External validation of scores predicting postoperative fistula after pancreatogastrostomy for pancreatoduodenectomy reconstruction. A single center experience.

BACKGROUND: Clinically relevant postoperative pancreatic fistula (CR-POPF) is the most frequent complication of pancreatic surgery and can be fatal. Selection and stratification of patients according to the risk of POPF are important for the perioperative management. Predictive metrics have been developed and validated in pancreatojejunostomy. Aim of this study is to assess whether the most used prognostic scores can be predictive of fistula following Wirsung-pancreaticogastrostomy (WPG) for pancreatoduodenectomy (PD)reconstruction. METHOD: This single-center prospective observational study included 212 PDs between January 2008 and October 2022 with a standardized WPG. All component variables of the six scores were separately validated in our cohort. The overall predictive ability of the six fistula scores was measured and compared with the receiver operating characteristics curves (ROC) method and expressed by the area under the ROC-curve (AUC). Univariate and multivariate logistic regression analyses were performed considering all risk factors in the scores in order to identify variables independently correlated with POPF in the WPG. RESULTS: CR-POPF occurred in 36 of 212 (17 %) patients. All scores showed poor prognostic stratification for the development of CR-POPF. The occurrence of CR-POPF was associated with nine factors: male gender (p = 0.003); BMI (kg/m2) (p = 0.005); ASA (%) (p = 0.003); Soft pancreatic texture (%) (p = 0.003), Pathology (p = 0.008); MPD (p = 0.011); EBL (mL) (p = 0.021); Preop. Bilirubin (mg/dl) (p = 0.038); Preop. Glucose (mg/dl) (p = 0.0369). Male gender (OR: 5.54, CI 1.41-21.3) and soft consistency of the remnant pancreas (OR: 3.83, CI 1.14-12.8) were the only independent prognostic factors on multivariate analysis. CONCLUSIONS: Our study including exclusively pancreatogastrostomies failed to validate the most used predictive scores for POPF. We found that only male gender and soft pancreatic texture are associated with POPF. Specific predictive scores following pancreatogasgtrostomy are needed.

Laparoscopic Left Hepatectomy for Hepatocellular Carcinoma Recurrence Following Liver Transplantation.

BACKGROUND: Despite the successful oncological results of liver transplantation, patients with hepatocellular carcinoma (HCC) can develop tumor recurrence. When technically feasible, liver resection represents the preferred treatment for recurrent HCC, even in the setting of transplanted patients. Recent progresses in minimally invasive liver resections have pushed the surgical community to attempt more challenging cases. We report a full laparoscopic left hepatectomy for HCC recurrence on transplanted liver. METHODS: A routine follow-up computed tomography (CT) scan of a 53-year-old male who previously underwent an orthotopic liver transplantation for alcoholic-related liver disease showed a 3 cm HCC in segment 4 in close relationship with the peripheral portion of the left portal pedicle. A full laparoscopic left hepatectomy was performed using an extrahepatic intraglissonean approach. RESULTS: Operative time was 332 min and blood loss was 100 mL. The patient had an uneventful postoperative recovery and was discharged home after 3 days. CONCLUSIONS: Laparoscopic liver resection on transplanted patients is feasible. Challenging clinical scenarios should only be attempted in referral centers and after an appropriate learning curve.1-8.

PLK1 targets NOTCH1 during DNA damage and mitotic progression.

Notch signaling plays a complex role in carcinogenesis, and its signaling pathway has both tumor suppressor and oncogenic components. To identify regulators that might control this dual activity of NOTCH1, we screened a chemical library targeting kinases and identified Polo-like kinase 1 (PLK1) as one of the kinases involved in arsenite-induced NOTCH1 down-modulation. As PLK1 activity drives mitotic entry but also is inhibited after DNA damage, we investigated the PLK1-NOTCH1 interplay in the G2 phase of the cell cycle and in response to DNA damage. Here, we found that PLK1 regulates NOTCH1 expression at G2/M transition. However, when cells in G2 phase are challenged with DNA damage, PLK1 is inhibited to prevent entry into mitosis. Interestingly, we found that the interaction between NOTCH1 and PLK1 is functionally important during the DNA damage response, as we found that whereas PLK1 activity is inhibited, NOTCH1 expression is maintained during DNA damage response. During genotoxic stress, cellular transformation requires that promitotic activity must override DNA damage checkpoint signaling to drive proliferation. Interestingly, we found that arsenite-induced genotoxic stress causes a PLK1-dependent signaling response that antagonizes the involvement of NOTCH1 in the DNA damage checkpoint. Taken together, our data provide evidence that Notch signaling is altered but not abolished in SCC cells. Thus, it is also important to recognize that Notch plasticity might be modulated and could represent a key determinant to switch on/off either the oncogenic or tumor suppressor function of Notch signaling in a single type of tumor.

