5-mm forceps was inserted via an umbilical incision. A laparoscopic fluorescence imaging system developed by Karl Storz Endoskope was utilized for fluorescent cholangiography. Between July 2010 and March 2022, 41 patients with infraportal RPBD underwent SILC. We conducted retrospective reviews of patient data, focusing on the clinical value of fluorescent cholangiography. RESULTS: Thirty-one patients underwent fluorescent cholangiography during SILC, but the remaining ten did not. Only one patient who did not undergo fluorescent cholangiography developed an intraoperative biliary injury. The detectability of infraportal RPBD before and during the dissection of Calot's triangle was 16.1% and 45.2%, respectively. These visible infraportal RPBDs were characterized as connections to the common bile duct. The confluence pattern of infraportal RPBD significantly influenced its detectability during the dissection of Calot's triangle (p < 0.001). CONCLUSIONS: The application of fluorescent cholangiography can lead to safe SILC, even for patients with infraportal RPBD. Its benefit is emphasized when infraportal RPBD is connected to the common bile duct.

The Goal of Intraoperative Blood Loss in Major Hepatobiliary Resection for Perihilar Cholangiocarcinoma: Saving Patients From a Heavy Complication Burden.

OBJECTIVE: To determine the goal of intraoperative blood loss in hepatectomy for perihilar cholangiocarcinoma. BACKGROUND: Although massive bleeding can negatively affect the postoperative course, the target value of intraoperative bleeding to reduce its adverse impact is unknown. METHODS: Patients who underwent major hepatectomy for perihilar cholangiocarcinoma between 2010 and 2019 were included. Intraoperative blood loss was adjusted for body weight [adjusted blood loss (aBL)], and the overall postoperative complications were evaluated by the comprehensive complication index (CCI). The impact of aBL on CCI was assessed by the restricted cubic spline regression. RESULTS: A total of 425 patients were included. The median aBL was 17.8 (interquartile range, 11.8-26.3) mL/kg, and the CCI was 40.6 (33.7-49.5). Sixty-three (14.8%) patients had an aBL<10 mL/kg, nearly half (45.4%) of the patients were in the range of 10 ≤aBL<20 mL/kg, and 37 (8.7%) patients had an aBL >40 mL/kg. The spline regression analysis showed a nonlinear incremental association between aBL and CCI; CCI remained flat with an aBL under 10 mL/kg; increased significantly with an aBL ranging from 10 to 20 mL/kg; grew gradually with an aBL over 20 mL/kg. These inflection points of ~10 and 20 mL/kg were almost consistent with the cutoff values identified by the recursive partitioning technique. After adjusting for other risk factors for the postoperative course, the spline regression identified a similar model. CONCLUSIONS: aBL had a nonlinear aggravating effect on CCI after hepatectomy for perihilar cholangiocarcinoma. The primary goal of aBL should be <10 mL/kg to minimize CCI.

Cyclodextrin Conjugated α-Bisabolol Suppresses FAK Phosphorylation and Induces Apoptosis in Pancreatic Cancer.

BACKGROUND/AIM: α-Bisabolol is an essential oil component extracted from plants, such as chamomile. We have previously reported that α-bisabolol suppressed proliferation, invasion, and motility of pancreas cancer. Cyclodextrin improved the solubility of α-bisabolol, therefore it enabled to administer intravenously. The aim of this study was to clarify the effect of cyclodextrin conjugated α-bisabolol (CD-BSB) and the signals pathways associated with α-bisabolol for pancreatic cancer. MATERIALS AND METHODS: Human pancreatic cancer cell lines were treated with or without CD-BSB. Cytomorphology and apoptosis were assessed in these treated groups. In addition, several phosphorylated proteins were analyzed to clarify the signal pathway concerning CD-BSB. In subcutaneous xenograft model, tumor volume and Ki-67 expression were evaluated among Control (untreated), CD-BSB, or Gemcitabine (GEM). RESULTS: CD-BSB significantly changed cytomorphology and induced apoptosis in pancreatic cancer cells. CD-BSB suppressed phosphorylation of focal adhesion kinase (FAK). In addition, pFAK 397 was inhibited by CD-BSB in a concentration-dependent manner in cancer cells. In the subcutaneous xenograft models, the tumor volume in the CD-BSB groups was lower than Control groups. Ki67-positive cells in CD-BSB treated group were lower than the GEM-treated groups. CONCLUSION: We clarified the efficiency of CD-BSB in xenograft tumor using intravenous administration. α-Bisabolol suppresses phosphorylation of FAK 397 and impairs cytoskeletal polymerization in a pancreatic cancer cell line. Further investigations are required to reveal the precise mechanisms of the antitumor effects of solubilized α-bisabolol to facilitate its clinical application. Our data indicate that solubilized α-bisabolol has therapeutic potential and could improve the prognosis of cancer patients.

