Safety of cholecystectomy performed by surgeons who prefer fundus first versus surgeons who prefer a standard laparoscopic approach.

Background: An alternative method to standard laparoscopic cholecystectomy (SLC) is the "fundus first" method (FFLC). Concerns have been raised that FFLC can lead to misinterpretation of important anatomical structures, thus causing complications of a more serious kind than SLC. Comparisons between the methods are complicated by the fact that FFLC is often used as a rescue procedure in complicated cases. To avoid confounding related to this we conducted a population-based study with comparisons on the surgeon level. Method: In GallRiks, the Swedish registry for Gallbladder surgery, we stratified all cholecystectomies performed 2006-2020 in three groups: surgeries carried out by surgeons that uses FFLC in <20 % of the cases (N = 150,119), in 20-79 % of the cases (N = 10,212) and in 80 % or more of the cases (N = 3176). We compared the groups with logistic regression, adjusting for sex, age, surgical experience, year of surgery and history of acute cholecystitis. All surgical complications (bleeding, gallbladder perforation, visceral perforation, infection, and bile duct injury) were included as outcome. A separate analysis was done with regards to operation time. Results: No difference in incidence of all surgical complications or bile duct injury were seen between groups. The rates of bleeding (OR 0.34 [0.14-0.86]) and gallbladder perforation (OR 0.61 [0.45-0.82]) were significantly lower in the "fundus first > 80% group" and the operative time was shorter (OR 0.76 [0.69-0.83]). Conclusion: In this study including >160,000 cholecystectomies, both methods was found to be equally safe. Key message: During laparoscopic cholecystectomy, the standard method of dissection and fundus first dissection are equally safe surgical techniques. Surgeons need to learn both methods to be able to use the one most appropriate for each individual case.

Effects of neoadjuvant therapy on health-related quality of life for patients with gastroesophageal cancer.

BACKGROUND: Neoadjuvant therapy in combination with surgery increases survival in gastroesophageal cancer; however, little is known about its impact on health-related quality of life. This study compared the impact of neoadjuvant therapy with that of surgery alone on the health-related quality of life in patients treated for gastroesophageal cancer. METHODS: A single-centre cohort study with prospectively collected data from patients undergoing curative intended treatment for gastroesophageal cancer between 2013 and 2020 was performed. Health-related quality of life was assessed prior to surgery and patients stratified according to neoadjuvant therapy or surgery alone. The primary endpoint was self-assessed health-related quality of life, evaluated using validated cancer-specific questionnaires. A pre-specified multivariable model adjusted for age, ASA score, and clinical T- and N-stage was used. RESULTS: A total of 361 patients were included, of whom 239 (61%) were treated with neoadjuvant therapy. Patients treated with neoadjuvant therapy reported less difficulties with eating restrictions (-11.9, p = 0.005), pain (-10.9, p = 0.004), and insomnia (-12.6, p = 0.004) than patients treated with surgery alone. Patients with oesophageal cancer and neoadjuvant therapy reported less dysphagia (-16.6, p < 0.001), eating restrictions (-23.2, p < 0.001), and odynophagia (-18.0, p = 0.002) than those who underwent surgery alone. CONCLUSION: Neoadjuvant therapy was associated with a significant reduction in symptoms affecting malnutrition and improved health-related quality of life in patients with gastroesophageal cancer. These results indicates that more patients might be available for neoadjuvant therapy, despite the baseline burden of gastroesophageal cancer.

Nutritional jejunostomy in esophagectomy for cancer, a national register-based cohort study of associations with postoperative outcomes and survival.

