Multimodal treatment strategies for locally advanced rectal cancer.

This review outlines the important multimodal treatment issues associated with locally advanced rectal cancer. Changes to chemotherapy and radiation schema, as well as modern surgical approaches, have led to a revolution in the management of this disease but the morbidity and mortality remains high. Adequate treatment is dependent on precise preoperative staging modalities. Advances in staging via endorectal ultrasound, computed tomography, MRI and PET have improved pretreatment triage and management. Important prognostic factors and their impact for this disease are under investigation. Here we discuss the different treatment options including modern tumor-related surgical approaches, neoadjuvant as well as adjuvant therapies. Further clinical progress will largely depend on the broader implementation of multidisciplinary treatment strategies following the principles of evidence-based medicine.

The cytotoxicity of anti-CD22 immunotoxin is enhanced by bryostatin 1 in B-cell lymphomas through CD22 upregulation and PKC-ßII depletion.

BACKGROUND: In spite of potent first-line therapies for chronic lymphocytic leukemia, treatment remains palliative and all patients frequently relapse. Treatment options for these patients are more limited. BL22 is a recombinant protein composed of the variable region of a monoclonal antibody that binds to CD22 and of PE38, a truncated Pseudomonas exotoxin. BL22 is a very potent drug already used in patients with hairy cell leukemia, whereas in chronic lymphocytic leukemia its cytotoxicity is limited by a lower expression of CD22. Here we demonstrate that this limitation can be overcome by pre-activation of chronic lymphocytic leukemia cells with bryostatin 1. DESIGN AND METHODS: Primary malignant B cells from chronic lymphocytic leukemia and mantle cell lymphoma patients were used in vitro to assess the therapeutic impact of drug combinations using BL22 and bryostatin 1. RESULTS: We demonstrate that bryostatin 1 sensitizes chronic lymphocytic leukemia cells for the cytotoxic effects of BL22 through activation of protein kinase C and subsequently increased CD22 surface expression. Dose and time response analysis reveals that activation of protein kinase C further activates an autocrine feedback loop degrading protein kinase C-ßII protein. Depletion of protein kinase C-ßII and upregulation of CD22 persist for several days following pre-stimulation with bryostatin 1. Therefore, our data provide a rationale for the sequential administration of BL22 following bryostatin 1 treatment. In addition to primary chronic lymphocytic leukemia cells, bryostatin 1 also sensitizes diffuse large B-cell lymphoma and mantle cell lymphoma cells to BL22 induced apoptosis. CONCLUSIONS: Our data suggest that the combination of bryostatin 1 with antibodies directed against CD22 is a potent drug combination for the treatment of low- and high-grade B-cell lymphoma.

Significance of histopathological tumor regression after neoadjuvant chemotherapy in gastric adenocarcinomas: a summary of 480 cases.

OBJECTIVE: An increasing number of patients with locally advanced gastric carcinomas (GC) are being treated with preoperative chemotherapy before surgery. BACKGROUND: Histopathological tumor regression may have an important prognostic impact in addition to the UICC-TNM classification system. METHODS: We evaluated the histopathological tumor regression in 480 surgical resection specimens of GC after neoadjuvant cisplatin-based chemotherapy, using an established system encompassing three tumor regression grades based on the estimation of the percentage of residual tumor tissue at the primary tumor site in relation to the macroscopically identifiable former tumor bed. Tumor regression was correlated to clinicopathological characteristics and patient survival. RESULTS: Of the patients in this study, 102 (21.2%) had complete or subtotal tumor regression (<10% residual tumor), 121 (25.2%) had partial tumor regression (10-50% residual tumor), and 257 (53.5%) had minimal or no regression (>50% residual tumor). Tumor regression was significantly associated with posttreatment tumor category (pT), lymph node status (pN), lymphatic invasion status (pL), and resection status (P < 0.001). Major histopathological regression was less frequent in tumors of the distal stomach and tumors of nonintestinal type (P = 0.003). Tumor regression (P = 0.009) and postoperative Lymph node status (P < 0.001) were independent prognostic factors for survival in a multivariate analysis of tumor regression, ypT/N/L category, resection status, grading and Lauren´s classification. CONCLUSIONS: Assessment of histological tumor regression after preoperative chemotherapy in GC provides objective and highly valuable prognostic information in addition to posttherapeutic lymph node status. A standardized tumor regression grading system should be implemented in pathological reports of these tumors.

Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages.