Antitumor Effects of Deep Ultraviolet Irradiation for Pancreatic Cancer.

BACKGROUND/AIM: Deep ultraviolet (DUV) light spans within the 250 nm to 350 nm invisible wavelength range. Although it strongly damages various cells, the efficacy of DUV irradiation on pancreatic cancer cells has never been clarified. The purpose of this study was to reveal the antitumor effects of DUV irradiation on pancreatic cancer cells. MATERIALS AND METHODS: Human pancreatic cancer cell lines were eradicated with DUV or ultraviolet A (UVA) for 5 s. Several angiogenesis-related proteins were studied in cancer cells after DUV irradiation using a protein antibody array. A subcutaneous xenograft model was established by inoculation of pancreatic cancer cells into mice. Tumors in this model were irradiated with DUV or UVA once or twice for two weeks. Tumor volumes in these groups (DUV×1: one irradiation, DUV×2: two irradiations, and untreated) were analyzed one week after the second irradiation. RESULTS: DUV irradiation significantly changed the cytomorphology of pancreatic cancer cells. In addition, DUV irradiation induced apoptosis on pancreatic cancer cells more strongly than UVA irradiation and no irradiation. Interestingly, lower expression of thrombospondin 1 (TSP1) and tissue inhibitor of metalloproteinase 1 (TIMP1) was identified after DUV treatment. The tumor volume in the DUV-treated groups (DUV×1 and DUV×2) was smaller than that in the untreated group. CONCLUSION: Further investigations are required to reveal the precise mechanisms of the antitumor effects of DUV irradiation and to facilitate its clinical application as a new therapy for pancreatic cancer. Overall, DUV irradiation can be potentially used as a therapeutic option of pancreatic malignancy.

Early Prediction of a Serious Postoperative Course in Perihilar Cholangiocarcinoma: Trajectory Analysis of the Comprehensive Complication Index.

OBJECTIVE: The aim of this study was to visualize the postoperative clinical course using the comprehensive complication index (CCI) and to propose an early alarming sign for subsequent serious outcomes in perihilar cholangiocarcinoma. BACKGROUND: Surgery for this disease carries a high risk of morbidity and mortality. The developmental course of the overall morbidity burden and its clinical utility are unknown. METHODS: Patients who underwent major hepatectomy for perihilar cholan-giocarcinoma between 2010 and 2019 were reviewed retrospectively. All postoperative complications were evaluated according to the Clavien-Dindo classification (CDC), and the CCI was calculated on a daily basis until postoperative day 14 to construct an accumulating graph as a trajectory. Group-based trajectory modeling was conducted to categorize the trajectory into clinically distinct patterns and the predictive power of early CCI for a subsequent serious course was assessed. RESULTS: A total of 4230 complications occurred in the 484 study patients (CDC grade I, n = 27; II, n = 132; IlIa, n = 290; IIIb, n = 4; IVa, n = 21; IVb, n = 1; and V, n = 9). The trajectory was categorized into 3 patterns: mild (n = 209), moderate (n = 235), and severe (n = 40) morbidity courses. The 90-day mortality rate significantly differed among the courses: 0%, 0.9%, and 17.5%, respectively (P<0.001). The cutoff values of the CCI on postoperative days 1, 4, and 7 for predicting a severe morbidity course were 15.0, 28.5, and 40.6 with areas under the curves of 0.780, 0.924, and 0.984, respectively. CONCLUSIONS: The CCI could depict the chronological increase in the overall morbidity burden, categorized into 3 patterns. Early CCI potentially predicted sequential progression to serious outcomes.