PURPOSE: Insertion of a nutritional jejunostomy in conjunction with esophagectomy is performed with the intention to decrease the risk for postoperative malnutrition and improve recovery without adding significant catheter-related complications. However, previous research has shown no clear benefit and there is currently no consensus of practice. METHODS: All patients treated with esophagectomy due to cancer during the period 2006-2017 reported in the Swedish National Register for Esophageal and Gastric Cancer were included in this register-based cohort study from a national database. Patients were stratified into two groups: esophagectomy alone and esophagectomy with jejunostomy. RESULTS: A total of 847 patients (45.27%) had no jejunostomy inserted while 1024 patients (54.73%) were treated with jejunostomy. The groups were comparable, but some differences were seen in histological tumor type and tumor stage between the groups. No significant differences in length of hospital stay, postoperative surgical complications, Clavien-Dindo score, or 90-day mortality rate were seen. There was no evidence of increased risk for significant jejunostomy-related complications. Patients in the jejunostomy group with anastomotic leaks had a statistically significant lower risk for severe morbidity defined as Clavien-Dindo score ≥ IIIb (adjusted odds ratio 0.19, 95% CI: 0.04-0.94, P = 0.041) compared to patients with anastomotic leaks and no jejunostomy. CONCLUSION: A nutritional jejunostomy is a safe method for early postoperative enteral nutrition which might decrease the risk for severe outcomes in patients with anastomotic leaks. Nutritional jejunostomy should be considered for patients undergoing curative intended surgery for esophageal and gastro-esophageal junction cancer.

Circulating carnosine dipeptidase 1 associates with weight loss and poor prognosis in gastrointestinal cancer.

BACKGROUND: Cancer cachexia (CC) is linked to poor prognosis. Although the mechanisms promoting this condition are not known, several circulating proteins have been proposed to contribute. We analyzed the plasma proteome in cancer subjects in order to identify factors associated with cachexia. DESIGN/SUBJECTS: Plasma was obtained from a screening cohort of 59 patients, newly diagnosed with suspected gastrointestinal cancer, with (n = 32) or without (n = 27) cachexia. Samples were subjected to proteomic profiling using 760 antibodies (targeting 698 individual proteins) from the Human Protein Atlas project. The main findings were validated in a cohort of 93 patients with verified and advanced pancreas cancer. RESULTS: Only six proteins displayed differential plasma levels in the screening cohort. Among these, Carnosine Dipeptidase 1 (CNDP1) was confirmed by sandwich immunoassay to be lower in CC (p = 0.008). In both cohorts, low CNDP1 levels were associated with markers of poor prognosis including weight loss, malnutrition, lipid breakdown, low circulating albumin/IGF1 levels and poor quality of life. Eleven of the subjects in the discovery cohort were finally diagnosed with non-malignant disease but omitting these subjects from the analyses did not have any major influence on the results. CONCLUSIONS: In gastrointestinal cancer, reduced plasma levels of CNDP1 associate with signs of catabolism and poor outcome. These results, together with recently published data demonstrating lower circulating CNDP1 in subjects with glioblastoma and metastatic prostate cancer, suggest that CNDP1 may constitute a marker of aggressive cancer and CC.

Liver parenchyma access and lesion marker via the endovascular route.

BACKGROUND: Neoadjuvant chemotherapeutic regimens for metastatic colorectal cancer are now so effective that they can cause "vanishing" lesions. With new advances such as local ablation, intra-arterial treatments in bolus with pumps or with beads, and isolation of hepatic perfusion, the need for a working channel to the liver may be warranted, ideally reducing the risk of spreading neoplastic cells. MATERIALS AND METHODS: The endovascular trans-vessel wall Extroducer device makes it possible to gain direct access to the liver parenchyma. The distal tip is then detached, to act as both a marker and a securing plug in the vessel defect. We used ex vivo and in vivo tests to evaluate the device as a working channel for local administration of substances to the parenchyma and as a marker for detection with both transabdominal and intraoperative ultrasonography. RESULTS: We could deploy the Extroducer device without any hemorrhagic or thromboembolic complications in vivo, and we were able to detect all markers ex vivo and in vivo using both transabdominal and intraoperative ultrasonography. Furthermore, we found that it is possible to administer substances to the liver parenchyma using the catheter. CONCLUSIONS: The trans-vessel wall technique can be used to establish a working channel to the liver parenchyma for administration of any substance, such as chemotherapeutic agents or cells. The detached device can also be used as a marker for ultrasound-guided partial liver resection in "vanishing lesions." The technique should have a low risk of seeding of neoplastic cells. This study in large animals forms a strong basis for translation to clinical studies.

