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Background Decrease in blood pressure (BP) is the major goal of adrenalectomy for primary aldosteronism. Nevertheless, the optimal timing to assess these outcomes and the needed duration of follow-up are uncertain. We systematically reviewed the literature regarding trends in BP-related outcomes during follow-up after adrenalectomy. Methods A systematic literature search of medical literature from PubMed, Embase and the Cochrane Library regarding BP-related outcomes (i.e. cure of hypertension rates, BP and antihypertensives) was performed. The Quality In Prognosis Studies risk of bias tool was used. Results Of the 2057 identified records, 13 articles met the inclusion criteria. Overall study quality was low. In multiple studies, the biggest decrease in BP was shown within the first month(s) after adrenalectomy and afterwards BP often remained stable during long-term follow-up. Conclusions Based on the available studies one might suggest that long follow-up is unnecessary, since outcomes seem to stabilize within the first months.

Background Aims of this study were to describe the stepwise implementation and expansion of robotic HPB surgery in a high volume HPB unit in the Netherlands and to analyze clinical outcomes of all robotic liver resections and robotic pancreatoduodenectomies performed within this program. Methods After proctoring by expert international surgeons, HPB surgeons were introduced to robotic liver resection and robotic pancreatoduodenectomy in a stepwise fashion. Data from two prospective databases containing all consecutive patients who underwent robotic liver resection or robotic pancreatoduodenectomy between August 1st, 2015 and March 1st, 2019 were analyzed post hoc. Results In total, 77 consecutive robotic liver resections and 68 consecutive robotic pancreatoduodenectomies were performed. Five surgeons were consecutively introduced to robotic HPB surgery. Mean operative time for robotic liver resection was 160 ± 78 min. Mean operative time for robotic pancreatoduodenectomy was 420 ± 67 min. Operative times remained stable over time and were not affected by the introduction of new surgeons. Conclusion Stepwise implementation and expansion of robotic HPB surgery within one unit over a three-and-half year period is feasible and associated with good clinical outcomes. Despite introducing new surgeons to the technique, operative times, an indicator of the learning process, remained stable over time.

Background: Early recognition of postoperative pancreatic fistula might decrease the risk of subsequent life threatening complications. The aim of this review was to systematically evaluate the accuracy of postoperative clinical, biochemical and radiologic variables for early recognition of clinically relevant postoperative pancreatic fistula. Methods: A systematic literature search was performed up to August 2018. Clinical studies reporting on the association between postoperative variables and clinically relevant postoperative pancreatic fistula were included. Variables were stratified: early prediction (postoperative day 1–2) versus early diagnosis (day 3) and had to be reported in 2 cohorts. Results: Overall, 37 included studies reported on 17 different diagnostic variables after 8701 pancreatic resections. Clinically relevant postoperative pancreatic fistula occurred in 1532/8701 patients (18%). Early prediction variables included elevated serum and drain amylase (day 1). Identified variables for early diagnosis were: non-serous drain efflux (day 3); positive drain culture (day 3); elevated temperature (any day); elevated C-Reactive Protein (CRP; day 4); elevated white blood cell count (day 4) and peripancreatic collections on computed tomography (CT; day 5–10). Conclusion: This review provides a comprehensive overview of postoperative variables associated with clinically relevant pancreatic fistula. Incorporation of variables in future algorithms could potentially mitigate the clinical impact of postoperative pancreatic fistula.