Massive pelvic recurrence of uterine leiomyomatosis with intracaval-intracardiac extension: video case report and literature review.

BACKGROUND: Uterine leiomyomas represent the gynecological neoplasm with the highest prevalence worldwide. This apparently benign pathological entity may permeate into the venous system causing the so-called intravenous leiomyomatosis of the uterus (IVL). IVL may seldom extend to large caliber veins and reach the right cardiac chambers or pulmonary arteries and cause signs of right sided congestive heart failure and sudden death. Due to its low incidence, however, IVL with intracardiac extension is often misdiagnosed resulting in deferred treatment. No consensus has been obtained regarding the standard surgical approach to be used for this rare condition. We describe the case of a massive pelvic recurrence of uterine leiomyomatosis with intracardiac extension and provide a review of the literature, analyzing management and surgical outcomes. CASE PRESENTATION: We present the case of a 46-year-old premenopausal woman presenting with lower-extremity edema, recurrent syncopes and a history of subtotal hysterectomy for multiple uterine fibroids. She was diagnosed with pelvic recurrence of uterine leiomyomatosis and IVL with cardiac involvement. A two-stage surgical excision of the intracardiac-intracaval mass and pelvic leiomyomatosis was performed. The patient had an uneventful recovery and no evidence of recurrence was observed on follow-up. CONCLUSIONS: By virtue of the rarity of the present pathology, awareness is widely scarce and diagnosis is often delayed. Early recognition is difficult due to initial aspecific and subtle clinical manifestations. Nevertheless, suspicion should be held high in premenopausal women with known history of uterine leiomyomata, presenting with cardiovascular symptoms and evidence of a free-floating mass within the right cardiac chambers. In-depth imaging is crucial for defining its anatomical origin and relations. Prompt surgical treatment with radical excision of pelvic and intravenous leiomyomatosis guarantees favorable outcomes and excellent prognosis with low rates of recurrence, whereas delayed diagnosis and treatment exposes to increased risk of congestive heart failure and sudden death.

Transarterial Radioembolization Can Downstage Intermediate and Advanced Hepatocellular Carcinoma to Liver Transplantation.

BACKGROUND: Transarterial radioembolization (TARE) is an effective treatment to control tumor growth and improve survival in hepatocellular carcinoma (HCC). The role of TARE in downstaging patients to liver transplantation (LT) is unclear. The aim of this study was to investigate the downstaging efficacy of TARE for intermediate and advanced HCC. METHODS: Intention-to-treat analysis with multistate modeling was performed. Patients moved through 5 health states: (1) from TARE to listing, (2) from TARE to death without listing, (3) from listing to LT, (4) from listing to death without LT, and (5) from transplant to death. Factors affecting the chance of death after TARE were considered to stratify outcomes. RESULTS: Two hundred fourteen patients underwent TARE. Of those, 43.9% had radiological response, 29.9% were listed, and 22.8% were transplanted. The probability of being alive without LT was 40.5% 1 y after TARE and 11.5% at 5 y. The chance of being listed was 9.4% at 1 y and 0.9% at 5 y. The probability of dying after TARE without LT was 38% at 1 y and 73% at 5 y. The overall survival of patients receiving LT was 61% at 5 y after transplant. Tumor beyond up-to-seven criteria, alfafetoprotein >400 ng/mL, and albumin-bilirubin ≥2 were associated with death. Three risk groups were associated with different response, chances of being listed, and receiving LT. Median survival was 3 y for low-risk, 1.9 y for intermediate-risk, and 9 mo for high-risk patients (P < 0.001). CONCLUSIONS: In intermediate and advanced HCC, TARE allows for a 44% chance of response, 30% downstaging, and 23% probability of permitting LT. Patient's and tumor's characteristics allow for risk stratification and predict survival from TARE.

Challenging Scenarios and Debated Indications for Laparoscopic Liver Resections for Hepatocellular Carcinoma.

