Effect of preoperative chemoradiotherapy on outcome of patients with locally advanced esophagogastric junction adenocarcinoma-a pilot study.

BACKGROUND: To date, few studies of preoperative chemotherapy or chemoradiotherapy (crt) in gastroesophageal junction (gej) cancer have been statistically powered; indeed, gej tumours have thus far been grouped with esophageal or gastric cancer in phase iii trials, thereby generating conflicting results. METHODS: We studied 41 patients affected by locally advanced Siewert type i and ii gej adenocarcinoma who were treated with a neoadjuvant crt regimen [folfox4 (leucovorin-5-fluorouracil-oxaliplatin) for 4 cycles, and concurrent computed tomography-based three-dimensional conformal radiotherapy delivered using 5 daily fractions of 1.8 Gy per week for a total dose of 45 Gy], followed by surgery. Completeness of tumour resection (performed approximately 6 weeks after completion of crt), clinical and pathologic response rates, and safety and outcome of the treatment were the main endpoints of the study. RESULTS: All 41 patients completed preoperative treatment. Combined therapy was well tolerated, with no treatment-related deaths. Dose reduction was necessary in 8 patients (19.5%). After crt, 78% of the patients showed a partial clinical response, 17% were stable, and 5% experienced disease progression. Pathology examination of surgical specimens demonstrated a 10% complete response rate. The median and mean survival times were 26 and 36 months respectively (95% confidence interval: 14 to 37 months and 30 to 41 months respectively). On multivariate analysis, TNM staging and clinical response were demonstrated to be the only independent variables related to long-term survival. CONCLUSIONS: In our experience, preoperative chemoradiotherapy with folfox4 is feasible in locally advanced gej adenocarcinoma, but shows mild efficacy, as suggested by the low rate of pathologic complete response.

Complete response to preoperative chemoradiation and survival in esophageal cancer: a pooled analysis of three single-institution phase II trials.

This pooled analysis was performed using individual patient data from three phase II trials that included on the whole 113 esophageal cancer treated preoperatively with chemoradiotherapy (CRT), in order to analyze the efficacy and survival outcomes according to the achievement of the pathologic complete response (pCR). Thirty-nine patients were treated with 5-fluorouracil/cisplatin and RT (40 Gy), 33 patients received paclitaxel/cisplatin weekly during weeks 1-6 with and RT (46 Gy), 41 patients were treated with induction bio-chemotherapy with cetuximab and FOLFOX-4 followed by concomitant cetuximab and RT of 50.4 Gy. One hundred and two out of 113 resected patients were included in the survival analysis. The median overall survival (OS) time for the whole population was 21.5 months. The 12, 24, and 36 months OS rates were 85.4, 45.2, and 33%, respectively. The difference in survival probability between patients with pCR and patients with partial response or stable disease after treatment was significant (P= 0.0002, hazard ratios = 0.21, 95% CI 0.18-0.60). On multivariate analysis, the pathologic response and histology were the only covariates independently associated with OS (P= 0.0157 and P= 0.0212, respectively). In our series, complete responder patients had a significant longer survival probability after treatment when compared to patients with partial response or stable disease.

A multicenter phase II study of induction chemotherapy with FOLFOX-4 and cetuximab followed by radiation and cetuximab in locally advanced oesophageal cancer.

BACKGROUND: Preoperative chemoradiotherapy (CRT) improves the survival of patients with oesophageal cancer when compared with surgery alone. METHODS: We conducted a phase II, multicenter trial of FOLFOX-4 and cetuximab in patients with locally advanced oesophageal cancer (LAEC) followed by daily radiotherapy (180 cGy fractions to 5040 cGy) with concurrent weekly cetuximab. Cytokines levels potentially related to cetuximab efficacy were assessed using multiplex-bead assays and enzyme-linked immunosorbent assay at baseline, at week 8 and at week 17. Primary end point was complete pathological response rate (pCR). RESULTS: In all, 41 patients were enroled. Among 30 patients who underwent surgery, a pCR was observed in 8 patients corresponding to a rate of 27%. The most frequent grade 3/4 toxicity was skin (30%) and neutropenia (30%). The 36-month survival rates were 85 and 52% in patients with pathological CR or PR vs 38 and 33% in patients with SD or PD. CONCLUSIONS: Incorporating cetuximab into a preoperative regimen for LAEC is feasible; no correlation between cytokines changes and patient outcome was observed. Positron emission tomography/computed tomography study even if influenced by the small number of patients appears to be able to predict patients outcome both as early and late metabolic response.