Introduction The incidence, timing, and implications of recurrence in patients who underwent neoadjuvant treatment and surgical resection of borderline resectable (BRPC) or locally advanced (LAPC) pancreatic cancer are not well established. Materials and methods Patients with BRPC/LAPC who underwent post-neoadjuvant resection between 2007 and 2015 were included. Associations between clinicopathologic characteristics and specific recurrence locations, recurrence-free survival (RFS), and overall survival from resection (OS) were assessed using Cox regression analyses. Results For 231 included patients, median survival from diagnosis and resection were 28.0 and 19.8 months, respectively. After a median RFS of 7.9 months, 189 (81.8%) patients had recurred. Multiple-site (n = 87, 46.0%) and liver-only recurrence (n = 28, 14.8%) generally occurred earlier and resulted in significantly worse OS when compared to local-only (n = 52, 27.5%) or lung-only recurrence (n = 18, 9.5%). Microscopic perineural invasion, yN1-yN2 status and elevated pre-surgery CA 19-9 >100 U/mL were associated with both local-only and multiple-site/liver-only recurrence. R1-margin was associated with local-only recurrence (HR 2.03). yN1-yN2 status and microscopic perineural invasion were independent predictors for both poor RFS and OS, while yT3-yT4 tumor stage (HR 1.39) and poor tumor differentiation (HR 1.60) were only predictive of poor OS. Adjuvant therapy was independently associated with both prolonged RFS (HR 0.73; median 7.0 vs. 10.9 months) and OS (HR 0.69; median 15.4 vs. 22.7 months). Conclusion Despite neoadjuvant therapy leading to resection and relatively favorable pathologic tumor characteristics in BRPC/LAPC patients, more than 80% of patients experienced disease recurrence, 72.5% of which occurred at distant sites.

High levels of oxidative stress in disseminated colorectal cancer tumor cells may form a therapeutically exploitable vulnerability. However, it is unclear whether oxidative stress and damage persist in metastases. Therefore, we analyzed markers of oxidative damage in primary colorectal tumors and their corresponding liver metastases. Markers of generic and oxidative DNA damage [phosphorylated histone H2AX (γH2AX) and 8-hydroxy-2'-deoxyguanosine (8-OHdG)] were significantly higher in liver metastases compared with their corresponding primary tumors. Chemotherapy and/or radiotherapy before tumor resection was associated with increased persistent oxidative DNA damage, and this effect was more pronounced in metastases. Immunohistochemistry-based molecular classification into epithelial- and mesenchymal-like molecular subtypes revealed that untreated mesenchymal-like tumors contained lower levels of oxidative DNA damage compared with epithelial-like tumors. Treated mesenchymal-like tumors, but not epithelial-like tumors, showed significantly higher levels of γH2AX and 8-OHdG. Mesenchymal-like tumors expressed significantly lower levels of phosphorylated nuclear factor erythroid 2-related factor 2, a master regulator of the antioxidant response, and nuclear factor erythroid 2-related factor 2-controlled genes. Of interest, a positive 8-OHdG status identified a subgroup of mesenchymal-like metastases with a poor overall survival. An increased capacity to tolerate therapy-induced oxidative damage in mesenchymal-like colorectal cancer may explain, at least in part, the poor responsiveness of these tumors to chemotherapy, which could contribute to the poor survival of this patient subgroup.

Background Robotic surgery is increasingly employed in complex procedures such as liver resection. Minor resections of the posterosuperior segments might benefit in particular from a robotic approach, since the size of the incision dominates the postoperative recovery rather than the extent of the resection [ 1 ]. We aimed to provide a standardized, step-wise guide to robotic liver resection of segment 7. Methods This video illustrates, step-by-step, robotic segment 7 resection. Patients are placed in left lateral position, slight anti-Trendelenburg. Three robotic ports are used and one conventional laparoscopic port is placed for bedside assistance. Next, segment 7 is mobilized. Intraoperative ultrasound is used to delineate the tumor and ensure a safe oncologic margin. The EndoWrist ® One™ Vessel Sealer (Extend) (Intuitive Surgical Inc., Sunnyvale, CA, USA) is used for transection of the hepatic parenchyma, combined with a bipolar Maryland Forceps (Intuitive Surgical, Sunnyvale, California, USA). Hem-o-lok clips (Teleflex Inc., Morrisville, NC, USA) or laparoscopic staplers (Medtronic, Minneapolis, MN, USA) are used to control the hepatic pedicle. A pringle manoeuvre is applied when deemed appropriate. To ensure hemostasis and biliostasis, TachoSil (Takeda Nederland b.v. Takeda, Zurich, Switzerland) is applied to the resection surface. The specimen is extracted through an enlarged trocar incision. Results This video illustrates robotic liver resection of segment 7 in a 72-year-old male with a past medical history of colorectal cancer. New, resectable liver metastases were detected during follow-up. The procedure was completed fully robotically. No postoperative complications occurred and the patient was discharged on postoperative day one. Conclusion This video provides a step-by-step guide to robotic liver resection of segment 7.

