Docetaxel, cisplatin and 5-fluorouracil-based induction chemotherapy followed by intensity-modulated radiotherapy concurrent with cisplatin in locally advanced EBV-related nasopharyngeal cancer.

BACKGROUND: This monocentric study evaluates the activity and tolerability of docetaxel (Taxotere), cisplatin and 5-fluorouracil (5-FU) (TPF) induction chemotherapy followed by intensity-modulated radiotherapy (IMRT) concurrent with high-dose cisplatin in Epstein-Barr virus -related locally advanced undifferentiated nasopharyngeal cancer. PATIENTS AND METHODS: We retrospectively reviewed the records of patients who received induction docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) on day 1, and 5-FU 750 mg/m(2)/day (96-h continuous infusion). Following induction, patients received full doses of IMRT concurrently with cisplatin 100 mg/m(2) every 21 days for three cycles. RESULTS: Thirty patients received three TPF cycles (median). Induction was well tolerated; the main toxicity was neutropenia (33%, grade 3-4). During chemoradiotherapy, neutropenia (40%) and mucositis (43%) were the most frequent grade 3-4 adverse events. Mean dose of IMRT was 68.8 Gy. Worst late toxicity was xerostomia. Complete response rate was 93%. At 35 months, two patients had locoregional recurrence, three had distant metastases, and one had both. Three-year progression-free survival and overall survival were 79% [95% confidence interval (CI) 64% to 94%] and 87% (95% CI 74%- to 100%), respectively. CONCLUSIONS: In this high-stage nonendemic cancer population, TPF followed by high-dose cisplatin IMRT was promising; this treatment approach deserves evaluation in randomized trials.

Pancreata from pediatric donors restore insulin independence in adult insulin-dependent diabetes mellitus recipients.

CONTEXT: The use of pediatric donors can increase the number of donors available for pancreas transplantation. AIM: The aim of this study was to verify if pancreas transplantation from pediatric donors is as effective as transplantation from adult donors to restore metabolic control in type 1 diabetic patients. MATERIALS AND METHODS: From 2000 to April 2009 we performed 17 pancreas transplantations from pediatric donors: 9 simultaneous kidney-pancreas (SPK), 6 pancreas transplantation alone (PTA), and 2 pancreas after kidney (PAK). All subjects received whole organs with enteric diversion of exocrine secretions; 11 underwent systemic and 6 underwent portal venous graft drainage. The immunosuppressive therapy was as follows: prednisone, mycophenolate mofetil, anti-thymocyte globulin (ATG), and cyclosporine or tacrolimus. The pediatric donor population had a mean age of 15.3 years (range, 12-17), a mean weight of 60.1 kg (range, 42-75), and a mean body mass index (BMI) of 21 (range, 17.9-23.4). RESULTS: After 9 years the overall patient survival rate was 94.12%, whereas the graft survival rate was 63.35%. Normal glucose and insulin levels were maintained either fasting or during oral glucose tolerance test (OGTT). The group of recipients of pediatric organs was compared with patients receiving organs from adult donors (n = 125); the mean glucose values were lower in the pediatric group, whereas insulin production was higher in the adult patients. Early venous thrombosis was 17.6% in the pediatric group and 20% in adult recipients (Fisher exact test, P = not significant [NS]). CONCLUSION: Pediatric donors restored insulin independence in adult diabetic recipients, representing a valid source of organs for pancreas transplantation.

CD20-related signaling pathway is differently activated in normal and dystrophic circulating CD133(+) stem cells.

Among the heterogeneous population of circulating hematopoietic and endothelial progenitors, we identified a subpopulation of CD133(+) cells displaying myogenic properties. Unexpectedly, we observed the expression of the B-cell marker CD20 in blood-derived CD133(+) stem cells. The CD20 antigen plays a role in the modulation of intracellular calcium homeostasis through signaling pathways activation. Several observations suggest that an increase in intracellular calcium concentration ([Ca(2+)](i)) could be involved in the etiology of the Duchenne muscular dystrophy (DMD). Here, we show that a CD20-related signaling pathway able to induce an increase in [Ca(2+)](i) is differently activated after brain derived neurotrophic factor (BDNF) stimulation of normal and dystrophic blood-derived CD133(+) stem cells, supporting the assumption of a "CD20-related calcium impairment" affecting dystrophic cells. Presented findings represent the starting point toward the expansion of knowledge on pathways involved in the pathology of DMD and in the behavior of dystrophic blood-derived CD133(+) stem cells.

