Sarah Molfino

Increased risk of second malignancy in pancreatic intraductal papillary mucinous tumors: Review of the literature

AIM To analyze the available evidence about the risk of extrapancreatic malignancies and pancreatic ductal adenocarcinoma associated to pancreatic intraductal papillary mucinous tumors (IPMNs). METHODS A systematic search of literature was undertaken using MEDLINE, EMBASE, Cochrane and Web-of-Science libraries. No limitations for year of publication were considered; preference was given to English papers. All references in selected articles were further screened for additional publications. Both clinical series and Literature reviews were selected. For all eligible studies, a standard data extraction form was filled in and the following data were extracted: study design, number of patients, prevalence of pancreatic cancer and extrapancreatic malignancies in IPMN patients and control groups, if available. RESULTS A total of 805 abstracts were selected and read; 25 articles were considered pertinent and 17 were chosen for the present systematic review. Eleven monocentric series, 1 multicentric series, 1 case-control study, 1 population-based study and 3 case report were included. A total of 2881 patients were globally analyzed as study group, and the incidence of pancreatic cancer and/or extrapancreatic malignancies ranged from 5% to 52%, with a mean of 28.71%. When a control group was analyzed (6 papers), the same incidence was as low as 9.4%. CONCLUSION The available Literature is unanimous in claiming IPMNs to be strongly associated with pancreatic and extrapancreatic malignancies. The consequences in IPMNs management are herein discussed.

Parietal and peritoneal localizations of hepatocellular carcinoma: is there a place for a curative surgery?

BackgroundThe clinical course of peritoneal and parietal recurrence of hepatocellular carcinoma (HCC-PPL) is not well known.MethodsTwenty-eight patients with a histologically proven HCC-PPL were analyzed out of a series of 515 patients operated for HCC (group 1). The risk factors, histological features, growing dynamic and results of surgical treatment were analyzed and compared with patients having other extrahepatic localizations of HCC (group 2; 26 patients). Survival data were also compared with patients with intrahepatic-only recurrence (group 3; 211 patients).ResultsIn group 1, a needle tract injury was present in 57.1% and a previous spontaneous rupture in 14.3% of cases. Parietal seeding was generally single, while peritoneal seeding was frequently multiple. Grading was poor in 84.7%, microvascular infiltration was observed in 57.1% and a rapid growth in 55.5% of cases. In Group 2, only 4 out of 26 patients underwent surgery. Survival was significantly better in group 3 than in group 1, and in group 1 than in group 2.ConclusionsExtrahepatic HCC recurrence is related to an aggressive biology of the cancer; many characteristics of high malignancy are usually present in these cases. After radical surgery for HCC-PPL, an acceptable survival may be obtained.

Indocyanine-Green Fluorescence-GUIDED Liver Resection of Metastasis from Squamous Cell Carcinoma Invading the Biliary Tree

Background. The concept of fluorescence-guided navigation surgery based on indocyanine green (ICG) is a developing interest in many fields of surgical oncology. The technique seems to be promising also during hepatic resection. Case Presentation. We reported our experience of ICG-fluorescence-guided liver resection of metastasis located at VIII Couinauds segment from colon squamous cell carcinoma of a 74-year-old male patient. Results. After laparotomy, the fluorescing tumour has been clearly identified on the liver surface. We have also identified that a large area of fluorescent parenchyma that gets from the peripheral of the lesion up to the portal pedicle such as the neoplasia would interest the right biliary tree in the form of neoplastic lymphangitis. This datum was not preoperatively known. Conclusion. Fluorescent imaging navigation liver resection could be a feasible and safe technique helpful in identifying additional characteristics of lesion. It could be a powerful tool but further studies are required.