The time between the moment of referral for the diagnostic workup for thyroid nodules and the outcome can be worrisome for patients. In general, patients experience high levels of anxiety during the evaluation of a lesion suspicious for cancer. Therefore, the implementation of same-day fine-needle aspiration cytology (FNAC) diagnosis is becoming standard-of-care for many solid tumors. Our aim was to assess the feasibility of same-day FNAC diagnosis for thyroid nodules and to assess patient anxiety during the diagnostic process.For feasibility of same-day FNAC diagnosis, we assessed the proportion of patients receiving a diagnosis at the end of the visit. Accuracy was measured by comparing histology with the FNAC result. Patient anxiety was measured by the State Trait Anxiety Inventory at 6 moments during the diagnostic workup.Of the 131 included patients, 112 (86%) were female, and the mean age was 53 years. All patients, except those with a nondiagnostic FNAC result (n = 26; 20%), had a diagnosis at the end of the day. There were only two discordant results. Anxiety levels at the beginning of the day were high throughout the group, State Trait Anxiety Inventory (STAI) score 43.1 (SD 2.0) and decreased significantly more in patients with a benign FNAC result (STAI score 30.2), compared to patients with a malignant or indeterminate result (STAI score 39.6).Distress of patients with a thyroid nodule undergoing same-day FNAC diagnostics was high. Same-day FNAC diagnosis is feasible and accurate for the evaluation of thyroid nodules. Therefore, same-day FNAC diagnosis seems a safer, more patient-friendly approach to diagnose thyroid nodules.

Background Pancreatic fistula is a potentially life threatening complication after a pancreatic resection. The aim of this systematic review was to evaluate the role of matrix bound sealants after a pancreatic resection in terms of preventing or ameliorating the course of a post operative pancreatic fistula. Methods A systematic search was performed in the literature from May 2005 to April 2015. Included were clinical studies using matrix bound sealants after a pancreatic resection, reporting a post operative pancreatic fistula (POPF) according to the International Study Group on Pancreatic Fistula classification, in which grade B and C fistulae were considered clinically relevant. Results Two were studies on patients undergoing pancreatoduodenectomy (sealants n = 67, controls n = 27) and four studies on a distal pancreatectomy (sealants n = 258, controls n = 178). After a pancreatoduodenectomy, 13% of patients treated with sealants versus 11% of patients without sealants developed a POPF ( P = 0.76), of which 4% versus 4% were clinically relevant ( P = 0.87). After a distal pancreatectomy, 42% of patients treated with sealants versus 52% of patients without sealants developed a POPF ( P = 0.03). Of these, 9% versus 12% were clinically relevant ( P = 0.19). Conclusions The present data do not support the routine use of matrix bound sealants after a pancreatic resection, as there was no effect on clinically relevant POPF. Larger, well designed studies are needed to determine the efficacy of sealants in preventing POPF after a pancreatoduodenectomy.

Background: Resection of colorectal liver metastases (CRLM) is often hindered by their location close to the major hepatic vessels. So far, radiofrequency ablation for perivascular tumours was thought to be ineffective and unsafe due to either the heat sink effect or vascular thrombosis. The aim of this study was to examine whether RFA using multipolar probes could be a safe and effective option for CRLM adjacent to major hepatic vessels. Methods: Patients were treated with multipolar RFA during an open procedure using 3 simultaneously placed electrodes. In 52 consecutive patients with CRLM, 144 tumours were ablated with RFA. In 16 out of 52 (31%) patients, metastases were abutting major hepatic vessels. We examined whether perivascular location was a risk factor for local tumour progression. The relation between perivascular location and time to local tumour progression and recurrence free survival was assessed using cox-regression analysis. Results: All patients were followed for at least 3 years after RFA unless they deceased before this time. Local tumour progression following RFA occurred in 17 out of 144 tumours (12%), of which 4 out of 21 were perivascular tumours. Tumour size was the only risk factor for local tumour progression in this study. Proximity to large vessels was neither a risk factor for local local tumour progression, nor for time to local tumour progression or recurrence free survival. Discussion: This study indicates that patients with CRLM abutting any of the large hepatic vessels can be safe and effectively treated with RFA when using a multipolar system.