A spiritual approach in the treatment of cancer: relation between faith score and response to chemotherapy in advanced non-small cell lung cancer patients.

BACKGROUND: The recent advances in the psychooncological and psychoneuroimmunological investigations of cancer patients has allowed the rediscovery of the importance of spiritual faith in influencing the clinical course of neoplastic disease, not only in terms of supportive care but also as a potential prognostic variable. MATERIALS AND METHODS: Clinical criteria were worked out to explore the existence of a real status of faith, in an attempt to correlate the degree of faith with the clinical response to chemotherapy, consisting of cisplatin plus gemcitabine, and the overall survival time in a group of 50 metastatic nonsmall cell lung cancer patients. RESULTS: The tumor response rate achieved in patients with a high degree of faith was significantly higher than in the other group of patients. Moreover, the mean postchemotherapeutic lymphocyte number was significantly higher in the patients with evident spiritual faith than in the other patients. Finally, the percent age of 3-year survival observed in the patients with a high degree of faith was significantly higher than that in the patients with a low faith score. CONCLUSION: This preliminary study suggests that spiritual faith may positively influence the efficacy of chemotherapy and the clinical course of neoplastic disease, at least in lung cancer, by improving the lymphocyte-mediated anticancer immune response.

T-helper/T-regulator lymphocyte ratio as a new immunobiological index to quantify the anticancer immune status in cancer patients.

BACKGROUND: The evaluation of the immune status of cancer patients is not routinely included in clinical oncological practice mainly because of the great number of candidate immune parameters that could potentially be the best index of the status of anticancer immunity. Until recently, the T-helper/T-suppressor lymphocyte ratio (CD4/CD8) was considered to be an index of immunosuppression in cancer patients. Successive studies documented the existence of several subtypes of CD4+ lymphocytes, as well as showing that CD8+ cells were not in fact suppressive, but cytotoxic lymphocytes. More recently, the existence of a subtype of T-helper lymphocytes has been demonstrated provided by an evident suppressive activity on anticancer immunity. These are the so-called T-regulator (T-reg) lymphocytes, which may be detected as CD4+CD25+ cells. MATERIALS AND METHODS: A study was carried out to evaluate CD4+/CD4+CD25+ ratio, corresponding to the T-helper/T-reg cell ratio (TH/TR), in a group of 50 cancer patients in relation to their disease extension and in 20 healthy controls. RESULTS: The mean TH/TR ratio observed in patients with metasytases was significantly lower with respect to that found in both patients without metastases and controls. On the contrary, the absolute mean number of T-reg cells was higher in patients with metastases than in those without, but the difference was not statistically significant. CONCLUSION: The evaluation of T-reg cells in terms of their proportion with respect to T-helper cell total number seems to be more appropriate than the simple measurement of their absolute count, in order to quantify cancer-related immunosuppression. Thus, the TH/TR ratio could represent a useful biological marker to explore the immune status of cancer patients.

Free-from-progression period and overall short preoperative immunotherapy with IL-2 increases the survival of pancreatic cancer patients treated with macroscopically radical surgery.

BACKGROUND: The treatment of pancreatic cancer is still rudimentary, even in the case of locally limited tumors, because of the high frequency of recurrence due to severe suppression of the anticancer immunity that is further amplified by surgery-induced immunosuppression, evidenced by a decline in lymphocyte numbers during the postoperative period. Previous studies in colorectal cancer demonstrated that surgery-induced lymphocytopenia may be abrogated by a brief preoperative administration of IL-2. MATERIALS AND METHODS: The study included 30 consecutive patients who were randomized to be treated by radical surgery alone as a control group or by a preoperative immunotherapy with IL-2 (12 MIU/day SC for 3 consecutive days) plus surgery. RESULTS: Mean lymphocyte numbers significantly decreased in patients treated with surgery only, whereas it significantly rose in the IL-2-treated group. After a follow-up of 36 months, both the free-from-progression period (FFPP) and the overall survival were significantly higher in patients treated with IL-2. CONCLUSION: These preliminary results suggest that a short-period preoperative immunotherapy with IL-2 is sufficient to modify host tumor interactions in operable pancreatic cancer, with a subsequent abrogation of postoperative lymphocytopenia and a prolongation of FFPP and overall survival time.

