Improvement in perioperative and long-term outcome after surgical treatment of hilar cholangiocarcinoma: results of an Italian multicenter analysis of 440 patients.

OBJECTIVE: To evaluate improvements in operative and long-term results following surgery for hilar cholangiocarcinoma. DESIGN: Retrospective multicenter study including 17 Italian hepatobiliary surgery units. PATIENTS: A total of 440 patients who underwent resection for hilar cholangiocarcinoma from January 1, 1992, through December 31, 2007. MAIN OUTCOME MEASURES: Postoperative mortality, morbidity, overall survival, and disease-free survival. RESULTS: Postoperative mortality and morbidity after liver resection were 10.1% and 47.6%, respectively. At multivariate logistic regression, extent of resection (right or right extended hepatectomy) and intraoperative blood transfusion were independent predictors of postoperative mortality (P = .03 and P = .006, respectively); in patients with jaundice, mortality was also higher without preoperative biliary drainage than with biliary drainage (14.3% vs 10.7%). During the study period, there was an increasingly aggressive approach, with more frequent caudate lobectomies, vascular resections, and resections for advanced tumors (T stage of 3 or greater and tumors with poor differentiation). Despite the aggressive approach, the blood transfusion rate decreased from 81.0% to 53.2%, and mortality slightly decreased from 13.6% to 10.8%. Median overall survival significantly increased from 16 to 30 months (P = .05). At multivariate analysis, R1 resection, lymph node metastases, and T stage of 3 or greater independently predicted overall and disease-free survival. CONCLUSIONS: Surgery for hilar cholangiocarcinoma has improved with decreased operative risk despite a more aggressive surgical policy. Long-term survival after liver resection has also increased, despite the inclusion of cases with more advanced hilar cholangiocarcinoma. Preoperative biliary drainage was a safe strategy before right or right extended hepatectomy in patients with jaundice. Pathologic factors independently predicted overall and disease-free survival at multivariate analysis.

Hepatic metastases from breast cancer.

The prognosis of patients with hepatic metastasis from breast cancer treated with systemic or regional chemotherapy is disappointing. When technically feasible, liver resection offers the best results. Eighteen patients out of 22 submitted to laparotomy underwent radical liver resection. Median follow-up from liver resection was 36 months. The median time interval between breast cancer diagnosis and disease recurrence was 35 months. Median disease-free survival and overall survival from liver resection were 66 and 74 months, respectively. Median survival time from breast cancer surgery was 88.5 months. Surgical treatment of liver metastases should be carried out on young and older patients alike when site of metastases is the liver alone. Neoadjuvant treatment and preoperative diagnostic laparoscopy should be planned in future experience.

Current role of surgery in the treatment of digestive fistulas.

UNLABELLED: Surgery is the main treatment of digestive fistulas (DF) but its role has changed over the last 40 years. The aim of this review is to analyze the surgical management of DF paying attention to timing and type of surgery. METHODS: We performed a review considering the following electronic databases: Medline, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Cochrane Central Register of Controlled Trials, EMBASE and the reference lists of the key papers. Literature searches were carried out using the following medical subject headings: "digestive fistula"; "gastrointestinal fistula"; "enterocutaneous fistula"; 'AND surgery"; "AND surgical treatment". Because the absence of randomized studies, we have considered the larger series or original techniques. RESULTS: Surgical treatment of DF has two indications: to treat complications due to DF juice action such as peritonitis, abscesses, gangrene, bleeding; and when a fistula fails to heal. In this case the surgical indication is often difficult to establish, because of the risk of making an inconclusive act. CONCLUSIONS: Indications to surgery, timing and choice of operation cannot often be standardized because they depend on a mixture of DF and patient characteristics. In specific cases, involvement of nutritionist and plastic surgeon is required.

Horner's syndrome as a complication of thyroidectomy: report of a case.

We report a case of Horner's syndrome (HS) occurring as a complication after total thyroidectomy. Horner's syndrome is characterized by myosis, eyelid ptosis, enophthalmos, and lack of sweating, with vascular dilatation of the lateral part of the face, caused by damage of the cervical sympathetic chain. We found only 28 other reports of HS developing after thyroidectomy, and only seven of these patients recovered completely. Of the 495 thyroidectomies performed at our hospital between 1997 and 2007, only one (0.2%) was complicated by the development of HS. The patient was a 35-year-old woman who underwent total thyroidectomy for Basedow-Graves' disease. Horner's syndrome manifested on postoperative day 2, but without anhydrosis or vascular dilatation of the face, and the symptoms resolved spontaneously 3 days later. The possible causes of HS after thyroidectomy include postoperative hematoma, ischemia-induced neural damage, and stretching of the cervical sympathetic chain by the retractor. The prompt and complete recovery of this patient suggests that the cervical sympathetic chain was damaged by retractor stretching.