SummaryPancreatic cancer is one of the most lethal malignancies due to its late diagnosis and limited response to treatment. Tractable methods to identify and interrogate pathways involved in pancreatic tumorigenesis are urgently needed. We established organoid models from normal and neoplastic murine and human pancreas tissues. Pancreatic organoids can be rapidly generated from resected tumors and biopsies, survive cryopreservation, and exhibit ductal- and disease-stage-specific characteristics. Orthotopically transplanted neoplastic organoids recapitulate the full spectrum of tumor development by forming early-grade neoplasms that progress to locally invasive and metastatic carcinomas. Due to their ability to be genetically manipulated, organoids are a platform to probe genetic cooperation. Comprehensive transcriptional and proteomic analyses of murine pancreatic organoids revealed genes and pathways altered during disease progression. The confirmation of many of these protein changes in human tissues demonstrates that organoids are a facile model system to discover characteristics of this deadly malignancy.

Highlights • Preoperative imaging is essential for minimal invasive parathyroidectomy. • Conventional imaging is often negative or inconclusive. • 18F-Fluorocholine PET–CT might be a solution. • We describe a patient with negative SPECT–CT and ultrasound. • Patient underwent successful surgery after positive PET–CT., Introduction Primary hyperparathyroidism is a common endocrine disorder for which the primary treatment is surgery. For minimal invasive parathyroidectomy adequate pre-operative imaging is essential. Conventional imaging is often inconclusive. There are reports that 18F-fluorocholine PET–CT might be a superior imaging modality, however evidence is still very scarce. This is the first report of a case with negative ultrasound and sestamibi SPECT–CT imaging that underwent successful minimal invasive surgery because of 18F-fluorocholine PET–CT. Presentation of case A 57 year-old man presented to us with complaints of fatigue. Laboratory results showed a biochemical primary hyperparathyroidism and an additional DEXA-scan revealed osteopenia of the lumbar spine. Conventional imaging consisting of neck ultrasound and Tc-99m-sestamibi SPECT–CT was however unable to localize the pathological gland. Subsequent 18F-fluorocholine PET–CT did clearly localize an adenoma dorsally of the left thyroid lobe which was removed at that exact location using minimal invasive parathyroidectomy. Histological examination confirmed the diagnosis adenoma and calcium levels remained normal at follow-up. Discussion There is clinical need for a superior imaging modality to detect pathological parathyroid glands to enable minimal invasive surgery. 18F-Fluorocholine is widely available. Conclusion 18F-Fluorocholine PET–CT is a promising new imaging modality for localizing parathyroid adenomas and enabling minimal invasive parathyroidectomy when conventional imaging fails to do. Clinicians should consider its use as a second line modality for optimal patient care.

Objective To determine the best surgical strategy for patients with multiple endocrine neoplasia type 2A (MEN 2A) who have primary hyperparathyroidism (PHPT). Methods We performed a systematic literature review and conducted a retrospective cohort study that included patients with PHPT identified from the MEN 2A database at the University Medical Center of Utrecht, Utrecht, the Netherlands, between 1979 and 2009. Results The review describes the course of worldwide parathyroid surgical management in MEN 2A PHPT over the past 75 years, which has evolved from aggressive parathyroid resections to minimally invasive parathyroidectomy (MIP). The study cohort included 20 patients. Primary surgery for parathyroid disease in patients with MEN 2A (n = 16) included MIP (n = 6), conventional neck exploration with resection of enlarged parathyroid gland(s) (n = 4), and resection of 1 or more enlarged gland(s) during total thyroidectomy (n = 6). Thirteen patients were initially cured after the primary operation. Five patients experi enced persistent or recurrent PHPT. After MIP, 1 patient had persistent PHPT, but no patient developed recurrent PHPT during 5 years of follow-up. Five patients had hypoparathyroidism after subtotal or total parathyroidectomy with autotransplantation, but only 1 patient had transient hypoparathyroidism after MIP. One patient had transient recurrent laryngeal nerve injury after MIP. Conclusions Surgery for PHPT in patients with MEN 2A has evolved from aggressive conventional exploration of all 4 glands to focused MIP, which appears to be a feasible approach. MIP has low rates of persistent and recurrent PHPT, and the complications are minimal. (Endocr Pract. 2011;17:7-15)