Efficacy of cancer chemotherapy in relation to synchronization of cortisol rhythm, immune status and psychospiritual profile in metastatic non-small cell lung cancer.

BACKGROUND: The prognosis of cancer and the efficacy of the various anticancer therapies depend not only on tumor characteristics, but also on the endocrine and immune status of patients. Moreover, studies have shown that the clinical course of the neoplastic disease is also influenced by the psychospiritual status of patients. It is thus probable that the influence of psychospirituality on tumor growth may be mediated by the immunoneuroendocrine system, as demonstrated by the recent advances in psychoneuroendocrinological research. However, at present there are only few data on the possible link between the psychospiritual status and immunoendocrine functions of cancer patients. This study was carried out to investigate the relationships existing among the psychospiritual profile, cortisol rhythm and lymphocyte number before and after chemotherapy, and the efficacy of chemotherapy itself in advanced cancer patients. PATIENTS AND METHODS: The study included 30 consecutive metastatic non-small cell lung cancer patients under chemotherapeutic treatment with cisplatin plus gemcitabine. The psychobiological investigations consisted of lymphocyte count, cortisol circadian rhythm, psychological profile using Rorschach test, and spiritual score, as assessed by a specific clinical test for spirituality. The control group consisted of 100 healthy volunteers. The patients who achieved a tumor regression, showed a significantly higher pre-treatment lymphocyte count and significantly lower alteration of the cortisol rhythm with respect to those who had no benefit from chemotherapy. Moreover, the lymphocyte mean number increased during chemotherapy in responder patients, whereas it progressively diminished in those who had disease progression. Lymphocytopenia and alterations of the cortisol rhythm prior to chemotherapy were associated with a loss of the psychosexual identity according the Rorschach test. Moreover, the mean spiritual score was lower in patients than in controls, although the difference was not significant. Finally, a low spiritual score prior to therapy was associated with a higher frequency of lymphocytopenia and cortisol rhythm alteration, as well as with a lower efficacy of chemotherapy itself. CONCLUSION: This preliminary study would suggest that the psychospiritual status of cancer patients may influence the efficacy of chemotherapy through the immunoneuroendocrine system.

T and B lymphocyte depletion has a marked effect on the fibrosis of dystrophic skeletal muscles in the scid/mdx mouse.

Abnormal connective tissue proliferation following muscle degeneration is a major pathological feature of Duchenne muscular dystrophy (DMD), a genetic myopathy due to lack of the sarcolemmal dystrophin protein. Since this fibrotic proliferation is likely to be a major obstacle to the efficacy of future therapies, research is needed to understand and prevent the fibrotic process in order to develop an effective treatment. Murine muscular dystrophy (mdx) is genetically homologous to DMD, and histopatological alterations are comparable to those of the muscles of patients with DMD. To investigate the development of fibrosis, we bred the mdx mouse with the scid immunodepressed mouse and analysed fibrosis histologically; we used ELISA analysis to determine TGF-beta1 expression. Significant reduction of fibrosis and TGF-beta1 expression was found in the muscles of the scid/mdx mice. However, we observed similar centrally located nuclei, necrosis, muscle degeneration and muscle force compared to the mdx animals. These data demonstrate a correlation between the absence of B and T lymphocytes and loss of fibrosis accompanied by reduction of TGF-beta1, suggesting the importance of modulation of the immune system in DMD.

Skin-derived stem cells transplanted into resorbable guides provide functional nerve regeneration after sciatic nerve resection.