MicroRNA profiling links miR-378 to enhanced adipocyte lipolysis in human cancer cachexia.

Cancer cachexia is associated with pronounced adipose tissue loss due to, at least in part, increased fat cell lipolysis. MicroRNAs (miRNAs) have recently been implicated in controlling several aspects of adipocyte function. To gain insight into the possible impact of miRNAs on adipose lipolysis in cancer cachexia, global miRNA expression was explored in abdominal subcutaneous adipose tissue from gastrointestinal cancer patients with (n = 10) or without (n = 11) cachexia. Effects of miRNA overexpression or inhibition on lipolysis were determined in human in vitro differentiated adipocytes. Out of 116 miRNAs present in adipose tissue, five displayed distinct cachexia-associated expression according to both microarray and RT-qPCR. Four (miR-483-5p/-23a/-744/-99b) were downregulated, whereas one (miR-378) was significantly upregulated in cachexia. Adipose expression of miR-378 associated strongly and positively with catecholamine-stimulated lipolysis in adipocytes. This correlation is most probably causal because overexpression of miR-378 in human adipocytes increased catecholamine-stimulated lipolysis. In addition, inhibition of miR-378 expression attenuated stimulated lipolysis and reduced the expression of LIPE, PLIN1, and PNPLA2, a set of genes encoding key lipolytic regulators. Taken together, increased miR-378 expression could play an etiological role in cancer cachexia-associated adipose tissue loss via effects on adipocyte lipolysis.

Non-malignant respiratory tract fistula from the oesophagus. A lethal condition for which novel therapeutic options are emerging.

OBJECTIVES: Fistulas between the oesophagus and the respiratory tract can occur as a complication to anastomotic dehiscence after oesophageal resection, without any signs of local residual tumour growth. Other causes that are, by definition, benign may rarely prevail. The traditional therapeutic approach is to divert the proximal portion of the oesophagus and transpose the conduit into the abdominal cavity. With the introduction and development of self-expandable metal stents (SEMS), new therapeutic options have emerged for these severe complications. We have evaluated our stent-based strategy for managing these life-threatening situations. METHODS: At Karolinska University Hospital, all patients admitted with an oesophago-respiratory fistula during the period 2003-2011 followed a stent-based strategy. On clinical suspicion, a prompt computed tomography scan was performed with contrast ingestion, to visualize the status of the anastomosis and the potential communications. Often an endoscopy was done to assess the oesophagus and the conduit. The respiratory tree was inspected through a concomitant bronchoscopy. The double-stent strategy presently applied meant that covered self-expandable metal stents (SEMS) were applied on the alimentary and airway sides to adequately cover the fistula orifice on both sides. The subsequent clinical course determined the ensuing therapeutic strategy. RESULTS: During the study period, 17 cases with oesophago-respiratory fistulas were treated at our unit, of which 13 exhibited fistulation following an oesophageal resection due to cancer and 4 cases had a benign underlying disease. The cancer patients did not show any obvious demographic profile when it came to the cancer sub-location, histological type of cancer, or treatment with neoadjuvant chemo- and radiochemotherapy. There was an equal distribution between hand-sutured and stapled anastomoses. In 10 of the cases, the anastomoses were located in the upper right chest; the remainder in the neck, and all reconstructions were carried out by a tubulized stomach. The diagnosis of the fistula tract between the anastomotic area and the respiratory tract was attained on the 15th postoperative day (median), with a range from 5 to 24 days. CONCLUSIONS: When an oesophago-respiratory fistula is diagnosed, even in a situation where no neoplastic tissue is prevailing, attempts should be made to close the fistula tract by SEMS from both directions, i.e. from the oesophageal as well as the respiratory side. By this means, a majority of these patients can be initially managed conservatively with prospects of a successful outcome, although virtually all will eventually require a single-stage resection and reconstruction.