Laparoscopic liver resections (LLRs) have been increasingly adopted for the treatment of hepatocellular carcinoma (HCC), with safe short- and long-term outcomes reported worldwide. Despite this, lesions in the posterosuperior segments, large and recurrent tumors, portal hypertension, and advanced cirrhosis currently represent challenging scenarios in which the safety and efficacy of the laparoscopic approach are still controversial. In this systematic review, we pooled the available evidence on the short-term outcomes of LLRs for HCC in challenging clinical scenarios. All randomized and non-randomized studies reporting LLRs for HCC in the above-mentioned settings were included. The literature search was run in the Scopus, WoS, and Pubmed databases. Case reports, reviews, meta-analyses, studies including fewer than 10 patients, non-English language studies, and studies analyzing histology other than HCC were excluded. From 566 articles, 36 studies dated between 2006 and 2022 fulfilled the selection criteria and were included in the analysis. A total of 1859 patients were included, of whom 156 had advanced cirrhosis, 194 had portal hypertension, 436 had large HCCs, 477 had lesions located in the posterosuperior segments, and 596 had recurrent HCCs. Overall, the conversion rate ranged between 4.6% and 15.5%. Mortality and morbidity ranged between 0.0% and 5.1%, and 18.6% and 34.6%, respectively. Full results according to subgroups are described in the study. Advanced cirrhosis and portal hypertension, large and recurrent tumors, and lesions located in the posterosuperior segments are challenging clinical scenarios that should be carefully approached by laparoscopy. Safe short-term outcomes can be achieved provided experienced surgeons and high-volume centers.

Minimally Invasive Surgery for Perihilar Cholangiocarcinoma: A Systematic Review of the Short- and Long-Term Results.

Surgery and postoperative systemic chemotherapy represent the standard treatment for patients with perihilar cholangiocarcinoma (PHC). Minimally Invasive Surgery (MIS) for hepatobiliary procedures has spread worldwide in the last two decades. Since resections for PHC are technically demanding, the role of MIS in this field is yet to be established. This study aimed to systematically review the existing literature on MIS for PHC, to evaluate its safety and its surgical and oncological outcomes. A systematic literature review on PubMed and SCOPUS was performed according to the PRISMA guidelines. Overall, a total of 18 studies reporting 372 MIS procedures for PHC were included in our analysis. A progressive increase in the available literature was observed over the years. A total of 310 laparoscopic and 62 robotic resections were performed. A pooled analysis showed an operative time ranging from 205.3 ± 23.9 and 840 (770-890) minutes, and intraoperative bleeding between 101.1 ± 13.6 and 1360 ± 809 mL. Minor and major morbidity rates were 43.9% and 12.7%, respectively, with a 5.6% mortality rate. R0 resections were achieved in 80.6% of patients and the number of retrieved lymph nodes ranged between 4 (3-12) and 12 (8-16). This systematic review shows that MIS for PHC is feasible, with safe postoperative and oncological outcomes. Recent data has shown encouraging results and more reports are being published. Future studies should address differences between robotic and laparoscopic approaches. Given the management and technical challenges, MIS for PHC should be performed by experienced surgeons, in high-volume centers, on selected patients.

Roux-en-Y gastric bypass as a salvage solution for severe and refractory gastroparesis in malnourished patients.

BACKGROUND: Gastroparesis (GP) is a rare condition for which several symptomatic treatments are available, but they may fail, leading to a discussion of gastrectomy. Few studies have described gastric-preserving surgery, particularly in malnourished patients. OBJECTIVE: To describe the treatment of severe refractory GP with Roux-en-Y gastric bypass (RYGB). SETTING: A university center. METHODS: A retrospective review was conducted of adult patients who underwent laparoscopic RYGB. Severity and frequency of GP symptoms were compared before and 1 year after surgery using the Gastroparesis Cardinal Symptom Index (GCSI) score (0-5), the vomiting (VM) score (0-4), and the visual analog scale (VAS) for abdominal pain. RESULTS: Of the 9 patients with refractory GP, 7 were malnourished and 2 had obesity. There were no postoperative deaths. One patient was operated on for internal hernia without bowel necrosis. The mean GCSI score decreased significantly from 3.6 (range: 1-5) preoperatively to 2.1 (range: .3-4.4) postoperatively (P = .0019). The mean VM score improved significantly after surgery, from .22 (range: 0-1 units) preoperatively to 2.55 (range: 1-4) postoperatively (P = .007). The mean VAS score also decreased significantly from 7.0 (range: 5-9) preoperatively to 2.44 (range: 0-7) postoperatively (P = .0015). A nonsignificant weight and albumin change was observed at 1 year postoperatively, with a tendency for weight regain in malnourished patients. CONCLUSION: In malnourished patients with severe and refractory GP, this study suggests the feasibility, safety, and efficacy of RYGB for the treatment of vomiting and abdominal pain.

