Ferdinando Carlo Maria Cananzi

cDNA-Microarray Analysis as a New Tool to Predict Lymph Node Metastasis in Gastric Cancer

BackgroundThe aim of the present study was to investigate whether microarray gene expression analysis can be used to predict lymph node status in gastric cancer.MethodsTwenty-nine patients undergoing gastrectomy for cancer were enrolled and subdivided according to the pathologic nodal involvement of their disease (N+ vs N0). Molecular profiling was performed by cDNA microarray on tumor tissue and healthy mucosa. Data were processed to identify differently expressed genes. Selected genes were categorized with gene ontology.ResultsCompared to healthy gastric mucosa, 52 genes were differently expressed in N+ patients, and 50 genes in N0 patients. Forty-five genes were similarly regulated in N+ and N0 patients, whereas 12 genes were differently expressed between N+ and N0 patients. Seven genes were exclusively expressed in N+ patients: Egr-1 was upregulated; Claudin-18, AKR1C2, Cathepsin E, CA II, TFF 1, and progastricsin were downregulated. Five genes were exclusively expressed in N0 patients: Complement C5 receptor 1, PLA2/VII, and MMP- 9 were upregulated; MAO-A and ID-4 were downregulated.ConclusionsMicroarray analysis could be a valuable tool to identify genes associated with lymph node metastasis in gastric cancer. This technique could improve the selection of patients with locally advanced disease who are candidates for extended lymph node dissection, multimodal treatment options, or alternative therapeutic strategies.

Role of surgery in the multimodal treatment of primary and recurrent leiomyosarcoma of the inferior vena cava.

The optimal treatment of leiomyosarcoma (LMS) of the inferior vena cava (IVC) is still unclear, especially in the metastatic and/or recurrent setting. We herein evaluated the long‐term outcome after aggressive management.

Preoperative chemotherapy in gastric cancer: expanding the indications, limiting the overuse

The three main European Oncologic Societies (ESMO, ESSO, ESTRO) have recently published the joint Guidelines for the Management of Gastric Cancer (GC) [1] that should drive daily clinical practice in a region where GC is the sixth commonest cancer diagnosis and the fourth commonest cause of cancer-related death [2]. The Guidelines properly emphasize the role of multidisciplinary treatment. In particular, preoperative chemotherapy (PCHT) has been advocated as the preferred pathway for operable disease with stage[T1N0 [1]. This statement has been made on the basis of the results of the pivotal MAGIC and FFCD trials [3, 4]. Considering that early stages at the presentation are relatively uncommon in Western countries, the current Guidelines have theoretically expanded the application of PCHT to the majority of newly diagnosed GC. However, such an extended application of PCHT may give rise to some issues, in particular in patient selection. The efficacy of PCHT could depend on some tumour features affecting the grade of response. Tumour site, grading, and Lauren’s histotype have been proposed as pre-therapeutic factors associated with response in a retrospective study including 410 patients [5], and signet-ring cell carcinoma has been reported to be less responsive to PCHT [6]. A phase II/III trial comparing surgery versus chemotherapy plus surgery in patients with a signet-ring cell GC is currently ongoing (NCT01717924) and will be probably yield clarification on this question. These findings confirm the importance of identifying reliable criteria in order to properly select patients for PCHT. Another point as regards post-operative morbidity after PCHT is that several studies have proven that gastrectomy after PCHT is safe in terms of complications [3, 4], and a recent meta-analysis showed no differences in post-operative morbidity and mortality rates between patients who did receive and who did not receive PCHT [7]. On the other hand, a recent Korean study including 123 patients who underwent PCHT followed by D2-gastrectomy reported a higher than expected rate of post-operative complications of 29.3 % [8]. Similarly, the EORTC phase III trial, prematurely closed due to low patient accrual, reported a higher rate of post-operative complications in the PCHT arm than in the control arm (27.1 vs. 16.2 %), although the difference was not statistically significant [9]. Importantly, in both studies D2 resection rate was more than 90 %, with a median number of harvested lymph nodes higher than 31. Conversely, in the MAGIC trial, a D2 resection was performed in about 40 % of patients, and in the FFCD trial the median number of retrieved nodes was 19 [3, 4]. These data may suggest that PCHT may increase surgical morbidity in patients treated with an extended surgical approach such as a D2-lymphadenectomy. Adequate surgery still remains the cornerstone in the treatment of operable GC, and D2-gastrectomy has been recently accepted as the standard surgical treatment also in the Western countries, especially in specialised centres [1]. In the MAGIC and FFCD trials, patients were frequently treated with \D2-lymphadenectomy, whereas a D2F. C. M. Cananzi (&) L. Cozzaglio V. Quagliuolo Surgical Oncology Unit, Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano, MI, Italy e-mail: fcm.cananzi@hotmail.it

