Isabel Alvarado

The role of surgery in primary gastric lymphoma: results of a controlled clinical trial.

Objective:We began a controlled clinical trial to assess efficacy and toxicity of surgery (S), surgery + radiotherapy (SRT), surgery + chemotherapy (SCT), and chemotherapy (CT) in the treatment of primary gastric diffuse large cell lymphoma in early stages: IE and II1. Summary Background Data:Management of primary gastric lymphoma remains controversial. No controlled clinical trials have evaluated the different therapeutic schedules, and prognostic factors have not been identified in a uniform population. Patients and Methods:Five hundred eighty-nine patients were randomized to be treated with S (148 patients), SR (138 patients), SCT (153 patients), and CT (150 patients). Radiotherapy was delivered at doses of 40 Gy; chemotherapy was CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) at standard doses. International Prognostic Index (IPI) and modified IPI (MIPI) were assessed to determine outcome. Results:Complete response rates were similar in the 4 arms. Actuarial curves at 10 years of event-free survival (EFS) were as follows: S: 28% (95% confidence interval [CI], 22% to 41%); SRT: 23% (95% CI, 16% to 29%); that were statistically significant when compared with SCT: 82% (95% CI, 73% to 89%); and CT: 92% (95% CI, 84% to 99%) (P < 0.001). Actuarial curves at 10 years showed that overall survivals (OS) were as follows: S: 54% (95% CI, 46% to 64%); SRT: 53% (95% CI, 45% to 68%); that were statistically significant to SCT: 91% (95% CI, 85% to 99%); CT: 96% (95% CI, 90% to 103%)(P < 0.001). Late toxicity was more frequent and severe in patients who undergoing surgery. IPI and MIPI were not useful in determining outcome and multivariate analysis failed to identify other prognostic factors. Conclusion:In patients with primary gastric diffuse large cell lymphoma and aggressive histology, diffuse large cell lymphoma in early stage SCT achieved good results, but surgery was associated with some cases of lethal complications. Thus it appears that CT should be considered the treatment of choice in this patient setting. Current clinical classifications of risk are not useful in defining treatment.

Specific c-K-ras Gene Mutations as a Tumor-Response Marker in Locally Advanced Rectal Cancer Treated With Preoperative Chemoradiotherapy

Background: Forty percent of patients with colorectal cancer develop mutations in the K-ras gene.Objective: Our objective was to evaluate whether the presence of c-K-ras gene mutations is a useful tumor-response marker in patients with locally advanced rectal cancer treated with preoperative chemoradiotherapy.Material and Methods: Thirty seven patients with locally advanced rectal cancer were treated with preoperative chemoradiotherapy. Four to six weeks later, surgery was performed. Specimens were classified according to the UICC-AJC classification. A segment of the tumor was obtained to analyze specific c-K-ras gene mutations. Restriction fragment length polymorphism (RFLP) and single strand confirmation polymorphism (SSCP) techniques were used with a set of probes to detect specific c-K-ras mutations in codons 12, 13, and 61. The 37 patients were divided into Group A (with mutations) and Group B (without mutations).Results: All 37 patients completed the scheduled treatment. Group A consisted of 12 patients, whose tumors were classified and specific c-K-ras mutations were located as follows: eight in codon 12, two in codon 13, and one in codon 61. Group B consisted of 25 patients. The tumors were classified and there were more early-stage tumors in Group A, whereas in Group B there were more advanced-stage tumors (P 5 .05, respectively). The mean follow-up was 36.2 6 18.3 months. All Group A patients survived, whereas 8 of the 25 patients in Group B died due to progressive metastatic disease. Survival in Group A was 100%, whereas in Group B it was 59% (P 5 .03).Conclusions: The presence of specific c-K-ras mutations is an indicator of tumor response in patients with locally advanced rectal cancer treated with preoperative chemoradiotherapy and surgery. Therefore, responding patients may be more amenable to less radical surgical procedures based on c-K-ras mutations.