Cetuximab, a chimeric human mouse anti-epidermal growth factor receptor monoclonal antibody, in the treatment of human colorectal cancer.

The recent successful development of monoclonal antibodies that target key components of biological pathways has expanded the armamentarium of treatment options for patients with colorectal cancer (CRC). In particular, the epidermal growth factor receptor (EGFR), a tyrosine kinase growth factor receptor involved in CRC development and progression, is exploited by the newest monoclonal antibody that is available for use in CRC patients. Cetuximab, the first chimeric monoclonal antibody, which has been generated against the EGFR, is currently registered in USA, Europe and worldwide, in combination with irinotecan in the treatment of metastatic CRC patients who have progressed on irinotecan containing chemotherapy. Cetuximab is well tolerated and does not exacerbate the toxicity of concomitant chemotherapy. Furthermore, a series of phase III clinical trials are currently evaluating the combination of cetuximab with standard chemotherapy regimens in the first-line treatment chemotherapy-naïve patients with metastatic CRC.

Counting alleles reveals a connection between chromosome 18q loss and vascular invasion.

The analysis of loss of heterozygosity (LOH) is perhaps the most widely used technique in cancer genetics. In primary tumors, however, the analysis of LOH is fraught with technical problems that have limited its reproducibility and interpretation. In particular, tumors are mixtures of neoplastic and nonneoplastic cells, and the DNA from the nonneoplastic cells can mask LOH. We here describe a new experimental approach, involving two components, to overcome these problems. First, a form of digital PCR was employed to directly count, one by one, the number of each of the two alleles in tumor samples. Second, Bayesian-type likelihood methods were used to measure the strength of the evidence for the allele distribution being different from normal. This approach imparts a rigorous statistical basis to LOH analyses, and should be able to provide more reliable information than heretofore possible in LOH studies of diverse tumor types.

Tandem action of exercise training and food restriction completely preserves ischemic preconditioning in the aging heart.

Ischemic preconditioning (IP) has been proposed as an endogenous form of protection against ischemia reperfusion injury. IP, however, does not prevent post-ischemic dysfunction in the aging heart but may be partially corrected by exercise training and food restriction. We investigated the role of exercise training combined with food restriction on restoring IP in the aging heart. Effects of IP against ischemia-reperfusion injury in isolated hearts from adult (A, 6 months old), sedentary 'ad libitum' fed (SL), trained ad libitum fed (TL), sedentary food-restricted (SR), trained- and food-restricted senescent rats (TR) (24 months old) were investigated. Norepinephrine release in coronary effluent was determined by high performance liquid cromatography. IP significantly improved final recovery of percent developed pressure in hearts from A (p<0.01) but not in those from SL (p=NS) vs unconditioned controls. Developed pressure recovery was partial in hearts from TL and SR (64.3 and 67.3%, respectively; p<0.05 vs controls) but it was total in those from TR (82.3%, p=NS vs A; p<0.05 vs hearts from TL and SR). Similarly, IP determined a similar increase of norepinephrine release in A (p<0.001) and in TR (p<0.001, p=NS vs adult). IP was abolished by depletion of myocardial norepinephrine stores by reserpine in all groups. Thus, IP reduces post-ischemic dysfunction in A but not in SL. Moreover, IP was preserved partially in TR and SR and totally in TR. Complete IP maybe due to full restoration of norepinephrine release in response to IP stimulus.

Interleukin-6 serum level correlates with survival in advanced gastrointestinal cancer patients but is not an independent prognostic indicator.