Efficacy of Extended Modification in Left Hemihepatectomy for Advanced Perihilar Cholangiocarcinoma: Comparison Between H12345'8'-B-MHV and H1234-B.

OBJECTIVE: The aim of this study was to verify the prognostic impact of the tumor exposure at the liver transection margin (LTM) in left-sided perihilar cholangiocarcinoma and the impact of middle hepatic vein (MHV) resection on this exposure. BACKGROUND: In perihilar cholangiocarcinoma, tumors are unexpectedly exposed at the LTM during left hemihepatectomy (LH). METHODS: Patients who underwent LH for perihilar cholangiocarcinoma during 2002 to 2018 were retrospectively evaluated. LH was classified into conventional and extended types, which preserved and resected the MHVs, respectively. Positive LTM was defined as the involvement of invasive carcinoma at the liver transection plane and/or the adjacent Glissonean pedicle exposed. The clinicopathologic features and survival outcomes were compared between procedures. RESULTS: Among 236 patients, conventional and extended LHs were performed in 198 and 38 patients, respectively. The LTM was positive in 31 (13%) patients, with an incidence of 14% versus 8% ( P = 0.432) and 24% versus 0% in advanced tumors ( P = 0.011). Tumor size ≥ 18 mm ( P = 0.041), portal vein invasion ( P = 0.009), and conventional LH ( P = 0.028) independently predicted positive LTM. In patients with negative LTM, the survival was comparable between the two groups: 60.4% versus 59.2% at 3 years ( P = 0.206), which surpassed 17.7% for those with positive LTM in the conventional group ( P < 0.001). Multivariable analysis demonstrated that LTM status was an independent prognostic factor ( P = 0.009) along with ductal margin status ( P = 0.030). CONCLUSIONS: The LTM status is an important prognostic factor in perihilar cholangiocarcinoma. Extended LH reduced the risk of tumor exposure at the LTM with a subsequent improvement in the survival, particularly in advanced tumors.

Impact of preoperative muscle mass and quality on surgical outcomes in patients undergoing major hepatectomy for perihilar cholangiocarcinoma.

PURPOSES: This study sought to define the impact of skeletal muscle mass and quality on postoperative outcomes in patients with perihilar cholangiocarcinoma. METHODS: Patients who underwent major hepatectomy for perihilar cholangiocarcinoma were included. The normalized total psoas area (TPA) (psoas muscle index [PMI]) and average Hounsfield units of the TPA (psoas muscle density [PMD]) were measured using preoperative computed tomography images. The cohort was dichotomized using the following indices: sex-specific lowest tertile (low PMI and low PMD) and other (normal PMI and normal PMD). Intraoperative and postoperative outcomes were compared, focusing on PMI and PMD. RESULTS: A total of 456 patients were analyzed. The intraoperative blood loss (IBL) was 21.3 ml/kg in the low PMI group and 17.2 ml/kg in the normal PMI group (P = .008). Patients in the low PMI or PMD group experienced postoperative infectious complications more frequently than those in the other groups. The median survival time was 37.8 months in the low PMI group and 54.2 months in the normal PMI group (P = .027). CONCLUSIONS: PMI and PMD were closely associated with IBL and postoperative infectious complications. Additionally, PMI impacted long-term survival. These results suggest an importance of improving muscle mass and quality before surgery.

Which modality is better to diagnose high-grade transformation in retroperitoneal liposarcoma? Comparison of computed tomography, positron emission tomography, and magnetic resonance imaging.