The regeneration in the peripheral nervous system is often incomplete and the treatment of severe lesions with nerve tissue loss is primarily aimed at recreating nerve continuity. Guide tubes of various types, filled with Schwann cells, stem cells, or nerve growth factors are attractive as an alternative therapy to nerve grafts. In this study, we evaluated whether skin-derived stem cells (SDSCs) can improve peripheral nerve regeneration after transplantation into nerve guides. We compared peripheral nerve regeneration in adult rats with sciatic nerve gaps of 16 mm after autologous transplantation of GFP-labeled SDSCs into two different types of guides: a synthetic guide, obtained by dip coating with a L-lactide and trimethylene carbonate (PLA-TMC) copolymer and a collagen-based guide. The sciatic function index and the recovery rates of the compound muscle action potential were significantly higher in the animals that received SDSCs transplantation, in particular, into the collagen guide, compared to the control guides filled only with PBS. For these guides the morphological and immunohistochemical analysis demonstrated an increased number of myelinated axons expressing S100 and Neurofilament 70, suggesting the presence of regenerating nerve fibers along the gap. GFP positive cells were found around regenerating nerve fibers and few of them were positive for the expression of glial markers as S-100 and glial fibrillary acidic protein. RT-PCR analysis confirmed the expression of S100 and myelin basic protein in the animals treated with the collagen guide filled with SDSCs. These data support the hypothesis that SDSCs could represent a tool for future cell therapy applications in peripheral nerve regeneration.

Triple arterial reconstruction improves vascularization of whole pancreas for transplantation.

We assessed the effect on duodenal stump vascular supply of reconstruction of the gastroduodenal artery performed before pancreas transplantation. The median pancreas graft and patient survival times were 144 and 72 months for cases with or without gastrointestinal bleeding. Transmural blood flow values were significantly different between the donor duodenal stump and the recipient anastomosed jejunum (P < .01). The rate of gastrointestinal bleeding was lower in patients who received a pancreatic graft with back-table reconstruction of the gastroduodenal artery (P = .005).

[Colorectal laparoscopic surgery. Single center experience with 599 cancer patients]. / Chirurgia laparoscopica colorettale. Esperienza monocentrica su 599 pazienti neoplastici.

PURPOSE: To analyze the results of laparoscopic colectomy for cancer of colon and rectum on early outcome. METHODS: Fifty hundred and ninety-nine consecutive unselected patients who underwent laparoscopic colectomy for cancer of the colon or rectum between January 1998 and December 2004 in a single Institution were prospectively evaluated. Tumor classification was by TNM stage. Patients were monitored for postoperative complications for 30 days after surgery. Follow-up was done by direct patient contact. RESULTS: Mean (SD) age was 65.8 (11.7) years. Mean (SD) ASA score was 2.0 (0.5). The following operations were performed: 248 left colectomies, 131 right colectomies, 26 sigmoid resections, 164 rectal resections, 21 abdominoperineal resections (Miles operation) and 9 total colectomies. Conversion rate was 7.2% (43/599 pts). The overall morbidity rate was 23.3% (143/599 pts). The mortality rate was 0.3% (2/599 pts). Anastomotic leak occurred in 45/599 (7.3%) patients. Re-operation rate was 4.6% (26/599 pts). Mean (SD) length of stay was 9.9 (5.8) days. The mean number (SD) of lymphnodes intraoperatively collected was 16.7 (9.8). Median (range) time of follow-up period was 20.2 months (6-68). One port-site metastasis was found at 18 months after surgery. Overall 5-years survival was 81%. Local recurrence rate in patients who underwent TME of the rectum was 4.4%. CONCLUSION: Laparoscopic colectomies is safe and effective in the treatment of colon and rectal cancer.

The role of intraoperative therapy by electron beam and combination of adjuvant chemotherapy and external radiotherapy in carcinoma of the pancreas.