Background & Aims Recently, we have shown that micro-metastases, in the hypoxic transition zone surrounding lesions generated by radiofrequency ablation (RFA), display strongly accelerated outgrowth. CD95 is best known for its ability to induce apoptosis but can also promote tumorigenesis in apoptosis-resistant tumor cells. Therefore, we tested whether CD95 signaling plays a role in accelerated outgrowth of colorectal liver metastases following RFA. Methods Hypoxia-induced invasion was assessed in three-dimensional EGFP-expressing C26 tumor cell cultures by confocal microscopy. CD95 localization was tested by immunofluorescence. Invasion and outgrowth of liver metastases following RFA were analyzed by post-mortem confocal microscopy and by morphometric assessment of tumor load. Neutralization of CD95L was performed by using antibody MFL4. CD95 was suppressed by lentiviral RNA interference. The role of host CD95L was assessed using gld mice. Results Micro-metastases in the hypoxic transition zone following RFA displayed a highly invasive phenotype and increased expression of CD95 and CD95L. Hypoxia-induced tumor cell invasion in vitro increased the expression of CD95 and CD95L and induced translocation of CD95 to the invasive front. In vitro invasion, metastasis invasion, and accelerated tumor growth in the transition zone were strongly suppressed by neutralizing CD95L or by suppressing tumor cell CD95. In contrast, metastasis invasion and outgrowth were unaffected in gld mice. Conclusions Hypoxia causes autocrine activation of CD95 on colorectal tumor cells, thereby promoting local invasion and accelerated metastasis outgrowth in the hypoxic transition zone following RFA. Further pre-clinical work is needed to assess the role of CD95L neutralization, either alone or in combination with chemotherapy, in limiting aggressive recurrence of liver metastases following RFA.

Background Substantial recurrence rates following partial liver resection for colorectal liver metastases (CRM) imply that small metastases remain undetected using intraoperative ultrasound (IOUS). The aim of this study was to evaluate the additional value of contrast enhanced IOUS (CE-IOUS) when compared to preoperative contrast enhanced computed tomography (CE-CT) and IOUS in liver surgery for CRM. Methods After obtaining informed consent, 39 consecutive patients with CRM were included prospectively for evaluation. The study population consisted of 26 male and 13 female patients with a median (range) age of 62 (49–83) years. A lesion-per-lesion analysis was performed with histopathological examination as the reference standard after resection and follow-up for unresected lesions. The added value of CE-IOUS in correctly diagnosing malignant lesions was statistically evaluated, using receiver operating characteristic curves. Results A total of 234 lesions were identified, 137 of which were malignant, according to the reference standard. The addition of CE-IOUS did not improve the diagnostic accuracy when compared to the combination of CE-CT and IOUS (P = 0.617). In one of two patients with newly detected lesions on CE-IOUS the extent of resection changed. Conclusions The addition of CE-IOUS to preoperative CE-CT and IOUS does not improve the ability to characterize already detected lesions. In a small number of patients it appears to facilitate the detection of new metastatic lesions with implications on surgical strategy.

Ischemia/reperfusion (I/R) is often inevitable during hepatic surgery and may stimulate the outgrowth of colorectal micrometastases. Postischemic microcirculatory disturbances contribute to I/R damage and may induce prolonged tissue hypoxia and consequent stabilization of hypoxia-inducible factor (HIF)-1alpha. The aim of this study was to evaluate the contribution of postischemic microcirculatory disturbances, hypoxia, and HIF-1alpha to I/R-accelerated tumor growth. Partial hepatic I/R attributable to temporary clamping of the left liver lobe induced microcirculatory failure for up to 5 days. This was accompanied by profound and prolonged perinecrotic tissue hypoxia, stabilization of HIF-1alpha, and massive perinecrotic outgrowth of pre-established micrometastases. Restoration of the microcirculation by treatment with Atrasentan and L-arginine minimized hypoxia and HIF-1alpha stabilization and reduced the accelerated outgrowth of micrometastases by 50%. Destabilization of HIF-1alpha by the HSP90 inhibitor 17-DMAG caused an increase in tissue necrosis but reduced I/R-stimulated tumor growth by more than 70%. In conclusion, prevention of postischemic microcirculatory disturbances and perinecrotic hypoxia reduces the accelerated outgrowth of colorectal liver metastases after I/R. This may, at least in part, be attributed to the prevention of HIF-1alpha stabilization. Prevention of tissue hypoxia or inhibition of HIF-1alpha may represent attractive approaches to limiting recurrent tumor growth after hepatic surgery.