Interleukin-6 (IL-6) is a pleiotropic cytokine that has been shown to regulate immune defense mechanisms and hematopoiesis. In addition, IL-6 may also be involved in malignant transformation and tumor progression. A poor prognosis in patients with multiple myeloma, renal cell carcinoma, ovarian cancer, or prostate cancer has been associated consistently with elevated IL-6 serum levels. The aim of this study was, therefore, to assess IL-6 serum levels in 68 advanced gastrointestinal cancer patients and to correlate them with prognosis. IL-6 serum levels were found to be significantly elevated in cancer patients with respect to controls. Moreover, patients with disseminated cancer displayed significantly higher IL-6 serum levels than patients without apparent metastases. On univariate analysis, both overall survival (OS) and time to disease progression (TTP) were shown to be affected by IL-6 serum levels. However, multivariate analysis failed to demonstrate an independent prognostic significance for IL-6 serum levels while confirming the role of previously established variables, such as performance status, carcinoembryonic antigen (CEA) serum levels, and distant metastases. In conclusion, this study showed that IL-6 serum levels were elevated in advanced gastrointestinal cancer patients and correlated with both OS and TTP. However, they were shown not to be an independent prognostic factor.

Serum interleukin-10 levels as a prognostic factor in advanced non-small cell lung cancer patients.

STUDY OBJECTIVE: To investigate the prognostic significance of interleukin (IL)-10 serum levels in advanced non-small cell lung cancer (NSCLC) patients. DESIGN: IL-10 serum levels were measured before chemotherapy, on completion of therapy, and at follow-up by means of a commercially available enzyme-linked immunoassay. The results were then analyzed in comparison with other prognostic variables, and a model predicting overall survival (OS) and time to treatment failure (TTF) was finally generated. SETTING: University hospital. PATIENTS: Sixty consecutive patients with TNM stage III or IV NSCLC undergoing conventional platinum-based regimens. RESULTS: Elevated levels of serum IL-10 were found in cancer patients with respect to healthy control subjects (17.7 +/- 4.4 vs 9.2 +/- 1.5 pg/mL, respectively; p < 0.05), with patients with metastatic disease showing significantly higher levels than patients with undisseminated cancer (21.0 +/- 4.2 vs 14.3 +/- 1.2 pg/mL, respectively; p < 0.05). Following completion of treatment, patients were classified as responders if they had achieved either one of the following: complete response, partial response, or stable disease; and nonresponders, in case of progressive disease. Retrospective analysis of basal IL-10 serum levels in these two subgroups showed a significant difference between responders and nonresponders (15.2 +/- 2.2 vs 21.4 +/- 4.2 pg/mL, respectively; p < 0.05). Moreover, a further significant increase in IL-10 serum levels was observed in nonresponders at the end of therapy (21.4 +/- 4.2 vs 26.0 +/- 4.3 pg/mL, prechemotherapy and postchemotherapy, respectively; p < 0.05), whereas values in responders were found to have significantly decreased (15.2 +/- 2.2 vs 14.8 +/- 2.2 pg/mL, prechemotherapy and postchemotherapy, respectively; p < 0.05). Using univariate and multivariate analyses, both OS and TTF were shown to be affected by the mean pathologic levels of IL-10. Stepwise regression analysis identified IL-10 serum level and stage as the prognostic factors related to OS, and IL-10 serum level and performance status as the prognostic factors related to TTF. CONCLUSIONS: In conclusion, this study shows that the measurement of pretreatment IL-10 serum levels is of independent prognostic utility in patients with NSCLC and may be useful for detection of disease progression.

Adverse effects of preoperative hepatic artery chemoembolization for resectable hepatocellular carcinoma: a retrospective comparison of 138 liver resections.

During the past 8 years we have treated 268 patients with primary hepatocellular carcinoma (HCC); total extirpation of the tumor was carried out in 138. Thirty-one of the patients with resectable HCCs had already been treated with transcatheter arterial embolization (TAE) of the liver before they were referred to us. The clinical values of preoperative TAE were retrospectively evaluated for those 31 patients and for the remaining 107 patients without TAE. There were no substantial differences between the two study groups in the clinical and histopathologic backgrounds. No differences were observed in the extent of liver resection, estimated blood loss during surgery, and operation time. During surgery, however, troublesome intra-abdominal complications relevant to TAE were encountered in 15 patients, and detection of tumors was impossible, even with intraoperative ultrasonography, in five patients in the group with TAE. Such findings were not present in any of the patients without TAE. Postoperative morbidity and mortality rates were similar in the two groups. There was no significant difference in the rate of recurrence of tumor in the liver, but the recurrence time was significantly shorter in the group with TAE. TAE did not improve the long-term survival rates in patients either with or without cirrhosis. Results of our study seem to indicate that preoperative TAE is meaningless in the treatment of resectable HCCs and therefore should be avoided, particularly in patients with advanced cirrhosis of the liver.