Large bowel auto-amputation and passage of a colon 'cast' after left hemicolectomy

The anal passage of a cast of the large bowel caused by ischemic injury has been reported only rarely in literature. We encountered this unusual complication after left hemicolectomy. On March 9, 2007 a previously healthy 52-year-old man was referred to surgical consult for treatment of adenocarcinoma of the sigmoid colon. The patient underwent left hemicolectomy, and pathologic staging was invasive adenocarcinoma of the sigmoid colon (UICC V, edition 2002 pT1, pN0). During surgery, high ligation of the inferior mesenteric artery (IMA) was performed. The splenic flexure was mobilized; end-toend, tension-free colorectal anastomosis was performed using a circular stapler, and both ends of bowel appeared well perfused. The anastomosis was airtight, and both doughnuts were complete. There was no recognized trauma to the colon or mesocolon, the colon appeared pink and viable at closure, blood loss totaled 400 ml, and no intraoperative hypotension or cardiac dysrhythmia occurred. A silicon drain tube through a separate skin incision was inserted near the anastomosis. During the first postoperative night, he developed fever, which resolved the day after. Intravenous antibiotic therapy (third-generation cephalosporin and metronidazole) was continued for 48 h. On day 5, bowel function returned, surgical drain tube was removed, and the patient was discharged on postoperative day 7 (March 16, 2007). On postoperative day 38 (April 16, 2007), the patient was referred to a surgical ambulatory consult because in the previous day, he had developed fever and he had passed per anum a 15-cm tubular-shaped membrane. He had not taken any medication. Laboratory data revealed a white blood cell count of 6.8×10/μl (normal, 4.1–9.8×10/μl) with 60% neutrophils (40–74%) and a hematocrit of 34% (37–47%). The remainder of the laboratory tests, including serum albumin, liver, and pancreatic enzymes, electrolytes were within normal limits. Chest X-ray and a 12-leads electrocardiogram were normal. On physical examination, there was no guarding or rebound tenderness. His bowel sounds appeared normal. Digital rectal exploration was unremarkable. Histopathology confirmed the specimen to be a 15-cm necrotic segment of colon with infarcted mucosa, submucosa, and muscularis propria. Despite this, the patient described only occasional bloating and diarrhea and maintained a twice-daily bowel habit and successfully tolerated fluids and food within the following 2 weeks. Because of relapsing fever, the patient was hospitalized on May 2, and a computed tomography scan of the abdomen was performed which demonstrated no intraperitoneal air, free fluid, or abscess. Stool cultures showed no abnormal growth, and clostridium difficile toxin was not detected. A water-soluble contrast study enema showed a near total obstruction of the colorectal anastomosis. Int J Colorectal Dis (2008) 23:551–552 DOI 10.1007/s00384-007-0394-8

Complications after gastrectomy for cancer: Italian perspective

Surgery for gastric cancer is associated with significant major morbidity and an estimated mortality rate of about 5%. A reliable comparison of post-operative outcomes is hampered by the lack of a clear, universally recognized, definition of the most frequent complications. This paper reports the final results of a project launched by the Italian Research Group for Gastric Cancer in September 2015, whose goal was to propose a comprehensive list of surgical-related, gastric cancer-specific complications, with their definitions. The project was carried out through a multicentric, mainly web-based, consensus of experts. The proposed list, following assessment and validation by a group of experts of the European Chapter of the International Gastric Cancer Association, will form the basis for implementing a “Complications Recording Sheet” that can be disseminated worldwide for proper and reliable post-operative assessment.