BACKGROUND: Survival in patients with retroperitoneal liposarcoma (RPLS) depends on the surgical management of the dedifferentiated foci. The present study investigated the diagnostic yield of contrast-enhanced CT, 18F-fluorodeoxyglucose positron emission tomography (PET), and diffusion-weighted MRI in terms of dedifferentiated foci within the RPLS. METHODS: Patients treated with primary or recurrent RPLS who underwent the above imaging between January 2010 and December 2021 were retrospectively reviewed. The diagnostic accuracy of the three modalities for histologic subtype of dedifferentiated liposarcoma (DDLS) and French Federation of Cancer Center (FNCLCC) grade 2/3 were compared using receiver operating characteristic curves and areas under the curves (AUCs). RESULTS: The cohort involved 32 patients with 53 tumors; 30 of which exhibited DDLS and 31 of which did FNCLCC grades 2/3. The optimal thresholds for predicting DDLS were mean CT value of 31 Hounsfield Unit (HU) (AUC = 0.880, 95% CI 0.775-0.984; p < 0.001), maximum standardized uptake value (SUVmax) of 2.9 (AUC = 0.865 95% CI 0.792-0.980; p < 0.001), while MRI failed to differentiate DDLS. The cutoff values for distinguishing FNCLCC grades 1 and 2/3 were a mean CT value of 24 HU (AUC = 0.858, 95% CI 0.731-0.985; p < 0.001) and SUVmax of 2.9 (AUC = 0.885, 95% CI 0.792-0.978; p < 0.001). MRI had no sufficient power to separate these grades. CONCLUSIONS: Contrast-enhanced CT and PET were useful for predicting DDLS and FNCLCC grade 2/3, while MRI was inferior to these two modalities.

Is a specific T classification needed for extrahepatic intraductal papillary neoplasm of the bile duct (IPNB) type 2 associated with invasive carcinoma?

BACKGROUND: The necessity of a specific T classification for extrahepatic intraductal papillary neoplasm of the bile duct (IPNB) type 2, one of the precursors of cholangiocarcinoma (CC), remains unclear. METHODS: Patients who underwent resection for extrahepatic biliary tumors were reviewed. Relapse-free survival (RFS) was compared between IPNB type 2 and CC, stratified by T classification. RESULTS: The cohort involved 443 patients with IPNB type 2 (n = 57) and CC (n = 386). In 342 patients with perihilar tumors, 5-year RFS of IPNB type 2 and CC group was 49.8% versus 34.5% (p = .012), respectively. The RFS was 54.6% versus 47.2% (p = .110) for pT1-2 tumors and 28.6% versus 22.7% (p = .436) for pT3-4 tumors, respectively. In 92 patients with distal tumors, 5-year RFS was 47.4% versus 42.1% (p = .678). The RFS was 68.2% versus 49.6% (p = .422) for pT1 tumors and 18.8% versus 38.3% (p = .626) for pT2-3 tumors, respectively. Multivariate analysis identified that poor histologic grade (HR, 2.105; p < .001), microscopic venous invasion (HR, 1.568; p = .002), and nodal metastasis (HR, 1.547; p < .001) were independent prognostic deteriorators, while tumor type (IPNB type 2 vs. CC) was not. CONCLUSIONS: Prognostic impact of IPNB type 2 was limited, suggesting unnecessity of a specific T classification for IPNB type 2 with invasive carcinoma.

A proposal of drain removal criteria in hepatobiliary resection.

BACKGROUND: Standardized criteria for drain removal in hepatobiliary resection are lacking. Here, we evaluated the outcomes of delayed removal policy in this extended surgery. METHODS: Patients undergoing hepatectomy with biliary reconstruction between 2012 and 2018 were retrospectively reviewed. The drains were removed on postoperative day (POD) 7 when the drainage fluid was grossly serous, biochemically normal, and negative for bacterial contamination as assessed by Gram staining; additionally, no abnormal fluid collection was confirmed by computed tomography. Clinically relevant abdominal complications (CRACs), including biliary leakage, pancreatic fistula or intra-abdominal abscess, served as the primary outcome measure. RESULTS: Among 374 study patients, surgical drains were removed in 166 (44.3%) patients who met the criteria. Of these patients, 16 (9.6%) patients subsequently required additional drainage due to CRAC. Drains were retained and exchanged in 208 (55.6%) patients who did not meet the criteria. Of these, exchanged drains were soon removed in 34 patients due to no signs of CRAC. The diagnostic ability of the criteria revealed 0.916 sensitivity, 0.815 specificity, and 0.866 accuracy. CONCLUSION: The four findings on POD 7 worked well as criteria for drain removal, and these criteria may be helpful in drain management after hepatobiliary resection.

