Roberto Coppola

Cetuximab and irinotecan as third-line therapy in advanced colorectal cancer patients: a single centre phase II trial

The epidermal growth factor receptor (EGFR), which participates in signalling pathways that are deregulated in cancer cells, is frequently mutated in colorectal-cancer cells. Cetuximab is a monoclonal antibody that specifically blocks the EGFR. We evaluated the efficacy of cetuximab in weekly combination with irinotecan in metastatic colorectal cancer patients refractory to previous treatments based on oxaliplatin or irinotecan. We included 55 heavily pretreated patients (colon/rectum: 34/11, M/F: 16/29, median age 63 years, range: 27–79) whose disease had progressed during or within an oxaliplatin-based first-line chemotherapy and a irinotecan-based second-line regimen. Patients were followed for tumour response and were also evaluated for the time to tumour progression, and safety of treatment. Cetuximab was given at an initial dose of 400 mg m−2, followed by weekly infusions of 250 mg m−2. Irinotecan was administered weekly at the dose of 90 mg m−2. All patients were assessable for treatment efficacy and safety response rate was 25.4% (95% CI: 21.7–39.6%); 38.2% (95 CI: 18.6–39.8%) of patients showed a disease stability as the best response. As a consequence, the overall tumour control rate was 63.6% (95% CI: 46.4–70.6%). The median time to progression was 4.7 months (95% CI: 2.5–7.1 months) and the median survival time was 9.8 months (95% CI: 3.9–10.1 months). The most common G3-4 noncutaneous side toxicities were: diarrhoea (16.4%), fatigue (12.7%) and stomatitis (7.3%). 89.1% of patients developed skin toxicity and 32.6% of cases was of grade 3–4. No allergic reactions were identified at any courses in any patients. Fever was documented in 27.3% of patients and was most commonly recorded after the first administration. Cetuximab has clinically significant activity even in heavily pretreated colorectal cancer patients progressed after both oxaliplatin and irinotecan-based chemotherapy regimens.

Fever After Zoledronic Acid Administration Is Due to Increase in TNF-α and IL-6

The most common adverse event typically associated with bisphosphonate therapy is transient fever. The aim of this study was to define the role of the main cytokines of the acute-phase reaction interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) involved in the pathogenesis of zoledronic acid-induced fever. Eighteen consecutive cancer patients with bone metastases were treated, for the first time, with a single dose of 4 mg zoledronic acid infusion. They were prospectively evaluated for circulating TNF-α, interferon-γ (IFN-γ), and IL-6 levels at different times, just before and 1, 2, 7, and 21 days after diphosphonate infusion. Clinical and standard laboratory parameters were recorded at the same time points. TNF-α circulating levels increased significantly 1 and 2 days after zoledronic acid infusion (respectively, p = 0.002 and p < 0.001) and then decreased to levels similar to the basal levels. IL-6 levels increased significantly 1 day after the infusion (p = 0.007), returning to values similar to ...

Prognostic factors after surgical resection for pancreatic carcinoma.

Surgical resection offers the only potential cure for pancreatic carcinoma. Several recent series have reported an encouraging increase in 5‐year survival rate exceeding 20% and have emphasized the importance of patient selection based on reproducible prognostic factors. The impact on survival of demographic, intraoperative, and histopatologic factors are investigated in this study.

Soluble Ig-Like Transcript 3 Inhibits Tumor Allograft Rejection in Humanized SCID Mice and T Cell Responses in Cancer Patients

Attempts to enhance patients’ immune responses to malignancies have been largely unsuccessful. We now describe an immune-escape mechanism mediated by the inhibitory receptor Ig-like transcript 3 (ILT3) that may be responsible for such failures. Using a humanized SCID mouse model, we demonstrate that soluble and membrane ILT3 induce CD8+ T suppressor cells and prevent rejection of allogeneic tumor transplants. Furthermore, we found that patients with melanoma, and carcinomas of the colon, rectum, and pancreas produce the soluble ILT3 protein, which induces the differentiation of CD8+ T suppressor cells and impairs T cell responses in MLC. These responses are restored by anti-ILT3 mAb or by depletion of soluble ILT3 from the serum. Immunohistochemical staining of biopsies from the tumors and metastatic lymph nodes suggests that CD68+ tumor-associated macrophages represent the major source of soluble ILT3. Alternative splicing, resulting in the loss of the ILT3 transmembrane domain, may contribute to the release of ILT3 in the circulation. These data suggest that ILT3 depletion or blockade is crucial to the success of immunotherapy in cancer. In contrast, the inhibitory activity of soluble ILT3 on T cell alloreactivity in vitro and in vivo suggests the potential usefulness of rILT3 for immunosuppressive treatment of allograft recipients or patients with autoimmune diseases.