BACKGROUND: Pancreatic cancer has an extremely poor prognosis and prolonged survival is achieved only by resection with macroscopic tumor clearance. There is a strong rationale for a neoadjuvant approach, since a relevant percentage of pancreatic cancer patients present with non-metastatic but locally advanced disease and microscopic incomplete resections are common. The objective of the present analysis was to systematically review studies concerning the effects of neoadjuvant therapy on tumor response, toxicity, resection, and survival percentages in pancreatic cancer. METHODS AND FINDINGS: Trials were identified by searching MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from 1966 to December 2009 as well as through reference lists of articles and proceedings of major meetings. Retrospective and prospective studies analyzing neoadjuvant radiochemotherapy, radiotherapy, or chemotherapy of pancreatic cancer patients, followed by re-staging, and surgical exploration/resection were included. Two reviewers independently extracted data and assessed study quality. Pooled relative risks and 95% confidence intervals were calculated using random-effects models. Primary outcome measures were proportions of tumor response categories and percentages of exploration and resection. A total of 111 studies (n = 4,394) including 56 phase I-II trials were analyzed. A median of 31 (interquartile range [IQR] 19-46) patients per study were included. Studies were subdivided into surveys considering initially resectable tumors (group 1) and initially non-resectable (borderline resectable/unresectable) tumors (group 2). Neoadjuvant chemotherapy was given in 96.4% of the studies with the main agents gemcitabine, 5-FU (and oral analogues), mitomycin C, and platinum compounds. Neoadjuvant radiotherapy was applied in 93.7% of the studies with doses ranging from 24 to 63 Gy. Averaged complete/partial response probabilities were 3.6% (95% CI 2%-5.5%)/30.6% (95% CI 20.7%-41.4%) and 4.8% (95% CI 3.5%-6.4%)/30.2% (95% CI 24.5%-36.3%) for groups 1 and 2, respectively; whereas progressive disease fraction was estimated to 20.9% (95% CI 16.9%-25.3%) and 20.8% (95% CI 14.5%-27.8%). In group 1, resectability was estimated to 73.6% (95% CI 65.9%-80.6%) compared to 33.2% (95% CI 25.8%-41.1%) in group 2. Higher resection-associated morbidity and mortality rates were observed in group 2 versus group 1 (26.7%, 95% CI 20.7%-33.3% versus 39.1%, 95% CI 29.5%-49.1%; and 3.9%, 95% CI 2.2%-6% versus 7.1%, 95% CI 5.1%-9.5%). Combination chemotherapies resulted in higher estimated response and resection probabilities for patients with initially non-resectable tumors ("non-resectable tumor patients") compared to monotherapy. Estimated median survival following resection was 23.3 (range 12-54) mo for group 1 and 20.5 (range 9-62) mo for group 2 patients. CONCLUSIONS: In patients with initially resectable tumors ("resectable tumor patients"), resection frequencies and survival after neoadjuvant therapy are similar to those of patients with primarily resected tumors and adjuvant therapy. Approximately one-third of initially staged non-resectable tumor patients would be expected to have resectable tumors following neoadjuvant therapy, with comparable survival as initially resectable tumor patients. Thus, patients with locally non-resectable tumors should be included in neoadjuvant protocols and subsequently re-evaluated for resection.

GM1 expression of non-Hodgkin's lymphoma determines susceptibility to rituximab treatment.

Immunotherapy with rituximab alone or in conjunction with chemotherapy has significantly improved the treatment outcome of B-cell lymphoma patients. Nevertheless, a subpopulation of patients does not respond to rituximab. The reason for treatment failure as well as the exact mechanism of action is still uncertain. The function of rituximab has long been associated with the partitioning of CD20 molecules to lipid microdomains. We now show that the extent of CD20 recruitment to lipid rafts correlates with response to rituximab. In addition, expression of the raft-associated sphingolipid GM1 on lymphoma cells is associated with the susceptibility of lymphoma cells to rituximab. Furthermore, we show substantially different GM1 expression in various primary non-Hodgkin's lymphomas. Whereas chronic lymphocytic leukemia (CLL) cells have a low GM1 expression, marginal zone lymphoma cells exhibit much higher levels. Differences were not only detected among various lymphoma subgroups but also within one lymphoma subtype. Interestingly, whereas CLL cells from patients with high GM1 expression responded to rituximab, patients with low GM1 expressing CLL cells did not. These data show the importance of membrane microdomains in the effect of rituximab and may offer a predictive factor for the responsiveness of lymphoma cells to rituximab.

Early response assessment using 3'-deoxy-3'-[18F]fluorothymidine-positron emission tomography in high-grade non-Hodgkin's lymphoma.

PURPOSE: To evaluate 3'-deoxy-3'-[(18)F]fluorothymidine-positron emission tomography (FLT-PET) for early monitoring response of high-grade non-Hodgkin's lymphoma to treatment with cyclophosphamide-adriamycin-vincristine-prednisone chemotherapy with or without rituximab immunotherapy (R-CHOP/CHOP). EXPERIMENTAL DESIGN: Twenty-two patients with histologically proven high-grade non-Hodgkin's lymphoma scheduled to undergo first line treatment with R-CHOP/CHOP were included. All patients received baseline imaging before therapy with FLT-PET. For noninvasive assessment of treatment response, FLT-PET was repeated at following time points: group 1 (n = 6), 1 and 6 weeks after R-CHOP/CHOP; group 2 (n = 16), 2 days after rituximab and 2 days after CHOP application. Emission images were acquired 45 min after injection of 300 to 370 MBq of FLT. FLT uptake was quantified by region-of-interest technique on a lesion basis. Maximum standardized uptake values (SUV) for FLT were calculated using circular region of interest (diameter, 1.5 cm). RESULTS: In all patients, morphologically proven lesions showed initially high FLT uptake (mean SUV, 8.1 +/- 3.9). In group 1, mean FLT SUV decreased 7 days after R-CHOP/CHOP by 77% (P < 0.001), the reduction in FLT SUV from baseline was 85% after 40 days (P = 0.003). In group 2, FLT uptake in patients without dexamethasone pretreatment revealed no significant reduction after rituximab (P = 0.3) but significantly decreased 2 days after CHOP to 32% compared with the baseline value (P = 0.004). CONCLUSIONS: Administration of R-CHOP/CHOP is associated with an early decrease in lymphoma FLT uptake. Interestingly, there was no reduction of FLT uptake after rituximab alone, indicating no early antiproliferative effect of immunotherapy. FLT-PET seems to be promising for early evaluation of drug effects in lymphoma.