Therapeutic approach to hepatocellular carcinoma: a difficult choice.

In this paper the most important problems regarding diagnosis and treatment of HCC will be discussed in detail by the Authors. In an analysis of therapeutic options, the methods used over the past decades will be looked at. The conclusion is that choices must always be made in a rational manner and with good sense.

Colorectal cancer: what has changed in diagnosis and treatment over the last 50 years?

AIMS AND BACKGROUND: This overview focuses on what has changed in the diagnosis and treatment of colorectal cancer over the last 50 years. METHODS: The most important international registers (SEER, European and Italian) as well as the literature have been consulted. Furthermore, many prognostic factors are analyzed with the aim to understand the reasons why 5-year survival has improved over the last two decades. RESULTS: Since the biologic characteristics of the tumor cannot be changed, improved survival must be supported by concomitant multiple factors, such as earlier diagnosis (as given by a more informed educational behavior and the advent of screening) as well as the wide use of colonoscopy and the technical improvement of surgical and medical treatment. However, it seems that the greatest improvement in survival is limited to 5-year controls, whereas long-term survival does not appear to show any significant improvement. CONCLUSIONS: We can hypothesize that our efforts have just delayed the inevitable end: death. Nevertheless, further research should be done to confirm this hypothesis, perhaps in the field of molecular biology, which may also be the right approach to understanding the biologic aggressiveness of each tumor.

Reduced likelihood of metastases in patients with microsatellite-unstable colorectal cancer.

PURPOSE: The outcome of patients with colorectal cancer is more favorable when the tumor exhibits high-frequency microsatellite instability (MSI). Although associated with earlier-stage tumors, MSI has been proposed as an independent predictor of survival. We tested the prognostic value of MSI in a large series of patients diagnosed with colorectal cancer in the last decade. EXPERIMENTAL DESIGN: The survival of 893 consecutive patients with colorectal cancer characterized by microsatellite status was analyzed. The 89 (10%) patients with MSI cancer were classified according to tumor mismatch repair (MMR) defect, MMR germ-line mutation, hMLH1 and p16 promoter methylation, BRAF and K-ras mutations, and frameshifts of target genes. RESULTS: The colorectal cancer-specific survival was significantly (P = 0.02) better in patients with MSI cancer than in those with stable tumor (MSS). MSI did not predict a significantly lower risk of cancer-related death if tumor stage was included in the multivariate analysis [hazard ratio, 0.72; 95% confidence interval (95% CI), 0.40-1.29; P = 0.27]. Instead, MSI was strongly associated with a decreased likelihood of lymph node (odds ratio, 0.31; 95% CI, 0.17-0.56; P < 0.001) and distant organ (odds ratio, 0.13; 95% CI, 0.05-0.33; P < 0.001) metastases at diagnosis, independently of tumor pathologic features. Molecular predictors of reduced metastatic risk, and then of more favorable prognosis, included TGFbetaRII mutation for all MSI tumors, hMSH2 deficiency for hereditary non-polyposis colorectal cancer, and absence of p16 methylation for sporadic hMLH1-deficient cancers. CONCLUSIONS: Tumor MSI is a stage-dependent predictor of survival in patients with colorectal cancer. The decreased likelihood of metastases in patients with MSI cancer is associated with specific genetic and epigenetic changes of the primary tumor.

[The lymph node dissection in thyroid carcinoma]. / La linfadenectomia nei carcinomi della tiroide.

Rule and indications of lymph node dissection (LD) in thyroid carcinoma is still under debate because of the biological variety of different histological types and the difficulty to have an accurate preoperative diagnosis of metastatic lymph nodes; moreover prognostic factors of metastatic lymph nodes are still unclear. The AA. have separately analyzed different thyroid carcinomas and different clinical situations requiring thyroid LD. Metastatic lymph nodes from differentiated carcinomas, including papillary and follicular type, range from 12 to 90% and apparently do not worsen the prognosis. Level II-VI LD is indicated in presence of metastatic lymph nodes or macroscopic nodal recurrence after a previous LD. No prognostic advantages have been demonstrated when LD is performed without clinical or instrumental evidence of metastatic disease, including suspected recurrence characterised only by plasma Thyreoglobulin increased values. Lymph node metastases from medullary carcinoma range from 25 to 63%. Level II-VI LD is indicated if node metastases are present, whereas prophylactic LD, confined to level VI, is always recommended. Controversies still remain about: 1) LD extension whether it is prophylactic (level VI vs. II- VI) or in case of nodal involvement (levels II- VI monolateral or bilateral), 2) LD indications in case of an increased plasma Calcitonin levels during the follow-up after total thyroidectomy, without clinical or instrumental evidence of nodes involvement. Anaplastic carcinoma represents 5% of all thyroid carcinomas; it is the most aggressive type with an early tendency to invade surrounding organs and to give metastases; prognosis is very poor. LD is indicated only for a palliation in cases with compression syndromes.