Transection of the liver parenchyma with an ultrasound dissector or a stapler device: results of a randomized clinical study.

BACKGROUND: Perioperative hemorrhage and postoperative bile leakage are severe complications of liver surgery. They may be related to the techniques used to divide the tissue. We designed a randomized clinical trial to compare the cavitron ultrasonic surgical aspirator (CUSA) and an endoscopic stapler device applied in routine clinical hepatic surgical practice. METHODS: All consecutive patients admitted for elective hepatic resective surgery--at least bisegmentectomy of the liver--were assessed for enrollment in the study. A total of 100 patients were subsequently randomized. There was a good balance between the study groups concerning issues that may be of relevance for the perioperative and postoperative courses. The primary objective of the study was to achieve an approximately 25 % reduction in perioperative blood loss and postoperative bile leakage. Secondary outcome variables were operating time, general postoperative morbidity, length of hospital stay, and direct medical costs. RESULTS: The amount of perioperative or postoperative blood loss did not differ significantly between the two groups. We observed a trend toward shorter transection and operating time for patients in whom staplers were used, but the difference did not reach statistical significance. The postoperative courses were close to identical in the respective study arms with no difference in bile leakage rates or in the total morbidity profiles. The direct medical costs were nonsignificantly lower in the group where staplers were used for liver transection. CONCLUSIONS: The results show that the use of endoscopic vascular staplers in liver surgery is feasible and safe. It offers an attractive alternative for division of the liver parenchyma during routine hepatic surgery, being comparable to the use of CUSA without adding extra costs.

Adipose tissue volume is decreased in recently diagnosed cancer patients with cachexia.

OBJECTIVE: Approximately 50% of patients with cancer develop cachexia. The aim of the present study was to determine if there were differences in the amount of visceral and subcutaneous adipose tissues at the time of the diagnosis among patients with cancer cachexia (CC), patients with cancer and a stable weight (WS), and patients with cancer and weight loss because of gastrointestinal obstruction (GO). METHODS: Patients with recently diagnosed cancer were divided into the CC, WS, and GO groups. Body composition was determined by bioimpedance. Basal metabolic rate and energy expenditure were estimated by indirect calorimetry. Visceral and subcutaneous white adipose tissues (WATs) were quantified by the segmentation of a 10-mm-thick computed tomographic slice obtained through the central part of the third lumbar vertebra. RESULTS: The body mass index and body fat were decreased in the CC and GO groups compared with the WS group, but there were no significant differences between the two weight-losing groups. Lean body mass, total body water, and energy expenditure were similar among the groups. The visceral WAT volume was decreased in the CC but not in the GO group compared with the WS group (P < 0.05). The subcutaneous WAT was decreased in the CC and GO groups compared with the WS group (P < 0.001). CONCLUSION: The WAT was decreased in the CC and GO groups compared with the WS group. Furthermore, patients with CC exhibited a selective decrease in visceral WAT. This may be new information regarding the WAT distribution in CC.

Mechanisms for skeletal muscle insulin resistance in patients with pancreatic ductal adenocarcinoma.