DNA ploidy as a significant prognostic factor after radical resection for large bowel carcinoma: a prospective study.

It is controversial whether cell DNA measurement is a reliable method to predict prognosis in radically resected large bowel carcinomas. A study using strict rules was undertaken on 54 consecutive patients to clarify the usefulness of DNA ploidy by image cytometric analysis as a prognostic indicator. The tumors were 39% diploid and 61% aneuploid. DNA ploidy was not related to more advanced stages and it, with histological grade and Dukes' stage, was an independent covariate and influenced both disease-free and overall survival. Aneuploid tumors showed the worse prognosis in all Dukes' stages. This prospective study shows that DNA ploidy is an important independent prognostic indicator of clinical outcome and recurrence rate, and it should be used to both select high-risk patients and guide postoperative treatments, particularly in early-stage large bowel carcinomas.

Serum interleukin-10 is an independent prognostic factor in advanced solid tumors.

Interleukin (IL)-10 is a Th2 type pleiotropic cytokine that has been found to be produced at the tumor site and to be increased in sera of patients suffering from different types of cancer. IL-10 has been shown to hinder a number of immune functions, i.e., T lymphocyte proliferation, Th1 type cytokine production, antigen presentation, and lymphokine-activated killer cell cytotoxicity. To assess its prognostic value, we measured serum levels of IL-10 in 118 patients with advanced solid tumors before treatment, after completion of therapy, and during follow-up. Other prognostic variables, to which IL-10 results were compared, were analyzed as well. IL-10 serum levels were found significantly elevated in cancer patients with respect to healthy controls. Of interest, a significant decrease in IL-10 serum levels was observed in the responder group, whereas a significant increase was recorded in the non-responder group. Using univariate and multivariate analyses, a significant relationship was shown between IL-10 serum levels and both overall survival (OS) and time to treatment failure (TTF). Stepwise regression analysis selected IL-10 serum level, performance status (PS), and stage as the best association of variables with significant impact on OS and TTF. In conclusion, this study shows that IL-10 has an independent prognostic significance in patients with advanced solid tumors and may be useful for monitoring disease progression.

Intraoperative ultrasonography in resection of small hepatocellular carcinoma associated with cirrhosis.

Preoperative detectability rates of hepatocellular carcinoma smaller than 5 cm in 113 cirrhotic patients were 91 percent by ultrasonography, 93 percent by computed tomography, and 92 percent by selective angiography. The combination of two methods produced detectability rates of 97 to 99 percent. One hundred three patients underwent various types of hepatic resection with the aid of intraoperative ultrasonography. Forty-four tumors (43 percent) were embedded in the liver, and these tumors were not detected by conventional surgical exploration. The detectability rates were 38 percent for hepatocellular carcinomas smaller than 2 cm, 57 percent for 2 to 3.5 cm tumors, and 71 percent for 3.5 to 5 cm tumors. All undetectable hepatocellular carcinomas were identified by intraoperative echography. The overall detection rate by this method was 98 percent, which was substantially higher than the preoperative rate. Intraoperative ultrasonography is a useful and indispensable method for performing atypical minor hepatectomy for the treatment of small hepatocellular carcinomas associated with liver cirrhosis.

Hemodynamic and pulmonary changes during open, carbon dioxide pneumoperitoneum and abdominal wall-lifting cholecystectomy. A prospective, randomized study.