[Does the Roux-en-Y-stasis syndrome still exist?]. / Esiste ancora la sindrome dell'ansa alla Roux?

Roux-en-Y-stasis syndrome (RYS) is a complication of subtotal gastrectomy characterized by delayed gastric emptying and vomiting. The aim of the study was to analyze RYS frequency with particular attention to diagnosis and therapy. From November 1996 to June 2004, we performed 147 distal gastrectomies with 5 cases of RYS: mean age 78 years, 3 male, 2 female, 4 adenocarcinoma and 1 GIST. Among the 5 cases, RYS was due to different causes: it was functional in 2 cases (with difficult gastric emptying due to a long gastric remnant in one patient, while the other was associated with duodenal fistula) and healed through medical therapy in both; a third patient had an edematous stenosis of the gastrojejunal anastomosis treated with medical therapy and the remaining 2 patients had jejunal obstruction due to adherences and required reoperations. RYS is a rare complication of subtotal gastrectomy determined by different causes. Recognizing the cause is very important for choice of appropriate therapy.

Gastric cancer: extent of lymph node dissection and requirements for a correct staging.

AIMS AND BACKGROUND: Lymphatic spread is an important prognostic factor in gastric cancer. The TNM classification requires at least 15 lymph nodes to stage and identify three prognostic groups according to the number of metastatic lymph nodes: N1 (1-6), N2 (7-15), N3 (> 15). The aim of this study was to investigate which type of lymph node dissection allows an accurate staging. METHODS: From 1996 to 2001, we treated 140 gastric cancer patients, 27 with D1 and 113 with D2 dissection. We evaluated lymph node count, status and ratio between metastatic and total number of excised lymph nodes, keeping 20% as the cutoff value. RESULTS: The mean number of lymph nodes was 18 and 33 respectively for D1 and D2 (P < 0.001), 41% of patients in D1 and 5% in D2 had less than 15 lymph nodes (P < 0.001). 59% in D1 and 73% in D2 (P = 0.145) had lymph node metastases, but this incidence decreased to 36% (P = 0.045) and 16% (P < 0.001) respectively for D1 and D2 when less than 15 lymph nodes were available. Considering the ratio between metastatic and total number of lymph nodes, 45% of D1 versus 3% of D2 (P < 0.001) in the N1 group exceeded 20%. CONCLUSIONS: D2 lymph node dissection is better than D1 in providing at least 15 lymph nodes required for a correct staging. We confirm the risk of a downstage when less than 15 lymph nodes are available.

Methylation framework of cell cycle gene inhibitors in cirrhosis and associated hepatocellular carcinoma.

One of the main regulatory pathways reported to be altered in hepatocellular carcinoma (HCC) is that of cell cycle control involving RB1 gene-related cell inhibitors. We investigated p14(ARF), p15(INK4B), p16(INK4A), p18(INK4C), and RB1 genes in a series of HCCs and associated cirrhosis with the goal of ascertaining their pattern of inactivation by gene methylation. Thirty-three HCCs, adjacent nonneoplastic cirrhotic tissues, and 6 HCC cell lines were studied. Cirrhoses (25 of 33, 76%), HCCs (31 of 33, 94%), and 3 of 6 (50%) cell lines showed 1 or more methylated genes. Cirrhoses (17 of 33, 51%) had more frequently than HCCs (11 of 33, 33%, P =.01) only 1 methylated gene. With the exception of p18(INK4C) the genes under study showed promoter methylation with frequency ranging from 82% (p16(INK4A) in HCC) to 33% and 39% (p15(INK4B) and p16(INK4A) in cirrhoses). In cases with only 1 methylated gene, p15(INK4B) in cirrhosis (8 of 17, 47%) and p16(INK4A) in HCC (10 of 11, 91%) were the more frequently altered. An optimal correlation was found between p15 and p16 gene methylation and complete protein loss in HCC detected by immunocytochemistry, whereas a partial loss of the same proteins was a feature of methylated cirrhoses. Inactivation by DNA methylation of several genes of the RB1 pathway is common to cirrhosis and HCC. An early pattern of methylatory events (1 methylated gene) is a feature of cirrhosis rather than HCC, whereas an advanced one (> or = 3 methylated genes) is characteristic of malignancy. Early methylation changes seem to involve p15(INK4B) and p16(INK4A) in cirrhosis and p16(INK4A) in HCC. In conclusion, a stepwise progression of methylating events is a feature of the sequence cirrhosis-HCC and contributes to the process of hepatic carcinogenesis with potential clinical implications.