Effect of neoadjuvant chemotherapy on HER-2 expression in surgically treated gastric and oesophagogastric junction carcinoma: a multicentre Italian study

Predictors of response to neoadjuvant chemotherapy are not available for gastric and oesophago-gastric junction carcinoma. HER-2 over-expression in breast cancer correlates with poor prognosis and high incidence of recurrence. First aim of this study was to evaluate if the HER-2 expression/amplification is predictive of response to neoadjuvant chemotherapy in terms of pathologic regression. Secondary aim was to evaluate if HER-2 expression varies after neoadjuvant treatment. Thirty-five patients with locally advanced gastric or oesophago-gastric junction carcinoma underwent preoperative chemotherapy and surgical resection at San Raffaele Scientific Institute and Spedali Civili of Brescia. HER-2 expression/amplification was evaluated on every biopsy at diagnosis time and on every surgical sample after neoadjuvant chemotherapy. Pathologic response to chemotherapy was evaluated according to TNM classification (ypT status and ypN status) and Mandard’s tumour regression grade classification. In our series 10 patients (28.6%) showed a reduction in HER-2 overexpression and in 6 of them (17.1%) HER-2 expression completely disappeared. Only three of the six patients with HER-2 disappearance had a complete pathological response to neoadjuvant chemotherapy. There was a strong correlation between HER-2 negativity on biopsy and absence of lymph node metastasis in surgical samples after neoadjuvant chemotherapy, irrespective of nodal status before chemotherapy. A direct correlation between HER-2 reduction after neoadjuvant chemotherapy and pathologic regression (primary tumour and lymph nodes) in surgical samples was found. HER-2 negativity may represent a predictor of pathologic response to neoadjuvant chemotherapy for gastric and oesophago-gastric junction adenocarcinoma. Neoadjuvant treatment can reduce HER-2 overexpression.

Distant nodal metastasis: is it always an unresectable disease?

This article aims at analyzing the published literature concerning the treatment of patients with gastric cancer and distant nodal metastases, actually considered metastatic disease. A systematic search was undertaken using Medline, Embase, Cochrane and Web-of-Science libraries. No specific restriction on year of publication was used; preference was given to English papers. Both clinical series and literature reviews were selected. Only 11 papers address the issue of surgery for nodal basins outside the D2 dissection area. From these papers, in selected cases extended surgery may prove useful in prolonging survival, when a comprehensive therapeutic pathway including chemotherapy is scheduled. In conclusion, in presence of nodal metastases outside the loco-regional nodes, surgery may be considered for metastatic nodes in stations 13 and 16, in selected cases.

The Muir-Torre syndrome: a typical case of misdiagnosis and consequent worsened prognosis