OBJECTIVE: Weight loss, glucose intolerance, and insulin resistance are seen in patients with pancreatic ductal adenocarcinoma (PDAC). Peripheral insulin resistance is decreased after tumor resection in patients with PDAC, which is consistent with the hypothesis that factors from the tumor may induce skeletal muscle insulin resistance. Our aim was to investigate the possible mechanisms for their skeletal muscle insulin resistance. Accordingly, the action of insulin on glucose metabolism and content of energy metabolites in muscle of patients with PDAC were investigated. To explore whether PDAC cells could influence muscle glucose uptake, myotubes were exposed to media conditioned by PDAC cells. METHODS: Muscle biopsies from patients with PDAC (n=13), cancer of other sites (n=8), chronic pancreatitis (n=8), and controls with benign diseases (n=8) were assessed for glycogen, adenosine triphosphate, and phosphocreatine content. Basal and insulin-stimulated glucose transport and incorporation into glycogen were also assessed. Myotubes were treated with media conditioned by PDAC (MiaPaca 2) cells and glucose transport was monitored. RESULTS: Insulin-stimulated glucose transport, muscle glycogen, and adenosine triphosphate content were decreased in patients with PDAC compared with controls, and insulin stimulation did not significantly increase glucose incorporation into glycogen in vitro in patients with PDAC. Adenosine triphosphate content correlated with glycogen content but not with glucose transport in skeletal muscle. Media conditioned with human PDAC cells did not affect basal or insulin-stimulated glucose transport in L6 myotubes. CONCLUSION: In patients with PDAC, muscle insulin resistance is an early and specific finding unrelated to weight loss, plasma free fatty acid levels, and energy status of the cell. PDAC cell-derived factors did not directly induce insulin resistance in myotubes, suggesting a lack of direct tumor-related effects.

Treatment of postoperative esophagorespiratory fistulas with dual self-expanding metal stents.

BACKGROUND: Fistulas between the esophagus and the respiratory tract can occur as a complication to anastomotic dehiscence after esophageal resection. The traditional therapeutic approach is to deviate the proximal portion of the esophagus and transpose the conduit into the abdominal cavity. With the introduction and development of self-expandable metal stents (SEMS), new therapeutic options have emerged for these severe complications. METHODS: One hundred sixty-seven consecutive esophageal resections were reviewed to address the outcome of a stent-based therapeutic strategy in cases with esophagorespiratory fistulas. The patency of each anastomosis was checked only at the time of clinical suspicion of leakage but then radiology, endoscopy, and bronchoscopy were used together. RESULTS: Seven patients developed esophagorespiratory fistula. All of these fistulas were diagnosed more than 1 week after the operation. Two patients (27%) died due to the fistula. Four could be successfully treated but in two of these we were forced to change strategy and either perform a colonic interposition or externalize the esophagus. One of these patients subsequently developed total respiratory failure and required extracorporal membrane oxygenation (ECMO) to recover. CONCLUSIONS: When an esophagorespiratory fistula is diagnosed, an attempt to close the fistula tract by SEMS from both the esophageal and the respiratory side is a feasible treatment option. This strategy has to be prolonged and aggressive with a commitment to repeatedly change stents and modify sizes and designs. Thereby a majority of these patients can be managed conservatively with prospects of a successful outcome.

Evidence for an important role of CIDEA in human cancer cachexia.

Loss of fat mass in cancer cachexia is linked to increased adipocyte lipolysis; however, the fate of the excess fatty acids (FA) generated by lipolysis is not known. We investigated if the adipocyte-specific gene cell death-inducing DNA fragmentation factor-alpha-like effector A (CIDEA) could be involved. CIDEA mRNA expression was assessed in s.c. white adipose tissue from 23 cancer cachexia patients, 17 weight-stable cancer patients, and 8 noncancer patients. CIDEA was also overexpressed in adipocytes in vitro. CIDEA expression was increased in cancer cachexia (P < 0.05) and correlated with elevated levels of FAs and reported weight loss (P < 0.001). CIDEA overexpression in vitro increased FA oxidation 2- to 4-fold (P < 0.01), decreased glucose oxidation by 40% (P < 0.01), increased the expression of pyruvate dehydrogenase kinase (PDK) 1 and PDK4 (P < 0.01), and enhanced the phosphorylation (inactivation) of the pyruvate dehydrogenase complex (PDC). Inactivation of PDC facilitates FA oxidation by favoring the metabolism of FAs over glucose to acetyl-CoA. In accordance with the in vitro data, PDK1 and PDK4 expression correlated strongly with CIDEA expression in white adipose tissue (P < 0.001). We conclude that CIDEA is involved in adipose tissue loss in cancer cachexia and this may, at least in part, be due to its ability to inactivate PDC, thereby switching substrate oxidation in human fat cells from glucose to FAs.