EUS-guided Nd:YAG laser ablation of normal pancreatic tissue: a pilot study in a pig model.

BACKGROUND Laser ablation with a neodymium:yttrium aluminum garnet (Nd:YAG) laser can achieve a high rate of complete tissue necrosis and has been applied as a minimally invasive, palliative option in hepatocellular carcinoma, liver metastasis in colorectal cancer, and malignant thyroid nodules. OBJECTIVE To assess the in vivo feasibility of EUS-guided laser ablation with an Nd:YAG laser of normal pancreatic tissue of a porcine model. DESIGN Prospective investigation. SETTING Hospital animal laboratory. SUBJECTS Eight pigs. INTERVENTIONS EUS-guided puncture of the pancreatic tail with a laser-beam fiber. An Nd:YAG laser (1.064 nm) was used, with an output power of 2 and 3 W and a total delivered energy of 500 and 1000 J in continuous mode. MAIN OUTCOME MEASUREMENTS The 24-hour follow-up of the pigs was focused on clinical and laboratory aspects. Results of histological studies of the pancreas were obtained 24 hours after the procedure on necroscopy tissue. RESULTS There were no technical limitations to the performance of the procedure. Tissue necrosis, localized in the pancreatic parenchyma, was observed in all animals on histological examination. The volume of ablation tissue ranged from a mean of 314 mm(3) to 483 mm(3). The ablation area ranged from a mean of 49 mm(2) to 80 mm(2). No major postprocedure complications were recorded, and all the pigs survived at 24 hours. LIMITATION Animal study. CONCLUSIONS EUS-guided laser ablation of the pancreas with an Nd:YAG laser is feasible in a porcine model.

Choledochocele : Changing Trends in Diagnosis and Management

Eighty-four patients with choledochocele collected from the world literature and one personal observation are reviewed. The main issues regarding clinical presentation, diagnostic work-up, and the treatment of this uncommon lesion are discussed. Abdominal pain was the most common clinical feature (91% of cases), followed by pancreatitis (38%), nausea or vomiting (35%), and jaundice (26%). In addition, associated lithiasis was found in 43% of the cases. Endoscopic retrograde cholangiopancreatography was the most useful diagnostic procedure and resulted in a correct diagnosis in all but one of the patients investigated by this method. Surgical excision of the duodenal luminal portion of the choledochocele was the treatment most commonly used (65% of cases). In recent years, operative endoscopy has also been increasingly used, with good results.

Apoptotic index or a combination of Bax/Bcl‐2 expression correlate with survival after resection of pancreatic adenocarcinoma

In the present study, the prognostic impact of factors involved in the apoptosis pathway were tested on 67 consecutive patients treated with surgical resection. Included in the study were all patients resected for pancreatic adenocarcinoma from 1988 to 2003. Expression analysis for p53, Bax, and Bcl‐2 were performed by immunohistochemical staining. Apoptotic cells were identified by the TUNEL method. These data were correlated with survival. Sixty‐seven tumor specimens were included in the study. A strong positive correlation was recorded between p53 overexpression and Bax expression levels (P < 0.001). By univariate analysis, overall survival seemed to be improved with Bcl‐2 and Bax expression (respectively, P = 0.0379 and 0.0311). The median survival time in patients with low apoptotic index was better versus those with a high index (P = 0.0127). Lymph node involvement was the only clinico‐pathologic parameter that significantly correlated with overall survival (P = 0.0202). By a multivariate Cox regression analysis, the only immunohistochemical parameter that influenced overall survival was the apoptotic index (P = 0.040). Tumors overexpression of both Bax and Bcl‐2 resulted the strongest independent prognostic factor (P = 0.013). This is the first study to report a statistically significant association of apoptosis to overall survival for pancreatic cancer patients treated with surgical resection. The contemporary overexpression of Bax and Bcl‐2 represents the strongest prognostic factor. J. Cell. Biochem.