BACKGROUND: Carbon dioxide (CO2) pneumoperitoneum effects are still controversial. The aim of this study was to investigate cardiopulmonary changes in patients subjected to different surgical procedures for cholecystectomy. METHODS: In this study, 15 patients were assigned randomly to three groups according to the surgical procedure to be used: open cholecystectomy (OC), CO2 pneumoperitoneum cholecystectomy (PP), and laparoscopic gasless cholecystectomy (abdominal wall lifting [AWL]), respectively. A pulmonary artery catheter was used for hemodynamic monitoring in all patients. A subcutaneous multiplanar device (Laparo Tenser) was used for abdominal wall lifting. To avoid misinterpretation of results, conventional anesthesia was performed with all parameters, and the position of the patients held fixed throughout surgery. The following parameters were analyzed: mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), cardiac index (CI), stroke volume index (SVI), central venous pressure (CVP), systemic vascular resistances index (SVRI), mean pulmonary arterial pressure (MPAP), pulmonary capillary wedge pressure (PCWP), pulmonary vascular resistances index (PVRI), peak inspiratory pressure (PIP), end-tidal CO2 pressure (ETCO)2, CO2 arterial pressure (PaCO2), and arterial pH. RESULTS: All the operations were completed successfully. The Laparo Tenser allowed good exposition of the surgical field. A slight impairment of the cardiopulmonary functions, with reduction of SVRI, MAP, and CI and elevation of pulmonary pressures and vascular resistance, followed induction of anesthesia. However, these effects tended to normalize in the OC and AWL groups over time. In contrast, CO2 insufflation produced a complex hemodynamic and pulmonary syndrome resulting in increased right- and left side filling pressures, significant cardiac index reduction, derangement of the respiratory mechanics, and respiratory acidosis. All of these effects normalized after desufflation. CONCLUSIONS: Cardiopulmonary adverse effects of general anesthesia were significant but transitory and normalized during surgery. Carbon dioxide pneumoperitoneum caused a significant impairment in cardiopulmonary functions. In high-risk patients, gasless laparoscopy may be preferred for reliability and absence of cardiopulmonary alterations.

Myxopapillary ependymoma of the ischioanal fossa.

Ependymomas outside the confines of the cranium and spinal cord are rare. Direct extension into the soft tissues of the sacrococcygeal area may occur from a primary ependymoma of the spinal cord, cauda equina or filum terminale. Alternatively they may occur as a primary pre-sacral, pelvic and abdominal tumour, or as a primary tumour of the skin and subcutaneous tissue of the sacrococcygeal area without any demonstrable connection with the spinal cord. The Authors report a case of myxopapillary ependymoma of the ischioanal fossa, demonstrated by MRI. To our knowledge, our case is the first lesion reported at this site.

Intraperitoneal adjuvant immunochemotherapy in operable gastric cancer with serosal involvement.

Since the peritoneal cavity is the most common site of initial recurrence in patients after surgery for gastric cancer, an intraperitoneal (IP) adjuvant treatment was tested in patients with resected gastric cancer with serosal involvement. Between March 1986 and September 1991, 44 consecutive patients with resected T3/T4-N0/N+ gastric cancer were given an IP combination, including cisplatin or carboplatin, etoposide, and alpha interferon-2b. The overall survival of these patients was compared with that observed in 47 historical controls (admitted to the same institutions from 1983 to 1986) with similar prognostic characteristics, who had not received adjuvant treatment after surgery. No major complication relating to the IP route was observed. Mild to moderate abdominal pain occurred in nine patients. Grade 3-4 myelotoxicity occurred in 14 patients. Interferon had to be reduced in five patients and suspended in one because of severe fatigue. Emesis occurred in 23/28 patients given cisplatin and 9/16 given carboplatin. At the time of this analysis (September 1992) median follow-up was 42 months (range 12-78) in the group receiving IP treatment, and 97 months (range 74-128) in the historical controls. There had been 20 deaths among treated patients compared with 36 in the control group. The 5-year estimated survival rate was significantly better in the patients who received IP adjuvant treatment (44% +/- 9 versus 23% +/- 6; P = 0.016). Using the Cox proportional hazard model with a backward procedure to correct for the influence of prognostic pretreatment variables, IP treatment again afforded a significant advantage in terms of survival (P = 0.04). Adjuvant IP immunochemotherapy appears to improve prognosis compared with historical controls in patients having operable gastric cancer with serosal infiltration.

Better survival in women than in men after radical resection of hepatocellular carcinoma.