Lipolysis--not inflammation, cell death, or lipogenesis--is involved in adipose tissue loss in cancer cachexia.

BACKGROUND: Cancer cachexia is an important, negative prognostic marker that has been linked to systemic inflammation and cell death through unclear mechanisms. A key feature of cancer cachexia is loss of white adipose tissue (WAT) because of increased adipocyte lipolysis and possibly reduced lipid synthesis (lipogenesis). In this study, the authors investigated whether alterations in fat cell numbers, lipogenesis, or cytokine and/or leukocyte infiltration could account for some of the functional changes observed in WAT in cancer cachexia. METHODS: Blood and subcutaneous WAT samples were obtained from a 10 weight-stable patients, from 13 weight losing (cachexia) patients with cancer, and from 5 patients without cancer (noncancer patients) who initially were classified with cancer. RESULTS: Systemic inflammation (increased circulating levels of interleukin 6 [IL-6]) and enhanced lipolysis were confirmed in the cachectic patients compared with the other patients. However, the messenger RNA expression of IL-6 and other cytokine or leukocyte markers, as well as WAT secretion of IL-6, were not altered in the patients with cachexia. Thus, the elevated serum levels of IL-6 that were observed in cachexia were not derived from WAT. Insulin-induced lipogenesis in adipocytes from patients with cachexia was the same as that in adipocytes from patients with weight-stable cancer and from noncancer patients (2.5-fold maximal stimulation; half-maximum effective concentration, approximately 0.03 nmol/L). Fat cell size was decreased but adipocyte numbers were normal in cancer patients with cachexia, suggesting that there was no major fat cell death. CONCLUSIONS: The current findings indicated that subcutaneous WAT does not contribute to the systemic inflammatory reaction and does not induce adipocyte insulin resistance in cancer cachexia. Moreover, increased fat cell lipolysis, not reduced lipogenesis or adipocyte cell death, appeared to be the primary cause of fat loss in this condition.

Mechanism of increased lipolysis in cancer cachexia.

Loss of fat mass is a key feature of cancer cachexia and has been attributed to increased adipocyte lipolysis. The mechanism behind this alteration is unknown and was presently investigated. We studied mature s.c. fat cells and differentiated preadipocytes from 26 cancer patients with and without cachexia. Hormone-induced lipolysis and expression of lipolysis-regulating genes were determined together with body composition and in vivo lipolytic activity (fasting plasma glycerol or fatty acids related to body fat). Body fat was reduced by 40% and in vivo lipolytic activity was 2-fold increased in cachexia (P = 0.001). In mature adipocytes, the lipolytic effects of catecholamines and natriuretic peptide were 2- to 3-fold increased in cachexia (P < 0.001). This was completely counteracted by inhibiting the rate-limiting lipolysis enzyme hormone-sensitive lipase (HSL). In cachexia, the expression levels of HSL mRNA and protein were increased by 50% and 100%, respectively (P = 0.005-0.03), which strongly correlated with in vitro lipolytic stimulation (r = 0.7-0.9). The antilipolytic effect of insulin in mature fat cells and the stimulated lipolytic effect in differentiated preadipocytes were unaltered in cachexia. Patients who lost weight due to other factors than cancer cachexia had no change in adipocyte lipolysis. In conclusion, adipocyte lipolysis is increased in cancer cachexia not due to nonepigenic factors or to weight loss per se, but most probably because of enhanced expression and function of adipocyte HSL. The selective inhibition of this enzyme may prevent fat loss in cancer patients.