Unresolved issues and controversies surrounding the management of colorectal cancer liver metastasis.

Ideally, tumors that might cause morbidity and mortality should be treated, preferably early, with proven, convincing, and effective therapy to prevent tumor progression or recurrence, while maintaining a favorable risk-benefit profile for the individual patient. For patients with colorectal cancer (CRC), this diagnostic, prognostic, and therapeutic precision is currently impossible. Despite significant improvements in diagnostic procedures, a sizable number of patients with CRC have liver metastases either at presentation or will subsequently develop it. And in many parts of the world, most cancer-related deaths are still due to metastases that are resistant to conventional therapy. Metastases to the liver occur in more than 50% of patients with CRC and represent the major determinant of outcome following curative treatment of the primary tumor. Liver resection offers the best chance of cure for metastases confined to the liver. However, due to a paucity of randomized controlled trials, its timing is controversial and a hotly debated topic. This article reviews some of the main controversies surrounding the surgical management of colorectal cancer liver metastases (CRLM).

Update on the optimal management of patients with vascular extension of pheochromocytoma.

AIM: Vascular extension of pheochromocytoma is extremely rare but highly resectable. The aim of this study was to review the available information in the literature for patients with this condition. METHODS: A systematic literature search produced individual data for 29 treated patients with vascular extension of pheochromocytoma mainly to the inferior vena cava. RESULTS: Out of 29 reported cases, 26 have been treated surgically. Nine of these patients required cardiopulmonary bypass. Two patients died untreated and one patient declined surgical treatment and discharged to follow-up. In 24 patients including nine with primarily missed diagnosis, surgery was documented as curative. CONCLUSION: Surgeons need to be aware of this extremely rare characteristic feature of pheochromocytoma and indicated medical work-up in order to properly diagnose and manage this challenging group of patients.

Expression and functional coupling of liver ß2 - adrenoceptors in the human hepatocellular carcinoma.

AIM: Hepatocellular carcinoma (HCC) is one of the most common cancers and a leading cause of death worldwide. There are now multiple lines of evidence demonstrating that the ß-adrenoceptor ( ß-AR) signaling plays an important role in the progression and metastasis of cancer and may become a novel target for cancer therapy. Little information exists regarding the status of ß-ARs and their postreceptor intracellular signaling cascade in the development of human HCC. This study was conducted to detect the expression signal transduction of the ß-ARs in liver membranes obtained from patients with HCC and elucidate their possible implication on HCC development. METHODS: The ß-AR density and subtype distribution were determined by receptor binding studies. Protein levels of the ß(2)-AR and G(s)(α) protein were determined by Western blot analysis. The receptor coupling efficiency and biochemical activities of the adenylate cyclase(AC) was also determined. RESULTS: In HCC liver membranes, the ß(2)-AR density was higher than the density in the nonadjacent nontumor liver membranes. The ß(2)-AR protein expression was 1.5-fold increased as compared with nonmalignant controls, and positively correlated with the receptor density. The G s protein expression as well as the receptor, AC and G protein-stimulated activation of the cAMP formation was reduced in HCC. CONCLUSION: The ß(2)-AR was upregulated in human HCC. Despite this upregulation of the receptor,there was an altered postreceptor signal transduction in HCC liver. The mechanisms responsible for this change in the growth of HCC and the nature of this alteration remain unclear.

Unchanged high mortality rates from acute occlusive intestinal ischemia: six year review.

OBJECTIVE: Acute intestinal ischemia (AII) is an uncommon surgical emergency that has been increasing in incidence and remains a highly lethal condition with a difficult diagnosis. We undertook this study to evaluate our experience in treating this condition with a view to expand the cumulative information in the literature. MATERIALS AND METHODS: Between January 2000 and December 2006, 60 patients with AII caused by thrombotic vascular event underwent surgery at our surgical center. The patients' medical records including data covering demographic features, comorbid medical conditions, medical risk factors, clinical symptoms, history and physical examination findings, and biochemical and radiologic examinations were reviewed. Operative records, the American Society of Anesthesiology physical status classification (ASA-PS), postoperative complications, duration of hospital stay, and final outcome were also considered. RESULTS: Of the 60 patients with primary thrombotic vascular event, 20 patients had embolism and 19 patients arterial thrombosis. In 21 patients, mesenteric venous thrombosis was the etiology of AII. The median age was 73 years (range, 43-96). Higher ASA classification, age >70 years, late presentation, and high serum lactate levels were predictors of adverse outcome. The overall death rate was 60% (36/60), which was within the range of that observed in the published series. CONCLUSION: AII remains a highly lethal condition. Mortality rates remain as high as they did decades ago due in part to advanced presentation and advanced age with multiple associated conditions and risk factors, all of which are independent predictors of adverse outcome.