A long-term survivor of advanced retroperitoneal dedifferentiated liposarcoma: a successful multimodal approach with extended resection and chemotherapy.

Surgical resection is the mainstay of treatment for retroperitoneal liposarcoma (RPLS). Herein, we describe a case of dedifferentiated RPLS successfully treated with an extended surgical approach with adjuvant chemotherapy. A 61-year-old male was referred to our hospital with a chief complaint of chest tightness. Abdominal computed tomography revealed a large retroperitoneal tumor, 11 cm in diameter, extensively invading the surrounding organs: the celiac axis, the splenic artery, the pancreatic body and tail, the lesser curvature of the stomach and the left adrenal gland. Endoscopic ultrasound-guided fine-needle aspiration biopsy confirmed dedifferentiated liposarcoma, suggesting aggressive tumor biology. We performed total gastrectomy combined with distal pancreatectomy with celiac axis and left adrenal gland resection with a curative intent. The postoperative course was almost uneventful. As the pathological findings indicated a positive margin with a well-differentiated liposarcoma component, we added adjuvant chemotherapy with four cycles of doxorubicin and ifosfamide (AI). Five years after primary surgery, regular follow-up CT demonstrated a pulmonary hilar lymph node enlargement and a tumor at paraesophageal locations. After downsizing chemotherapy with eribulin followed by pazopanib, he underwent partial esophagectomy with dissection of the paraesophageal tumor. The pathological findings indicated recurrence of dedifferentiated liposarcoma with a tumor-free surgical margin. He is currently alive without any evidence of recurrence almost 7 years after the first surgery and 15 months after the second surgery. The long-term survival gained in this patient indicates that extended resections and adjuvant chemotherapy could prolong survival in patients even with RPLS with dedifferentiated tumor histology.

Combined Vascular Resection for Locally Advanced Perihilar Cholangiocarcinoma.

OBJECTIVE: To evaluate the efficacy and safety of combined vascular resection (VR) in advanced perihilar cholangiocarcinoma (PHC). SUMMARY OF BACKGROUND DATA: Hepatectomy combined with portal vein resection (PVR) and/or hepatic artery resection (HAR) is technically demanding but an option only for tumor eradication against PHC involving the hilar hepatic inflow vessels; however, its efficacy and safety have not been well evaluated. METHODS: Patients diagnosed with PHC during 2001-2018 were included. Patients who underwent resection were divided according to combined VR. Patients undergoing VR were subdivided according to type of VR. Postoperative outcomes and OS were compared between patient groups. RESULTS: Among the 1055 consecutive patients, 787 (75%) underwent resection (without VR: n = 484, PVR: n = 157, HAR: n = 146). The incidences of postoperative complications and mortality were 49% (without VR vs with VR, 48% vs 50%; P= 0.715) and 2.1% (without VR vs with VR, 1.2% vs 3.6%; P= 0.040), respectively. The OS of patients who underwent resection with VR (median, 30 months) was shorter than that of those who underwent resection without VR (median, 61 months; P < 0.0001); however, it was longer than that of those who did not undergo resection (median, 10 months; P < 0.0001). OS was not significantly different between those who underwent PVR and those who underwent HAR (median, 29 months vs 34 months; P = 0.517). CONCLUSION: VR salvages a large number of patients from having locally advanced PHC that is otherwise unresectable and is recommended if the hilar hepatic inflow vessels are reconstructable, providing acceptable surgical outcomes and substantial survival benefits.

Mild Prognostic Impact of Postoperative Complications on Long-term Survival of Perihilar Cholangiocarcinoma.