Chemoradiotherapy in Gastric Cancer: A Door Ajar

TO THE EDITOR: The ARTIST (Adjuvant Chemoradiotherapy in Stomach Tumors) trial was designed to overcome one of the main limitations of the landmark Intergroup 0116 trial in which 90% of patients had suboptimal surgery (D0 or D1 lymphadenectomy) before receive adjuvant chemoradiation therapy (CRT). The real advantage of postoperative CRT in curatively D2 resected gastric cancer remained unknown, considering the hypothesis that D2 resection alone may be sufficient to locoregional disease control. Indeed, the first results of the Korean trial demonstrated that the addition of CRT did not significantly reduce recurrence after curative D2 gastrectomy. The final report of the ARTIST trial, published after a median follow-up of 7 years, has drawn the same conclusions as the first report, showing still no benefit in adding radiotherapy in the adjuvant setting. Nevertheless, some important issues have been raised from this updated report deserving further consideration. The early results of the trial showed that postoperative radiotherapy adds no benefit to D2 resection in term of locoregional recurrence or distant metastases between the two treatment arms. On the contrary, the updated results showed a significantly different pattern of recurrence, suggesting that adjuvant radiotherapy may reduce the rate of local recurrence even after D2 lymphadenectomy. This extremely important result seems to overturn the conclusion of the early report of the ARTIST trial, potentially providing a strong rationale for the administration of adjuvant CRT. In addition, this local effect might justify the overall result of the trial based on a population with a high rate of diffuse-type (with higher incidence of distant recurrence) and early-stage cancer (with lower overall recurrence rate). However, it remains unclear whether this result may depend on a real biological effect of CRT or not. After the subgroups analysis, Park et al stated that adjuvant radiotherapy may be of benefit in patients with node-positive disease and a high lymph node ratio (ie, the ratio between the number of metastatic and harvested lymph nodes). As properly highlighted by Park et al, this statement may be affected by the high number of N0/N1 patients (about 70%) included in the trial. Moreover, the depth of tumor infiltration (T stage) may strongly influence the survival of patients, but, unfortunately, the prognostic value of Tand its interactions with nodal status and administration of adjuvant CRT remain unknown, because no ad hoc analyses were performed in the study. Also, a high lymph node ratio value may depend on a high number of metastatic nodes or a low number of harvested nodes. Then, it would be of some interest to better define the patients with high lymph node ratio who received adjuvant RT, also considering the misleading categorization specified in the trial methods. Park and colleagues used a two-tier classification based on the mean value of the node ratio (, 0.083 v

Gastrointestinal: Videocapsule retention: rationale for surgical indication

0.083), including the N0 patients into a heterogeneous low-ratio group also encompassing patients with nodal metastases. A patient without nodal involvement (N0) will always have a node ratio zero regardless of the total number of removed/examined lymph nodes (ranging from 12 to 142 in the trial). This represents one of the main limitations of the ratio-based system, especially because several studies have demonstrated that the total number of retrieved nodes significantly affects the survival of patients with gastric cancer, even in N0 patients. It has been reported that the total lymph node count mainly depends on the extent of surgery but also depends on the anatomic variations and immune status of each patient and the technique of the pathologist in analyzing the surgical specimen. Also, the administration of preoperative treatment, commonly used in European Countries, has been advocated as a potential factor capable of significantly influencing the nodal harvesting in some cancer. On this basis, the administration of adjuvant CRT could be driven not solely by the N stage and the Japanese Gastric Cancer Association lymphadenectomy (less than v D2 or greater) but also by the actual number of removed and/or examined lymph nodes. Further data on the interactions between total nodal count and adjuvant CRT, also including patients with no nodal involvement and with high depth of tumor infiltration, are needed. Last, but not least, the results of the Korean trial may be not easily reproducible inWestern countries because of the well-known differences between tumor epidemiology (advanced stage at presentation, more proximal tumor location), treatment policies, and treatment outcomes. In conclusion, the final report of the ARTIST trial, leaving the door still ajar on adjuvant CRT in gastric cancer, opens the way for the future investigations about reliable patient and tumor-related criteria for appropriate patient selection and tailored treatments.

Limited lymph node dissection and metastatic lymph node ratio: a wave of trust

Small bowel resection containing the capsule with primary anastomosis was performed (Figure 2). The postoperative course was uneventful. Histopathologic evaluation of the resected bowel diagnosed a pT3N0M0 small bowel intestinal type adenocarcinoma. The term capsule retention is defined by a capsule remaining in the digestive tract for at least 14 days. The frequency of this complication depends mostly on the clinical indication for the capsule enteroscopy, and varies from less than 1% in patients with obscure gastrointestinal bleeding to 13% in Crohn’s disease. Most often capsule retention remains asymptomatic but acute small bowel obstruction and perforation may occur. Capsule retention has been described to occur with strictures due to non-steroidal anti-inflammatory drugs (NSAID), Crohn’s disease, small bowel tumors, radiation enteritis, and post-surgical anastomotic strictures. Retention may result in surgery in patients in whom medical treatment for Crohn’s disease or NSAID enteropathy would have sufficed. Therefore, in patients with known Crohn’s disease and/or inappropriate NSAID use, a “wait and see” policy may avoid unnecessary abdominal surgery. If a history of inflammatory bowel disease can be excluded, then capsule retention should be considered a clear-cut surgical indication. Contributed by