Colorectal cancer metastases affect the biochemical characteristics of the human liver beta-adrenoceptor-G-protein-adenylate cyclase system.

The sympathetic-catecholamine system is involved in the regulation of hepatic metabolic pathways mainly through cAMP-linked beta2-adrenoceptors (beta2-ARs) in humans and to a lesser extent through cAMP-independent mechanisms, but no information is available about the possible biochemical changes of beta2-ARs and their signalling pathways in human colorectal cancer (CRC) and colorectal cancer hepatic metastases (CRCHM). Changes in density and distribution of beta-ARs as well as in post-receptor signalling components were studied in membranes of human liver with CRCHM, and for comparison, in membranes of nonadjacent, non-metastatic human liver (NA-NM) obtained from 13 patients, using binding and competition binding studies. Studies were also carried out using normal and cancerous human colon tissues. In CRCHM, the density of beta-ARs (B(max)) was significantly reduced, compared to NA-NM liver tissues (40.09+/-2.83 vs. 23.09+/-3.24 fmol/mg protein; P<0.001). A similar decrease in the beta-AR density was observed in the colon with primary colorectal cancer compared to healthy colon (37.6+/-2.2 vs. 23.8+/-3.5 fmol/mg protein), whereas the affinity of ICYP binding to the receptor remained unaffected. Desensitized beta-ARs were uncoupled from stimulatory G-protein (G(S)), as total density of beta-adrenoceptors in the high affinity state was significantly reduced. Concomitantly, CRCHM elicited decrease in the catalytic adenylate cyclase (AC) activity (cAMP formation) in response to isoproterenol plus GTP or forskolin or NaF. In NA-NM and CRCHM liver, the inhibition-concentration curves of ICI 118.551 showed the presence of a homogeneous population of the beta2-AR subtypes. Neither the binding patterns nor the inhibition constant (K(i)) of ICI 118.551 were altered in CRCHM. In CRCHM, the hepatic beta-AR-G-protein(s)-AC signalling system was markedly impaired, thus, these changes may well influence beta-AR-mediated functions in both organs.

Complicated small-bowel diverticulosis: a case report and review of the literature.

While jejunoileal diverticula are rare and often asymptomatic, they may lead to chronic non-specific or acute symptoms. The large majority of complications present with an acute abdomen similar to appendicitis, cholecystitis or colonic diverticulitis but they also may appear with atypical symptoms. As a result, diagnosis of complicated jejunoileal diverticulosis can be quite difficult, and may solely depend on the result of surgical exploration. In the absence of contra-indications, diagnostic laparoscopy has the benefit of thorough examination of the abdominal contents and helps to reach an absolute diagnosis. Surgical resection of the involved small-bowel segment with primary anastomosis is the preferred treatment in patients with symptomatic complicated jejunoileal diverticular disease. An atypical presentation of complicated jejunal diverticulitis in conjunction with sigmoid diverticulitis diagnosed with laparoscopy and treated with surgical resection is presented.

Liver resection and transplantation in the management of hepatocellular carcinoma: a review.

Hepatocellular carcinoma (HCC) accounts for more than 80% of all primary liver cancers and is one of the most common malignancies worldwide. Most patients with HCC also suffer from concomitant cirrhosis, which is the major clinical risk factor for hepatic cancer and results from alcoholism, infection with the hepatitis B or hepatitis C virus, and other causes. HCC is often diagnosed at an advanced stage, when established treatment options provide limited benefit. Effective treatment for HCC includes liver resection and liver transplantation. Under most clinical circumstances, those options provide a high rate of complete response and are thought to improve survival. Partial hepatectomy is the therapy of choice in patients with HCC and a noncirrhotic liver. Usually, liver transplantation is not indicated for such patients, although in individual cases, transplantation may be considered. For most cirrhotic patients who fulfill the Milan criteria, liver transplantation is the ultimate treatment option. Liver transplantation restores liver function and ensures the removal of all hepatic foci of tumor as well as tissue with a high oncogenic potential for early tumor recurrence. Because of the present lack of available organs, living-donor liver transplantation (LDLT) is an increasingly popular alternative. LDLT enables recipients to avoid a long pretransplantation waiting time and increases the number of livers available for transplantation. It is also the most effective approach to reducing the dropout rate. Strategies to reduce tumor growth in patients who are awaiting liver transplantation are important to ensure that those individuals continue to fulfill the Milan criteria for transplantation. For that purpose, using ablative techniques or chemoembolization to control local tumor growth is useful.

Organotypic slice cultures of human gastric and esophagogastric junction cancer.