During the period between January 1980 and December 1987, 229 male and 39 female adult patients with primary hepatocellular carcinoma (HCC) were hospitalized in our unit. Radical hepatic resection was carried out in 90 (39.3%) males and 17 (43.6%) females in whom no specific cancer treatment had been attempted preoperatively. The 1-, 3-, and 5-year survival rates in the male and female patients were 78% and 70%, 45% and 52%, and 19% and 52%, respectively. The difference was significant after 47 months. No substantial differences were found between the two groups with respect to age, preoperative clinical condition and laboratory data, method of liver resection, postoperative morbidity and mortality, postoperative adjuvant chemotherapy, and histopathology of HCC and the liver. Only the incidence of alcohol abuse was significantly different, being higher in male than in female patients. However, the survival analysis demonstrated that alcohol abuse had had no influence on recurrence rate and long-term survival in either male or female patients. As a control, survival was analyzed for the patients with similar clinicopathological background but without HCC who had undergone distal splenorenal shunt for esophageal varices. There was no significant difference between the male and female patients. The current clinical results seems to support our hypothesis based upon sex hormone receptor studies that HCC may be androgen-dependent.

Retroperitoneal abscess after retained stones during laparoscopic cholecystectomy.

Laparoscopic cholecystectomy is associated with a significant risk of gallbladder perforations with bile and stone spillage. The retrieval of dropped stones is sometimes impossible, and intraperitoneally retained stones can be the source of serious complications, such as inflammatory masses or abscesses. The authors describe a patient in whom a large retroperitoneal abscess developed as a result of missed stone fragments during cholecystectomy. Although several cases of intraperitoneal abscess have been reported in the literature, retroperitoneal collection is very uncommon. Crushed and infected stones seem to be the essential prerequisite for abscess formation. Therefore, every attempt should be made to avoid stone spillage and intra-abdominally retained stones. Conversion to open surgery has to be considered in the presence of adverse factors, such as primary acute cholecystitis or cholecystitis induced by previous sphincterotomy, or bilirubinate stones believed to be infected. Abdominal abscess treatment requires removal of missed stones by surgical incision or new laparoscopic procedure because simple percutaneous drainage is usually unsuccessful.

[Hereditary colonic cancer. Analysis of 3 families at risk]. / Il cancro del colon eredo-familiare. Analisi di tre famiglie a rischio.

Hereditary colorectal cancer is a clearly identified entity today; it is transmitted as a dominant autosomal heritage, and represents about 25% of large bowel malignancies. The poor prognosis of this tumor, one of the most frequent in Western Countries, despite the improvements in therapeutic field, is due to a delated diagnosis that affects an advanced stage of disease in which the results of treatment are significantly worse, whereas cumulative 5-year survival rate is 35% vs 95% in early stage tumors. Existence of an inherited cancer, even in the absence, at present, of specific biomarkers, allows to identify a high risk population in which early diagnosis of colorectal cancer is possible, on the basis of anamnestic and clinical features. Only in this way, with the extension of the results to general population, prognosis of colorectal cancer will be improved.

[Segmentation of the liver and anatomical variants of the portal system]. / La segmentation du foie et les variations anatomiques du système porte.

The authors, who studied 605 human livers according to various techniques, present their own anatomo-surgical conception of human liver segmentation, based on the distribution of the whole intrahepatic Glisson's system, and by dividing the liver into two hemi-livers, right and left (the term "lobe" being reserved, according to Tôn-Thât-Tùng, for the classical anatomical lobes): the right hemi-liver is subdivided into two segments: anterior and posterior; the left hemi-liver is subdivided into three segments: medial (IV), lateral-anterior (III) and lateral-posterior (II); the dorsal segment (I) or the classical Spigel's lobe tends to overlap both half livers (more on the left than on the right). The authors then describe, indicating the percentages, the typical patterns and anatomical variants of intersegmental fissures and the portal system. During the discussion, the authors say that, according to their experience, the right hemi-liver segments can be divided into some smaller units: the posterior segment into two subsegments (VI and VII) and the anterior ones into three subsegments (V, VIIIi and VIIIe); and they justify the segmental division of the left hemi-liver. The authors conclude that statistical and analytical study can define a typical anatomical pattern but that, owing to many anatomical variants, it is easier to perform the transparenchymal approach to the vasculo-biliary structures, enveloped in the same Glisson's capsule, rather than to make long and dangerous dissections at the porta hepatis.