Prognostic Indicators in Stage IV Surgically Treated Gastric Cancer Patients: A Retrospective Multi-Institutional Study

To the Editor Metastatic lymph node ratio has been closely investigated in recent years because of its simplicity, reproducibility, and potential advantage of reducing the ‘‘stage migration’’ phenomenon in gastric cancer staging. Several authors, along with our experience, identified the lymph node ratio classification as an independent prognostic factor stronger than AJCC/UICC and JGCA classifications [1]. Moreover, this classification might be usefully implemented in any clinical practice, not being influenced by differences in the routine extension of lymph node dissection [2]. Pedrazzani et al. [3] report a retrospective series of a 526 patients with gastric cancer who underwent limited lymph node dissection and had a small (\15) number of analyzed nodes. In this series, they investigated the prognostic significance of lymph node ratio with cutoff values as follows: N ratio 0 (pNR0), 0%; N ratio 1 (pNR1), 1–25%; and N ratio 2 (pNR2), 25%. In their analysis no significant differences in survival were observed between pN1 and pN2 subsets. When the N ratio (1–25% vs. 25%) was taken into account, a significant difference was demonstrated between pNR1 and pNR2 with respect to survival (p = 0.017) and risk of death (p = 0.012). These results notwithstanding, the authors claimed a poor clinical utility of metastatic lymph node ratio because of poor allocation of patients in pNR1 category. Some features of data interpretation of this study warrant further assessment. First, the allocation of patients in pNR1 was poor as well as the allocation in pN2. At the same time, pNR classification significantly stratified patient outcome, whereas pN did not. I wonder why these results could not be considered of clinical utility. Should we need another more powerful prognostic factor? Second, the authors stated that the in pN1 category and in patients with one to three metastatic nodes, metastatic lymph node ratio can discriminate a subset of patients with better prognosis. In our opinion these results are in agreement with the changes proposed by the new seventh edition of AJCC/UICC [4] staging rules, whereas the old pN1 category will be subdivided in pN1 (1–2 metastatic lymph nodes) and pN2 (3–6 metastatic lymph nodes). By other means, in this study, the metastatic lymph node ratio was able to discriminate these patients. Third, the goal of cancer staging is to aid the clinician in planning treatment, to give some indication of prognosis, and to assist in evaluating the results of treatment. UICC/AJCC staging rules certainly represent the best system to estimate cancer prognosis but unfortunately are still affected by both surgical treatment and pathologic assessment; these ‘‘human’’ variables will always have strong impact on staging until they are universally standardized. In gastric cancer the appropriate extent of lymph node dissection continues to be debated and pathologic evaluation of gastric specimens constitutes a source of significant bias [5]. Considering these unsolved issues, in our opinion, metastatic lymph node ratio provides a meaningful prognostic factor when an official staging system cannot be applied and minimum data are lacking. A. Biondi (&) R. Persiani F. Cananzi M. Zoccali A. Tufo D. D’Ugo 1st General Surgery Unit, Department of Surgery, Catholic University, Largo A. Gemelli 8, 00168 Rome, Italy e-mail: biondi.alberto@tiscali.it

Sporadic desmoid tumors of the abdominal wall: the results of surgery

Introduction: The role of gastric resection in treating metastatic gastric adenocarcinoma is controversial. In the present study, we reviewed the short- and long-term outcomes of stage IV patients undergoing surgery. Methods: A retrospective review was conducted that assessed patients undergoing elective surgery for incurable gastric carcinoma. Short- and long-term results were evaluated. Results: A total of 122 stage IV gastric cancer patients were assessed. Postoperative mortality was 5.7%, and the overall rate of complications was 35.2%. The overall survival rate at 1 and 3 years was 58 and 19% respectively; the median survival was 14 months. Improved survival was observed for the factors age less than 60 years (p = 0.015), site of metastases (p = 0.022), extended lymph node dissection (p = 0.044), absence of residual disease after surgery (p = 0.001), and administration of adjuvant chemotherapy (p = 0.016). Multivariate analysis showed that residual disease and adjuvant chemotherapy were independent prognostic factors. Conclusions: The results of this study suggest that surgery combined with systemic chemotherapy in selected patients with stage IV gastric cancer can improve survival.