Splenic artery steal syndrome after liver transplantation - prophylaxis or treatment?: A case report and literature review.

Splenic artery steal syndrome (SASS) is a cause of graft hypoperfusion leading to the development of biliary tract complications, graft failure, and in some cases to retransplantation. Its management is still controversial since there is no universal consensus about its prophylaxis and consequently treatment. We present a case of SASS that occurred 48 hours after orthotopic liver transplantation (OLTx) in a 56-year-old male patient with alcoholic cirrhosis and severe portal hypertension, and who was successfully treated by splenic artery embolization. A literature search was performed using the PubMed database, and a total of 22 studies including 4,789 patients who underwent OLTx were relevant to this review. A prophylactic treatment was performed in 260 cases (6.2%) through splenic artery ligation in 98 patients (37.7%) and splenic artery banding in 102 (39.2%). In the patients who did not receive prophylaxis, SASS occurred after OLTx in 266 (5.5%) and was mainly treated by splenic artery embolization (78.9%). Splenic artery ligation and splenectomies were performed, respectively, in 6 and 20 patients (2.3% and 7.5%). The higher rate of complications registered was represented by biliary tract complications (9.7% in patients who received prophylaxis and 11.6% in patients who developed SASS), portal vein thrombosis (respectively, 7.3% and 6.9%), splenectomy (4.8% and 20.9%), and death from sepsis (4.8% and 30.2%). Whenever possible, prevention is the best way to approach SASS, considering all the potential damage arising from an arterial graft hypoperfusion. Where clinical conditions do not permit prophylaxis, an accurate risk assessment and postoperative monitoring are mandatory.

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) for advanced hepatocellular carcinoma with macrovascular invasion.

Patients with advanced hepatocellular carcinoma (HCC) and macrovascular invasion (MVI) have dismal prognosis and are referred to systemic treatment or palliation. To investigate the outcomes of patients with HCC and MVI undergoing the associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) procedure. Demographics and operative data were retrospectively reviewed. All types of hepatectomies and all types of ALPPS modifications were included. MVI was categorized according to the Japanese Liver Cancer Study Group classification. 28 patients were included. Viral aetiology was the most common cause of chronic liver disease (89.3%). 85.7% of patients were cirrhotic, with a median MELD score of 9 (7-10). MVI of the hepatic veins or inferior vena cava was diagnosed in 46.4% of patients while portal vein involvement was present in 64.2% of cases. Four patients (14.2%) were diagnosed with bile duct involvement. No patients died after Step 1 while complications occurred in 21.4% of cases. Following step 2, 3 patients (11.5%) died and 20 (69.2%) developed complications. Grade B and C post-hepatectomy liver failure occurred in 57.6% and 11.5% of patients, respectively. After a median follow-up of 18 months (7-35), median survival was 22 months (3-40). Eleven patients (39.3%) recurred. Median disease-free survival was 15 months (5-26). The ALPPS procedure is an extreme rescue approach in otherwise inoperable advanced HCC with MVI. The procedure is associated with high morbidity and mortality and patients' selection is pivotal. Oncological outcomes are safe and should be further investigated.

The Applications of 3D Imaging and Indocyanine Green Dye Fluorescence in Laparoscopic Liver Surgery.

Laparoscopic liver resections have gained widespread popularity among hepatobiliary surgeons and is nowadays performed for both standard and more complex hepatectomies. Given the increased technical challenges, preoperative planning and intraoperative guidance is pivotal in laparoscopic surgery to safely carry out complex and oncologically safe hepatectomies. Modern tools can help both preoperatively and intraoperatively and allow surgeons to perform more precise hepatectomies. Preoperative 3D reconstructions and printing as well as augmented reality can increase the knowledge of the specific anatomy of the case and therefore plan the surgery accordingly and tailor the procedure on the patient. Furthermore, the indocyanine green retention dye is an increasingly used tool that can nowadays improve the precision during laparoscopic hepatectomies, especially when considering anatomical resection. The use of preoperative modern imaging and intraoperative indocyanine green dye are key to successfully perform complex hepatectomies such as laparoscopic parenchymal sparing liver resections. In this narrative review, we discuss the aspects of preoperative and intraoperative tools that are nowadays increasingly used in experienced hepatobiliary centers.