Dear Editor: Muir-Torre syndrome (MTS) is an autosomal dominant cancer susceptibility syndrome considered to be a subset of the Lynch II syndrome. The diagnostic criteria requires one or more sebaceous neoplasm (sebaceous adenomas and/or carcinomas) in association with visceral malignancies, the most frequent being colorectal and genitourinary cancers [1]. The diagnosis of Lynch syndrome generally requires a review of family history of cancer, specimen analysis (including microsatellite instability and loss of MMR protein expression as revealed by immunoistochimical assessment), and genetic analysis, i.e., the determination of the primary DNA sequence of MMR genes (MLH1, MLH2, MSH6). If the patient is not correctly diagnosed as affected by the Lynch syndrome, treatment may finally result not adequate in terms of completeness of preoperative staging and extension of colonic removal. We present the case of a 60-year-old man presenting with recurrent colon cancer and recurrent sebaceous carcinoma of the thoracic wall, in which the syndrome has been recognized late during the clinical course, and this has entailed a delay in recurrence diagnosis, with subsequent worsened prognosis. His medical history comprised bilateral nefrectomy for polycystic kidneys (associated with polycystic liver) and subsequent renal transplantation 25 years before. In 2000, when he was 47 years old, non-occluding colonic neoplasm in the ascending colon was diagnosed and treated with laparotomic right hemicolectomy. Pathological examination confirmed mucinous adenocarcinoma, stage T2N0M0. At this time, no suspicion was raised of a possible Lynch syndrome. In 2010, the patient underwent resection of a cutaneous lesion in the pre-sternal region, which was demonstrated to be a sebaceous carcinomaWorld Health Organization (WHO) grade II; 1 year later, the patient suffered a local recurrence of sebaceous carcinoma, treated with brachytherapy, which failed in complete necrotizing of the tumor, and subsequent further extended surgical resection, en-bloc with part of the underlying stern. At this point, immunohistochimical determination was carried out for MMR proteins, showing a defective expression of MSH2 and MSH6 proteins, a normal expression of MLH1 and microsatellite instability. However, no clear indications were given to the patient and his family for familial and personal screening; prophylactic colectomy was no advised. In 2013, the patient had colorectal cancer screening positive test (fecal occult blood test), followed by colonoscopy that found a transverse colon cancer. At the same time, a macroscopic further recurrence of the thoracic wall neoplasm became evident. Contrast-enhanced computed tomography (CT) confirmed the presence of masses in the thoracic wall as well as an occluding neoplasm of the proximal descending colon, without liver and pulmonary metastases. Therefore, the patient underwent resection of the remnant transverse and left colon and ileo-rectum anastomosis and at the same time resection of the thoracic lesions, which were removed en-bloc with pericardial mediastinal fat (which contained macroscopically evident neoplastic nodules) and excision of IX, VIII, VII, VI right costal cartilage, IX, VIII, VII left costal cartilage, inferior sternal third, and the anterior diaphragmatic crura. Reconstruction of the thoracic wall and diaphragm was done using a Marlex mesh prosthesis, fixed with non-absorbable suture to the remaining ribs, sternum, and diaphragm, to delimit the abdominal cavity. The mesh G. L. Baiocchi : E. Chiocchi :W. Vermi : S. Molfino : F. Gheza : F. Biasca :N. Portolani : S. M. Giulini Department of Clinical and Experimental Sciences, Surgical Clinic, University of Brescia, Brescia, Italy

Is there a role for treatment-oriented surgery in stage IV gastric cancer? A systematic review

To analyze the available evidence on the role of treatment-oriented surgery in stage IV gastric cancer (metastatic disease), a systematic literature search was undertaken using Medline, Embase, Cochrane, and Web-of-Science libraries. The search was not restricted to articles published within a given year range. Articles written in English language (or with abstracts written in English) were considered. All references in the chosen articles were further screened to find additional relevant publications. Both clinical series and literature reviews were included. Stage IV gastric cancer is classified into four subcategories: positive peritoneal cytology without clear macroscopic peritoneal involvement (surgery is usually performed in these cases); gross appearance peritoneal carcinomatosis [surgery, eventually with hyperthermic intraoperative peritoneal chemotherapy (HIPEC) may be considered in very selected cases with limited PCI]; nodal metastases outside the loco-regional nodes (surgery may not be denied for metastatic nodes in stations 13 and 16); and hematogenous metastases (surgery should be performed in selected cases with liver metastases suitable to R0 resection). The analysis incorporated the new biological classification of stage IV gastric cancer recently proposed by Japanese researchers (Yoshida et al. in Gastric Cancer 19:329–338. https://doi.org/10.1007/s10120-015-0575-z, 2015) into the four aforementioned subcategories to make the comparison of the issues discussed meaningful. The take home message from the existing literature is that treatment-oriented surgery may be performed in a significant proportion of patients with stage IV gastric cancer.

Rituximab Treatment Prevents Lymphoma Onset in Gastric Cancer Patient-Derived Xenografts