Background In mouse models for metastatic growth of colorectal carcinoma (CRC) cells in the liver, tumor growth is routinely measured by determining the area of liver tissue that has been replaced by tumor tissue (hepatic replacement area [HRA]). This technique has several major disadvantages. Modern visualization techniques make it possible to image tumor growth noninvasively. In the present report, we validated bioluminescence imaging of liver metastases by comparing it to standard HRA measurements and liver weight. Materials and methods BALB/c mice received an intrasplenic injection of luciferase-expressing C26 CRC cells and the spleen was subsequently removed. On days 5, 7, 9, and 11 after injection, luciferase activity was measured. After imaging, the mice were sacrificed and the livers was removed, weighed, and fixed. HRA was determined by analyzing liver tissue sections. Comparative trend analyses between luciferase activity, wet liver weight, and HRA were then performed. Results Luciferase activity, wet liver weight, and HRA all increased over time. Statistical analyses showed that all three types of measurements display a highly significant degree of correlation. Conclusions The measurement of tumor growth in the liver by imaging luciferase activity correlates well with the standard method of determining the HRA and with the increase in liver weight that results from tumor growth. Given the great advantages of measuring luciferase activity over measuring HRA, we conclude that bioluminescent imaging is a reliable and superior method for measuring experimental CRC growth in the liver.

Surgery may be regarded as an angiogenesis-inducing condition since it evokes the release of many angiogenic factors. Regarding the mechanistic overlap between tumor-associated neovascularisation and (physiological) angiogenesis in response to injury and hypoxia, surgery may promote the uncontrolled growth of residual dormant tumor cells. With the advent of anti-angiogenic agents, surgeons will be faced with more patients undergoing surgery for primary and secondary tumors under anti-angiogenic treatment. This could present problems with regard to angiogenesis-dependent phenomena such as wound repair, healing of intestinal anastomoses and liver regeneration. In this review we will discuss these matters from a biomedical and clinical point of view.

Item does not contain fulltext Antiangiogenic therapy is a highly promising new strategy in the treatment of cancer. One of the first angiogenesis inhibitors described was angiostatin, a 38-kDa internal proteolytically generated fragment of plasminogen. In a previous study we found that angiostatin affected physiological angiogenesis as well as tumor angiogenesis. It impaired healing when administered during repair of experimental colonic anastomoses, as reflected by a decrease in mechanical strength. On histology, we observed a decrease in factor VIII-stained vessel amount and volume in angiostatin-treated colonic anastomoses. The exact working mechanism of angiostatin has not been elucidated. Based on the available studies on proposed working mechanisms of angiostatin, we have attempted to address histological differences in physiological angiogenesis between the tissues of colonic anastomoses of mice with impaired healing and control mice. After angiostatin treatment there was more inflammatory tissue as a result of impaired healing. Furthermore, we found fewer vessels in the granulation tissue after angiostatin treatment. However, especially with respect to extracellular matrix (ECM), endothelial cell apoptosis, proliferation, or neutrophil influx, no gross differences were discerned 1 week following surgery, using histology and immunohistochemistry techniques.