Transplantation of a Severely Traumatized Liver During the COVID-19 Pandemic: A Case Report and Review of the Literature.

Shortages of grafts for liver transplant remain a persistent problem. The use of lacerated livers for liver transplant can add an option for extended criteria donations, especially during the COVID-19 pandemic. We present the case of a successful liver transplant performed using a high-grade lacerated liver previously treated with superselective arterial embolization and packing for bleeding control. In view of the absence of guidelines for the use of lacerated livers for transplant, we also performed a review of the literature on injured liver grafts that were used for liver transplants. Meticulous care and careful selection of recipients were essential prerequisites for achieving successful outcomes.

The loss of ATP2C1 impairs the DNA damage response and induces altered skin homeostasis: Consequences for epidermal biology in Hailey-Hailey disease.

Mutation of the Golgi Ca(2+)-ATPase ATP2C1 is associated with deregulated calcium homeostasis and altered skin function. ATP2C1 mutations have been identified as having a causative role in Hailey-Hailey disease, an autosomal-dominant skin disorder. Here, we identified ATP2C1 as a crucial regulator of epidermal homeostasis through the regulation of oxidative stress. Upon ATP2C1 inactivation, oxidative stress and Notch1 activation were increased in cultured human keratinocytes. Using RNA-seq experiments, we found that the DNA damage response (DDR) was consistently down-regulated in keratinocytes derived from the lesions of patients with Hailey-Hailey disease. Although oxidative stress activates the DDR, ATP2C1 inactivation down-regulates DDR gene expression. We showed that the DDR response was a major target of oxidative stress-induced Notch1 activation. Here, we show that this activation is functionally important because early Notch1 activation in keratinocytes induces keratinocyte differentiation and represses the DDR. These results indicate that an ATP2C1/NOTCH1 axis might be critical for keratinocyte function and cutaneous homeostasis, suggesting a plausible model for the pathological features of Hailey-Hailey disease.

PARP inhibitor ABT-888 affects response of MDA-MB-231 cells to doxorubicin treatment, targeting Snail expression.

To overcome cancer cells resistance to pharmacological therapy, the development of new therapeutic approaches becomes urgent. For this purpose, the use of poly(ADP-ribose) polymerase (PARP) inhibitors in combination with other cytotoxic agents could represent an efficacious strategy. Poly(ADP-ribosyl)ation (PARylation) is a post-translational modification that plays a well characterized role in the cellular decisions of life and death. Recent findings indicate that PARP-1 may control the expression of Snail, the master gene of epithelial-mesenchymal transition (EMT). Snail is highly represented in different resistant tumors, functioning as a factor regulating anti-apoptotic programmes. MDA-MB-231 is a Snail-expressing metastatic breast cancer cell line, which exhibits chemoresistance properties when treated with damaging agents. In this study, we show that the PARP inhibitor ABT-888 was capable to modulate the MDA-MB-231 cell response to doxorubicin, leading to an increase in the rate of apoptosis. Our further results indicate that PARP-1 controlled Snail expression at transcriptional level in cells exposed to doxorubicin. Given the increasing interest in the employment of PARP inhibitors as chemotherapeutic adjuvants, our in vitro results suggest that one of the mechanisms through which PARP inhibition can chemosensitize cancer cells in vivo, is targeting Snail expression thus promoting apoptosis.

Poly(ADP-ribosyl)ation is involved in the epigenetic control of TET1 gene transcription.

TET enzymes are the epigenetic factors involved in the formation of the sixth DNA base 5-hydroxymethylcytosine, whose deregulation has been associated with tumorigenesis. In particular, TET1 acts as tumor suppressor preventing cell proliferation and tumor metastasis and it has frequently been found down-regulated in cancer. Thus, considering the importance of a tight control of TET1 expression, the epigenetic mechanisms involved in the transcriptional regulation of TET1 gene are here investigated. The involvement of poly(ADP-ribosyl)ation in the control of DNA and histone methylation on TET1 gene was examined. PARP activity is able to positively regulate TET1 expression maintaining a permissive chromatin state characterized by DNA hypomethylation of TET1 CpG island as well as high levels of H3K4 trimethylation. These epigenetic modifications were affected by PAR depletion causing TET1 down-regulation and in turn reduced recruitment of TET1 protein on HOXA9 target gene. In conclusion, this work shows that PARP activity is a transcriptional regulator of TET1 gene through the control of epigenetic events and it suggests that deregulation of these mechanisms could account for TET1 repression in cancer.