Lymphadenectomy in gastric cancer: prognostic role and therapeutic implications.

AIMS: Surgeons involved in the treatment of gastric cancer are interested in the extent of lymphadenectomy as the latter may not only influence the reliability of the tumour, node and metastasis classification but also be relevant for the long-term oncological outcome. The purpose of the study was to evaluate the prognostic role of the number of resected lymph nodes (as an indicator of the scope of lymphadenectomy) and of the number of metastatic lymph nodes on the long-term mortality for all causes and to provide clinicians with estimates of predictive survival probabilities. METHODS: The study involved 615 cancer patients subjected to a curative (R0) subtotal or total gastrectomy in a randomized Italian trial. According to the trial protocol, a D2 lymphadenectomy had been advised. The number of resected and metastatic lymph nodes was analysed as a continuous variable in multiple Cox models. RESULTS: There was no difference in operative mortality (about 1.8%) according to the number of lymph nodes in the specimen (< or =15, 16-25, >25). The risk of long-term death for all causes tended to decrease with increasing number of resected lymph nodes up to about 25, and then could be considered stable for wider lymphadenectomies. An increasing risk of death for all causes was associated with an increasing number of metastatic lymph nodes; the risk could be considered stable for more than 20 metastatic lymph nodes. CONCLUSIONS: A lymphadenectomy including more than 25 lymph nodes is suggested, provided that there is a low risk of operative mortality.

[Integrated treatments of rectal carcinoma (review)]. / I trattamenti integrati del carcinoma rettale (review).

We have reviewed the international literature regarding the treatment of rectal carcinoma. Over the last decades the evolution of treatment methods has led to a drastic fall in the incidence of local recurrences which has gone from a wide range (15-40%) to a much lower figure (10%). This favourable result has been reached also due to improvement in surgical techniques (total mesorectal excision) and to the use of an association of preoperative radio and chemotherapy. However, the drugs and dosage of these as well as of the RT still have to be defined. In our experience the integrated treatment has brought a downstaging of the T in 60% of cases and of the N in 15%.

Concurrent Pheochromocytoma, Paraganglioma, Papillary Thyroid Carcinoma, and Desmoid Tumor: A Case Report with Analyses at the Molecular Level.

Reports on the association of papillary thyroid carcinoma with paraganglionic or desmoid tumors have appeared infrequently. The former setting usually affects middle-aged females; the latter is typical of familial adenomatous polyposis. We report the case of a 69-yr-old man in whom two abdominal masses had been instrumentally detected following an access of abdominal pain. Save for a moderate hypertension, he was asymptomatic and an impalpable thyroid nodule was detected by ultrasonography. A high urinary noradrenaline output and cytology of the masses raised the suspicion of pheochromocytoma. At laparotomy, an adrenal pheochromocytoma and a paracaval paraganglioma were excised. Subsequently, hemithyroidectomy was performed, and histopathology revealed papillary microcarcinoma. A nodule of desmoid tumor was also removed from the abdominal wall. An analysis of RET, APC, and TP53 gene mutations, and of RET and NTRK1 gene rearrangements, yielded negative results. No in vitro transforming activity was detected in the tumor DNA when assayed in transfection experiments. The lack of a consistent family history also made unlikely the possibility of identifying the putative germline defect by linkage analyses. Should this unusual aggregation of tumors represent a new entity, a number of genetic alterations have now been excluded.

Prognostico dos tumores desmoides associados a polipose adenomatosa familiar: experiencia do I.N.T. - Milao / Prognosis of desmoid tumor associated with familial adenomatous polyposis: milano experience

Relatamos estudo retrospectivo sobre a rara associaçao polipose adenomatosa familiar e desmoides, comparando, nestes casos, o comportamento do desmoide com a sua forma classica. Durante o periodo de janeiro de 1979 a dezembro de 1987 o I.N.T. - Milao atendeu seis casos com esta condiçao. O tratamento do desmoide foi cirurgico em todos os casos. Todos os pacientes evoluiram para o tumor desmoide mesenterico irressecavel, exceto um caso, cujo seguimento foi inferior a mediana. Dois pacientes faleceram em decorrencia do desmoide mesenterico. O percentual de multicentricidade do desmoide foi de 83%, assim como o de recidiva. Comparando estes achados e os de outras series da associaçao com a forma classica de tumor desmoide, concluimos que nestes casos ha um pior prognostico, face a multicentricidade e a frequencia de ocorrencia de desmoide intra-abdominal, principalmente mesenterico