Value of ERCP in the diagnosis and management of pre-and postoperative biliary complications in hydatid disease of the liver

Twenty-nine patients with symptomatic hydatid disease of the liver were evaluated preoperatively by endoscopic retrograde cholangiopancreatography (ERCP) in the years 1982–1987. In the same period, 6 patients who previously underwent surgery for the parasitic disease also underwent ERCP because of postoperative symptoms of biliary obstruction.Findings at ERCP excluded biliary tract involvement in 11 cases. Positive findings were shown in 24 patients, including compression of the bile ducts in 4, small cysto-biliary communications in 5, intrabiliary rupture in 9, residual hydatid material in the common bile duct, and sclerosing cholangitis in 3.Endoscopic removal of migrated hydatid debris was achieved in 8 patients, avoiding reoperation in 4.

Carcinoma of the ampulla of Vater: morphological and immunophenotypical classification predicts overall survival.

Objectives The objective of the study was to verify if histopathological differentiation of ampullary carcinoma after surgical resection may be related to survival. Methods The prognostic role of an accurate histological and immunohistochemical classification has been investigated in a multicentric series of carcinoma of the ampulla of Vater. Immunohistochemical expression of cytokeratin 7 (CK7) and CK20 were analyzed in the different morphological histotypes of ampullary cancers, and results were compared with overall survival. Results Of 72 ampullary cancers, 48.6% were classified as pancreaticobiliary-type carcinomas, 43.1% were classified as intestinal-type carcinomas, and 8.3% were classified as “unusual”-type carcinomas. Cytokeratin 20 was expressed in 28 (90.3%) of the 31 intestinal-type carcinomas, whereas it was always negative in the pancreaticobiliary histotype; CK7 was expressed in 32 (91.4%) of the 35 pancreaticobiliary-type carcinomas and in 18 (58.1%) of the 31 intestinal-type carcinomas. By univariate analysis, overall survival was influenced significantly by pathological T factor, lymph node involvement, and histological/immunohistochemical subtyping. Furthermore, using a multivariate Cox regression model, lymph node metastasis and CK20 were identified as significant independent factors related to prognosis. Conclusion Our results prove the clinical use of ampullary cancer subclassification based on different histotypes and indicate the useful role of the CK7/CK20 expression profile for consistent histopathological classification and prognostic relevance.

Pelvic and perineal reconstruction following abdominoperineal resection: the role of gracilis flap.

Pelvic and perineal cancer can arise from different structures: genitourinary system, bowel, or skin. The optimal approach to these patients, to ameliorate their immediate and long-term prognosis, implies a multidisciplinary team of specialists, such as oncologic surgeons, plastic surgeons, oncologists, and radiotherapists, working together to tailor an individualized treatment planning for each patient. Nowadays, sphincter-preserving operations are the treatment of choice for rectal cancer in the majority of patients, and seldom an abdominoperineal resection (APR) is necessary, mainly because of early diagnosis and the widespread use of neoadjuvant treatments. Conversely, APR is mandatory when cancer sphincter involvement is demonstrated either from rectal or anal cancer or in case of recurrent rectal carcinoma with sphincteral muscle invasion. APR was first performed by Miles in 1908; it consists of resection of the rectum and of the anal canal, incorporating a variable tract of sigmoid colon and en bloc removal of perianal skin. Radiation therapy, often delivered in the neoadjuvant setting to reduce tumor bulk to achieve safer margins, causes important and irreversible alterations to irradiated tissues. These procedures lead to wide loss of substance, with surgical scars and postactinic sclerosis. Following oncologic surgery, reconstruction is accomplished either through direct closure, or, if this is not feasible, by means of advance, rotation, transposition, or free flaps. In our experience, gracilis flap (GF) is the first choice for pelvic-perineal reconstruction. It was one of the first flaps used in perineal reconstruction, described by Bartholdson and Hulten in 1975, even though in 1972, Orticochea had already used the musculocutaneous version of this flap for penile reconstruction. In 1976, McCraw et al used it as a musculocutaneous flap for vaginal reconstruction. Its localization in the vicinity of the defect and easy elevation account for its common use. No functional impairment follows as other adductor muscles of the thigh supersede its function. Moreover, the gracilis donor site is commonly outside the field of irradiation and thus provides healthy tissues for reconstruction. Gracilis muscle can be used to perform unilateral or bilateral, muscular, or musculocutaneous flap reconstruction. The aim of the present study is to compare retrospectively the outcomes of 2 homogeneous groups of patients with rectal carcinomas, undergoing APR, in whom the perineal wound was closed either directly or with a GF.