Patient-Derived Xenografts (PDXs), entailing implantation of cancer specimens in immunocompromised mice, are emerging as a valuable translational model that could help validate biologically relevant targets and assist the clinical development of novel therapeutic strategies for gastric cancer. More than 30% of PDXs generated from gastric carcinoma samples developed human B-cell lymphomas instead of gastric cancer. These lymphomas were monoclonal, Epstein Barr Virus (EBV) positive, originated tumorigenic cell cultures and displayed a mutational burden and an expression profile distinct from gastric adenocarcinomas. The ability of grafted samples to develop lymphomas did not correlate with patient outcome, nor with the histotype, the lymphocyte infiltration level, or the EBV status of the original gastric tumor, impeding from foreseeing lymphoma onset. Interestingly, lymphoma development was significantly more frequent when primary rather than metastatic samples were grafted. Notably, the development of such lympho-proliferative disease could be prevented by a short rituximab treatment upon mice implant, without negatively affecting gastric carcinoma engraftment. Due to the high frequency of human lymphoma onset, our data show that a careful histologic analysis is mandatory when generating gastric cancer PDXs. Such care would avoid misleading results that could occur if testing of putative gastric cancer therapies is performed in lymphoma PDXs. We propose rituximab treatment of mice to prevent lymphoma development in PDX models, averting the loss of human-derived samples.

Predictive Factors of Secondary Normocalcemic Hyperparathyroidism after Roux-en-Y Gastric Bypass

Objective Aim of this study is to evaluate determinants of secondary normocalcemic hyperparathyroidism (SNHPT) persistence in patients who have undergone Roux-en-Y gastric bypass on vertical-banded gastroplasty. Methods 226 consecutive patients submitted to bariatric surgery were prospectively enrolled and divided in two groups on the basis of preoperative presence of SNHPT. For each patient, we evaluated anthropometric and laboratory parameters. Calcium metabolism (calcemia, PTH, and 25-hydroxy vitamin D serum levels) was studied before surgery and at 6-month intervals (6, 12, and 18 months) as surgical follow-up. Results Based on presurgical SNHPT presence or absence, we defined group 1—201 patients and group 2—25 patients, respectively. Among the group 1, 153 (76%) recovered from this endocrinopathy within 6 months after surgery (group 3), while the remaining 48 patients (24%) had persistent SNHPT (group 4). Comparing the anthropometric and laboratory data of group 3 with group 2, the only statistically significant factor was the elapsed time since a prior effective medically controlled diet that led to a steady and substantial weight loss. We found also a statistically significant difference (p < 0.05) between group 3 and group 4 in term of % of weight loss and PTH levels. Conclusions Patients suitable for bariatric surgery must have history of at least one efficient medically controlled diet, not dating back more than 5 years before surgery. This elapsed time represent the cut-off time within which it is possible to recover from SNHPT in the first semester after Roux-en-Y gastric bypass on vertical-banded gastroplasty. The treatment of vitamin D insufficiency and the evaluation of SNHPT before bariatric surgery should be recommended. The clinical significance of preoperative SNHPT and in particular SNHPT after bariatric surgery remains undefined and further studies are required.

Recurrence in node-negative advanced gastric cancer: Novel findings from an in-depth pathological analysis of prognostic factors from a multicentric series

AIM To analyze the clinicopathological characteristics of patients with both node-negative gastric carcinoma and diagnosis of recurrence during follow-up. METHODS We enrolled 41 patients treated with curative gastrectomy for pT2-4aN0 gastric carcinoma between 1992 and 2010, who developed recurrence (Group 1). We retrospectively selected this group from the prospectively collected database of 4 centers belonging to the Italian Research Group for Gastric Cancer, and compared them with 437 pT2-4aN0 patients without recurrence (Group 2). We analyzed lymphatic embolization, microvascular infiltration, perineural infiltration, and immunohistochemical determination of p53, Ki67, and HER2 in Group 1 and in a subgroup of Group 2 (Group 2bis) of 41 cases matched with Group 1 according to demographic and pathological characteristics. RESULTS T4a stage and diffuse histotype were associated with recurrence in the group of pN0 patients. In-depth pathological analysis of two homogenous groups of pN0 patients, with and without recurrence during long-term follow-up (groups 1 and 2bis), revealed two striking patterns: lymphatic embolization and perineural infiltration (two parameters that pathologists can easily report), and p53 and Ki67, represent significant factors for recurrence. CONCLUSION The reported pathological features should be considered predictive factors for recurrence and could be useful to stratify node-negative gastric cancer patients for adjuvant treatment and tailored follow-up.