AIMS AND BACKGROUND: In the treatment of pancreatic carcinomas, one modality is intraoperative radiotherapy (IORT). A study was carried out to assess the feasibility of IORT alone or in a multimodality approach with postoperative adjuvant chemotherapy and external radiotherapy and to compare local control and survival of patients. Another objective of this retrospective study was to verify prognostic factors in resected patients treated with IORT. METHODS: From January 1985 through September 1992, 54 adenocarcinomas of the pancreas (unresectable and resected patients) were treated with IORT by electron beam at the San Raffaele Hospital and then analyzed. Comparison was also carried out between IORT-treated resected patients and a non-randomized control group of resected patients treated without IORT in the same period. RESULTS: In unresectable patients treated by laparotomy bypass and IORT, overall median survival was 6 months and 8 months in non-metastatic patients. Relief of severe pain present in 14 patients was observed in 85% within 12 days of IORT. As regards resected patients, the most important finding was that significantly better local control resulted from IORT. In fact, overall, local relapses were 25% in the IORT group and 55.8% in the non-IORT group (control group); instead, survival of the IORT group was not significantly longer than that of the control group. From a statistical analysis of resected patients treated with IORT and performed on prognostic factors on the basis of available data, survival was significantly influenced by tumor pathologic grading and diameter; postoperative adjuvant therapy was not a significant prognosis factor. CONCLUSIONS: IORT has a role in local control of unresectable pancreatic carcinomas and in control of resultant severe pain. In resected patients, IORT is effective in decreasing local recurrences but has little impact on survival. To obtain more satisfactory results, new and more effective adjuvant therapies and better abdominal prophylaxis should be tested.

[Computerized tomography versus nuclear magnetic resonance in acute pancreatitis]. / Tomografia computerizzata versus risonanza magnetica nucleare nella pancreatite acuta.

The aim of the study was to compare Computed Tomography (CT) and Nuclear Magnetic Resonance (MR) scan's diagnostic reliability in acute pancreatitis (AP). During a 44-month period 21 patients with a clinical and laboratory diagnosis of AP were submitted to CT and MR study. The scans were evaluated according to pancreatitis degree and presence and rate of necrosis. Pancreatitis degree was assessed using Balthazar's grading for CT scans; a similar classification was used for MR scans. Thirteen patients had oedematous pancreatitis and 8 necrotic pancreatitis. Necrosis was diagnosed intraoperatively or in non operated patients with CT scan. MR staging was identical to that of the CT ones except for 2 patients who were grade E at CT and grade D at MR. MR identified necrosis in all 8 patients with necrotic AP whereas CT diagnosed only 5 patients properly since 3 scans were performed without contrast medium infusion because of renal failure. MR proved to be a valid alternative in AP diagnosis: it provide the same diagnostic and prognostic information as CT and does not need contrast infusion, which makes it preferable to CT in the follow-up of severe AP evolution.

Intraoperative radiation therapy adjuvant to resection in the treatment of pancreatic cancer.

BACKGROUND: Local recurrence is the most frequent site of failure after resection for pancreatic cancer. Tolerance, local control, and survival obtained by the association of resection and intraoperative radiation therapy (IORT) were reported. METHODS: Between June 1985 and March 1993, 90 resections for pancreatic cancer were performed at the authors' institution. For 43 patients, IORT was added to resection (Group 1), whereas the other 47 patients underwent resection alone (Group 2), because of either the unavailability of linear accelerator or the patient's refusal. In Group 1, radiation doses from 12.5 to 20 Gy, with electron beam energies between 6 and 12 MeV, were delivered. Extension of the disease was similar in the two groups of patients: mean diameter of the tumor was 3.2 cm in Group 1 and 3.4 cm in Group 2; percentage of third degree stage disease (International Union Against Cancer classification) was 65.1% in Group 1 and 57.4% in Group 2; and tumor clearance was incomplete in 39.5% of patients in Group 1 and in 34.0% in Group 2. RESULTS: Operative mortality and overall early post-operative complications were respectively 2.3% and 23.2% in Group 1 and 2.1% and 23.4% in Group 2. One-year, 2-year, and 3-year survival rates were respectively 71%, 24%, and 7% in Group 1 and 49%, 16%, and 10% in Group 2 (P was not significant). Median disease free survival was 13 months in Group 1 and 8 months in Group 2 (P was not significant). A local recurrence was detected in 27.0% of patients in Group 1 and in 56.4% of patients in Group 2 (P < 0.01). CONCLUSIONS: The results suggest a better local control in patients with pancreatic cancer undergoing adjuvant IORT.

Behavior of tumor markers CA19.9, CA195, CAM43, CA242, and TPS in the diagnosis and follow-up of pancreatic cancer.