OBJECTIVE: To evaluate the impact of complications on long-term survival in patients with perihilar cholangiocarcinoma. BACKGROUND: Surgical resection for perihilar cholangiocarcinoma is vulnerable to postoperative complications. The prognostic impact of complications in patients with this disease is unknown. METHODS: The medical records of patients who underwent curative-intent hepatectomy for perihilar cholangiocarcinoma between 2010 and 2017 were reviewed retrospectively. The comprehensive complication index (CCI) was calculated based on all postoperative complications, which were graded by the Clavien-Dindo classification (CDC). Patients were divided into high and low CCI groups by the median score, and survival was compared between the 2 groups. RESULTS: Excluding 8 patients who died in hospital, 369 patients were analyzed. The CDC grade was I in 20 (5.4%), II in 108 (29.3%), III in 224 (60.7%), and IV in 17 (4.6%) patients. The CCI increased with increasing CDC grade; the median was 42.9 (range, 15.0-98.9). Overall survival differed significantly between the high (n = 187) and low (n = 182) CCI groups (41.2% vs 47.9% at 5 years; P = 0.041). However, multivariable analyses demonstrated that traditional clinicopathological factors were independent predictors of survival and that the dichotomized CCI was not. In addition, the CCI score as a continuous variable was not an independent prognostic factor for overall survival in the multivariable analyses (hazard ratio per 1 CCI score: 1.00, 95% confidence interval: 0.99-1.01, P = 0.775). CONCLUSIONS: Cumulative postoperative complications after resection of perihilar cholangiocarcinoma only moderately deteriorate long-term survival, and should not be an argument to deny surgery in this high-risk population.

Superiority of clinical American Joint Committee on Cancer T classification for perihilar cholangiocarcinoma.

BACKGROUND: Clinical tumor staging is essential information for making a therapeutic decision in cancer. This study aimed to identify the optimal tumor classification system for predicting resectability and survival probability in perihilar cholangiocarcinoma. METHODS: Patients who were treated for perihilar cholangiocarcinoma between 2009 and 2018 were enrolled. Local tumor extension was staged radiologically according to a diameter-based classification system in addition to the AJCC, Blumgart, and Bismuth systems. Survival and resectability were compared between T subgroups, and the discriminability of the four systems was assessed with Harrell's concordance index (C-index). RESULTS: Among 702 study patients, 559 (80.0%) underwent laparotomy, 489 (70.0%) of whom underwent resection. The resectability significantly decreased for more advanced tumors in all systems (P < .001); the AJCC system had the greatest discriminability for resectability (area under the curve 0.721). Overall survival at 5 years was 69.9% for AJCC cT1, 45.8% for cT2, 31.8% for cT3, and 15.3% for cT4 tumors (cT1 vs cT2; P = .002, cT2 vs cT3; P = .008 and cT3 vs cT4; P < .001). The AJCC system had the largest C-index of 0.627. CONCLUSIONS: The AJCC T system was the optimal classification system for predicting resectability and survival in perihilar cholangiocarcinoma.

Adjuvant S-1 vs gemcitabine for node-positive perihilar cholangiocarcinoma: A propensity score-adjusted analysis.

BACKGROUND: The efficacy of adjuvant chemotherapy for biliary cancers remains controversial because of conflicting results from previous phase 3 studies that used different key drugs and enrolled patients with heterogeneous tumor sites and disease stages. Fluoropyrimidine seems more beneficial than gemcitabine (GEM) combination regimens in the adjuvant setting; however, data comparing the survival benefit between GEM- and fluoropyrimidine-based regimens are lacking. METHODS: Patients who underwent resection for node-positive perihilar cholangiocarcinoma were included. The patients who underwent adjuvant chemotherapy were divided into the S-1 and GEM groups according to the regimen. The recurrence-free survival (RFS) and the overall survival (OS) were compared between the groups and adjusted with propensity scores generated from 14 potentially confounding clinicopathological factors. RESULTS: In total, 186 patients (Surgery alone, n = 71; S-1, n = 60; GEM, n = 55) were included. The S-1 and GEM completion rates were 75% and 65%, respectively. Among the patients who underwent adjuvant therapy, the RFS was longer in the S-1 group patients than the GEM group patients (median, 24.4 months vs 14.9 months; P = .044) whereas the OS was not significantly different between the groups (median, 48.5 months vs 35.0 months; P = .324). After propensity score adjustment, the differences in RFS and OS between the groups were more evident (HR: 2.696, 95% CI: 1.739-4.180 P < .001; HR: 1.988, 95% CI: 1.221-3.238, P < .001, respectively). CONCLUSIONS: Compared with adjuvant GEM monotherapy, adjuvant S-1 monotherapy may improve survival in node-positive perihilar cholangiocarcinoma patients.