Gastric and esophagogastric junction cancers are heterogeneous and aggressive tumors with an unpredictable response to cytotoxic treatment. New methods allowing for the analysis of drug resistance are needed. Here, we describe a novel technique by which human tumor specimens can be cultured ex vivo, preserving parts of the natural cancer microenvironment. Using a tissue chopper, fresh surgical tissue samples were cut in 400 µm slices and cultivated in 6-well plates for up to 6 days. The slices were processed for routine histopathology and immunohistochemistry. Cytokeratin stains (CK8, AE1/3) were applied for determining tumor cellularity, Ki-67 for proliferation, and cleaved caspase-3 staining for apoptosis. The slices were analyzed under naive conditions and following 2-4 days in vitro exposure to 5-FU and cisplatin. The slice culture technology allowed for a good preservation of tissue morphology and tumor cell integrity during the culture period. After chemotherapy exposure, a loss of tumor cellularity and an increase in apoptosis were observed. Drug sensitivity of the tumors could be assessed. Organotypic slice cultures of gastric and esophagogastric junction cancers were successfully established. Cytotoxic drug effects could be monitored. They may be used to examine mechanisms of drug resistance in human tissue and may provide a unique and powerful ex vivo platform for the prediction of treatment response.

Focus on parathyroid carcinoma.

Parathyroid carcinoma is a malignant neoplasm affecting 05-2 per cent of all patients with primary hyperparathyroidism that was first described by de Quevain in 1904. To day it continues to defy diagnosis and treatment. It is difficult to diagnose in part because of its rarity, lack of definitive diagnostic markers and overlapping clinical features of benign primary hyperparathyroidism. As a result initial surgical treatment is inadequate essentially leading to disease recurrence where complete cure is unlikely. En bloc surgical resection remains the only curative treatment, and high priorities are improving diagnostic methods, and clinical staging for resection once the disease is suspected. Margin status at resection is related to prognosis. Thus, a trend towards aggressive surgical management has improved outcomes. The recurrence rate of parathyroid carcinoma is as high as 80% with survival rates <50% at 10 years. Results of chemotherapy are disappointing. However, recent trials using radiation therapy are promising, but require further study.

Altered liver α1-adrenoceptor density and phospholipase C activity in the human hepatocellular carcinoma.

The human hepatocellular carcinoma (HCC) is a common cancer with high mortality rate. We examined the density and coupling to phospholipase C (PLC) of the α(1)-adrenoceptors. In HCC liver, the α(1)-adrenoceptor density - as assessed by [³H]-Prazosin binding - was significantly reduced to about 75% when compared to non-adjacent non-tumorous liver (NA-NL) (P=0.0002). The decrease in maximal α(1)-adrenoceptor concentration (B(max)) was accompanied by a significant reduction in noradrenaline-stimulated PLC activity (P<0.032 versus NA-NL) (assessed by [³H]-PIP(2) hydrolysis). GTPγS-stimulated PLC activity in HCC livers did not statistically differ from NA-NL livers. NaF, which activates all G-proteins, stimulated PLC in both HCC and NA-NL livers to a similar extent. The altered noradrenaline-induced functional responsiveness of HCC livers was not reflected by changes in the binding affinity of [³H]-Prazosin for α(1)-adrenoceptors (NA-NL: 0.066 ± 0.010 pmol/l; tumour: 0.067 ± 0.020 pmol/l). These results demonstrate that human HCC causes profound alteration of the hepatic α(1)-adrenoceptor signal transduction pathway and may account for a negative cancer related metabolism of carbohydrates and wasting syndrome in tumour patients.

Signet-ring cell carcinoma arising in the gastric stump after duodenopancreatectomy for ductal adenocarcinoma of the pancreas: a case report.

The development of malignancy in the gastric stump following surgery for peptic ulcer disease is well recognized. There are also few reports on carcinomas occurring after surgery for malignant gastric disease. However, carcinoma of the gastric stump after duodenopancreatectomy is extremely rare. We describe what we believe to be an unusual case of signet-ring cell carcinoma of the gastric stump developing at the anastomotic site 5 years after duodenopancreatectomy for ductal adenocarcinoma of the pancreatic head. We performed remnant gastrectomy and Roux-en-Y gastrojejunostomy as a curative resection. This experience clearly underlies that g astric stump carcinoma (GSC) may mimic metastatic disease recurrence leading to diagnostic confusion after surgery for malignancy. Although an increased risk of gastric stump carcinoma after pancreatoduodenectomy for pancreatic cancer has not been established, the possibility of such a complication should be kept in mind when evaluating patients after gastric resection who present with symptoms of metastatic disease recurrence years after the primary operation. Investigations should be independent of the entity of the primary disease or its localization, since GSC may well be amenable to surgical cure as demonstrated in the presented case. Outpatient follow up results of the last four years indicated no recurrence in this case.