We compared the recently proposed tumor markers CA195, CA242, and CAM43 with a widely used antigen, CA19.9, and a circulating marker of cellular proliferation, TPS, to define their specificity, sensitivity, and cost-benefit ratio. The tumor markers were measured in 41 pancreatic carcinoma patients and in two control groups, the first comprising 19 patients with benign pancreatic diseases, the second comprising 41 healthy blood donors. Sensitivities were 79% for CA19.9, 57% for CA242, 60% for CAM43, 76% for CA195, and 98% for TPS. Specificities calculated for the group with pancreatic diseases were 60% for CA19.9, 84% for CA242, 95% for CAM43, 53% for CA195, and 22% for TPS. Specificities for the blood donor group were 100% for CA19.9, 93% for CA242, 98% for CAM43, 85% for CA195, and 88% for TPS. Positive values for the tumor markers appeared from second stage (Hermreck classification). Metastases, invasion of lymph nodes, and coupling of cancer-associated antigens did not significantly modify marker sensitivity. In pancreatic carcinoma, CA19.9 showed good sensitivity (79%) and high specificity (60-100%). In view of their own advantages (e.g., high specificity of CAM43, high sensitivity of TPS in recurrences) and limits (e.g., low sensitivity of CAM43, very low sensitivity of TPS), the other markers could be used alone or with CA19.9. Two pairs of tumor markers showed high similarity in our study: CA19.9 and CA195, and CAM43 and CA242.

Pancreatic cancer versus chronic pancreatitis: diagnosis with CA 19-9 assessment, US, CT, and CT-guided fine-needle biopsy.

The authors prospectively performed serum CA 19-9 assessment, ultrasound (US), computed tomography (CT), and CT-guided fine-needle aspiration biopsy (FNAB) of the pancreas in 81 consecutive patients with suspected chronic pancreatitis or pancreatic neoplasm. The final diagnosis was pancreatic cancer in 54 patients and chronic pancreatitis in 27 patients. CA 19-9 assessment, US, CT, and FNAB were considered nondiagnostic, respectively, in 0%, 25%, 19%, and 6% of cases. When a definite diagnosis was rendered, the positive predictive value was 90% for CA 19-9 assessment, 95% for US, 98% for CT, and 100% for FNAB; the negative predictive value was, respectively, 69%, 95%, 86%, and 100%. The accuracy of all diagnostic and nondiagnostic studies was 81% for CA 19-9 assessment, 72% for US, 77% for CT, and 94% for FNAB. It is concluded that CT-guided pancreatic FNAB is the most reliable examination for enabling differential diagnosis of pancreatic cancer and chronic pancreatitis. When the pancreas is well visualized at US, the negative predictive value for pancreatic cancer is more accurate than that of CA 19-9 assessment and CT.

[Fine needle aspiration of pancreatic masses. A study of 81 cases]. / Agoaspirato con ago sottile (FNAB) delle masse pancreatiche. Studio di 81 casi.

Study of 81 cases. Fine Needle Aspiration Biopsy (FNAB) was performed under computerized thomography scan (CT) in 81 patients with documented pancreatic mass (54 with neoplasia and 27 with chronic pancreatitis). This procedure, when associated to the immediate cytological evaluation of the adequacy of the smears, permits to obtain 100% in sensibility, specificity and predictive value of positive cases. These results and the study of the literature confirm CT-guided FNAB of the pancreas as the procedure of choice to resolve problems of differential diagnosis in pancreatic masses.

CT-guided pancreatic percutaneous fine-needle biopsy in differential diagnosis between pancreatic cancer and chronic pancreatitis.

Differential diagnosis between pancreatic cancer and chronic pancreatitis is still difficult to establish. In 63 patients with suspected pancreatic neoplasm we performed: serum CA 19-9 assessment, abdominal ultrasound. CT scan and CT-guided pancreatic percutaneous fine-needle biopsy. The conclusive diagnosis was pancreatic cancer in 40 patients and chronic pancreatitis in 23 patients. With regard to the differential diagnosis, sensitivity and specificity were respectively 80% and 78% for serum CA 19-9, 75% and 65% for abdominal US. 85% and 70% for CT scan. 00% and 87% for percutaneous fine-needle biopsy. We conclude that CT-guided percutaneous fine-needle biopsy is the most reliable method for differential diagnosis between pancreatic cancer and chronic pancreatitis.