Understanding the regenerative behavior of transplanted hepatocytes is of great importance for developing and improving such novel therapeutic strategies as hepatocellular transplantation and ex vivo gene therapy. In this study the proliferative responsiveness of transplanted syngeneic rat hepatocytes was examined in relation to the timing of the administration of a mitogenic stimulus. For this purpose nuclear bromodeoxyuridine incorporation after partial hepatectomy was investigated during the early post-transplant phase. The response of intrasplenically transplanted hepatocytes was compared to that of liver cells engrafted in polytetrafluoroethylene solid supports that had been implanted intraperitoneally 4 weeks prior to transplantation. Nonstimulated, engrafted hepatocytes exhibited a labeling index of ∼0-1% independent of the transplantation technique used. This "spontaneous" labeling index did not change with time. Partial hepatectomy, executed simultaneously with hepatocyte transplantation through either technique, did not result in significant alteration of this proliferation index. Delayed kinetics were found not to be responsible for this lack of responsiveness. When the mitogenic stimulus was given between 2 and 6 weeks post-transplantation, a significant increase in labeling index was observed in comparison to sham-treated control animals. Maximal labeling indices of ∼3-4% were found if the stimulus took place at 4 weeks post-transplantation. Both the pattern and the extent of the proliferative response seen in liver cells engrafted in solid supports were similar to the ones found in intrasplenic hepatocytes, indicating adequate vascularization of the supports. This data provides the first description of proliferative response in hepatocytes transplanted by the solid support technique, which may offer an attractive alternative to the intrasplenic route. It further suggests that, in analogy with the in vitro situation, a lag time exists between hepatocyte isolation/transplantation and their maximal responsiveness to physiological stimuli. It is concluded that timing of the administration of a proliferative stimulus is important for obtaining a maximal response of transplanted hepatocytes during the early post-transplantation phase.

In this study, performed to assess the effect of auxiliary heterotopic liver transplantation on portal hypertension and hypersplenism, eight patients with chronic liver disease who underwent the procedure and had functioning grafts for at least 6 months were analyzed. The transplantation resulted in (a) normalization of platelet and leukocyte counts, (b) reduction of splenomegaly by 20% +/- 3% (P less than 0.02), (c) disappearance of ascites, and (d) diminution of esophageal varices in all patients. Intraoperatively, the mean portacaval pressure gradient decreased with 54% +/- 7% after recirculation of the graft (P less than 0.05). In conclusion, a functioning auxiliary heterotopic liver graft decompresses portal hypertension and reverses hypersplenism.

contralateral pleura make necessary a clinical study. We showed the feasibiliy of VAM dissection in resecting the paratracheal mesothelial cysts. Our cases showed the interest of using VAM for left-sided BPF. The dissection of the trachea through its natural route enables tracheal mobilization. The mediastinal shift is not a contraindication for VAM but represents a risk for contralateral pleural opening during transpericardial sternotomy or the modified Abruzzini technique. Previous mediastinoscopy is not a contraindication inasmuch as the morbidity is not increased and there is a low risk of contamination. Our 2 cases showed good technical results. The first patient is still alive 2 years after the procedure. Unfortunately, the second patient died of severe sepsis. Perhaps all types of surgery in the presence of severe sepsis are risky. In conclusion, each patient must be treated individually. The best method of closure must be based on the unique set of circumstances. Direct surgical repair can be achieved in most patients. The VAM technique is our choice for a long (at least 10 mm) bronchial stump on the left side because its specific morbidity is minimal compared with transpericardial sternotomy or a transthoracic approach.

Epidermal growth factor receptor (EGFR)-targeting therapeutics have shown efficacy in the treatment of colorectal cancer patients. Clinical studies have revealed that activating mutations in the KRAS protooncogene predict resistance to EGFR-targeted therapy. However, the causality between mutant KRAS and resistance to EGFR inhibition has so far not been demonstrated. Here, we show that deletion of the oncogenic KRAS allele from colorectal tumor cells resensitizes those cells to EGFR inhibitors. Resensitization was accompanied by an acquired dependency on the EGFR for maintaining basal extracellular signal-regulated kinase (ERK) activity. Deletion of oncogenic KRAS not only resensitized tumor cells to EGFR inhibition but also promoted EGF-induced NRAS activation, ERK and AKT phosphorylation, and c-FOS transcription. The poor responsiveness of mutant KRAS tumor cells to EGFR inhibition and activation was accompanied by a reduced capacity of these cells to bind and internalize EGF and by a failure to retain EGFR at the plasma membrane. Of 16 human colorectal tumors with activating mutations in KRAS, 15 displayed loss of basolateral EGFR localization. Plasma membrane localization of the EGFR could be restored in vitro by suppressing receptor endocytosis through Rho kinase inhibition. This caused an EGFR-dependent increase in basal and EGF-stimulated ERK phosphorylation but failed to restore tumor cell sensitivity to EGFR inhibition. Our results demonstrate a causal role for oncogenic KRAS in desensitizing tumor cells not only to EGFR inhibitors but also to EGF itself.