Prognostic significance of retrieved lymph nodes per specimenin resected rectal adenocarcinoma after preoperative chemoradiation therapy

BACKGROUND Histologic examination of a regional lymphadenectomy specimen ordinarily should include 12 or more lymph nodes. However, in specimens from patients who received preoperative chemoradiotherapy this number has not yet been established. METHODS From January 1990 to December 2000, 210 patients with rectal adenocarcinoma located between 0 and 10 cm from anal verge with invasion into perirectal fat, tethered or fixed to the pelvis, diagnosed by computed tomography (CT) scan and/or rectal ultrasound were included. All patients received 45 Gy+bolus infusion of 5-FU (450 mg/m2/days 1-5, 28-33 of RT) 4-8 weeks after surgery was performed. Specimens were mapped and sliced. Lymph nodes were studied under clearing or manual techniques. Five-year survival was calculated by Kaplan-Meier method and comparison of groups with log-rank test. Multivariate Cox regression analysis was performed to find risk factors affecting local control and survival. RESULTS There were 126 males and 84 females; mean age was 55.2 years. Low anterior resection was performed in 112 patients, abdominoperineal resection in 85, and pelvic exenteration in 13. Total retrieved lymph nodes numbered 2,554, of which 252 contained metastasis. The group was divided into patients with 1-10 retrieved lymph nodes (n=119) and patients with > or = 11 retrieved lymph nodes (n=91). Median follow-up was 49 months. Local recurrence was as follows: 15% in patients with specimens containing 1-10 lymph nodes and conversely 7.4% in those with > or = 11 (p=0.01). Five-year survival of patients with 1-10 lymph nodes was 48%, whereas for those with > or = 11 lymph nodes it was 69% (p=0.02). CONCLUSIONS Retrieval of at least 11 lymph nodes in the surgical specimen is not only a powerful tool to properly stage patients with rectal adenocarcinoma treated with preoperative chemoradiotherapy and surgery, but it is also of prognostic relevance in that 5-year survival and local recurrence were better in this group of patients.

p53 protein overexpression and response to induction chemoradiation therapy in patients with locally advanced rectal adenocarcinoma

AbstractBackground: The association between mutations in the p53 gene and prognosis in colorectal cancer remains controversial. This report evaluates the role of p53 protein to predict the response of neoadjuvant chemoradiation therapy in patients with primary locally advanced rectal adenocarcinoma. Methods: Between January 1993 and December 1994, 26 patients were seen with locally advanced primary rectal adenocarcinoma, located between 0 and 10 cm from the anal verge, demonstrated clinically and by CT scan. Each received 45 Gy of preoperative radiation therapy (RT) concomitantly with bolus infusion of 5-fluorouracil (5-Fu) (450/mg/m2 on days 1 to 5 and 28 to 33 of RT). Surgery was performed between 4 and 8 weeks later. All the primary tumors were mapped and sliced. The response rate was divided according to the percentage of malignant cells in the rectal wall and perirectal fat. Lymph nodes were studied with the manual or modified clearing technique. p53 mutant status was assessed immunohistochemically from sections of the formalin-fixed, paraffin-embedded pretreatment biopsy and the resected specimen. Results: There were 14 females and 12 males, with a mean age of 54 years. All received the scheduled treatment. An abdominoperineal resection (n=10), low anterior resection (n=10), and pelvic exenteration (n=6) were performed. The stages of tumors were as follows: no residual tumor (n=4); T2 (n=6); T3–4 (N=9); and T3–4, N1,2 (n=7). Fourteen specimens (54%) had mutated p53, and 10 (71%) had >50% of residual tumor, whereas only two (17%) of the specimens with normal p53 had >50% of residual tumor (P=.018). Eight of the 10 low anterior resections were performed in patients whose specimens expressed normal p53. Conclusion: Our results suggest that the determination of p53 is a factor in predicting tumor response in patients who undergo preoperative chemoradiation therapy for rectal adenocarcinoma.

A molecular analysis by gene expression profiling reveals Bik/NBK overexpression in sporadic breast tumor samples of Mexican females

BackgroundBreast cancer is one of the most frequent causes of death in Mexican women over 35 years of age. At molecular level, changes in many genetic networks have been reported as associated with this neoplasia. To analyze these changes, we determined gene expression profiles of tumors from Mexican women with breast cancer at different stages and compared these with those of normal breast tissue samples.Methods32P-radiolabeled cDNA was synthesized by reverse transcription of mRNA from fresh sporadic breast tumor biopsies, as well as normal breast tissue. cDNA probes were hybridized to microarrays and expression levels registered using a phosphorimager. Expression levels of some genes were validated by real time RT-PCR and immunohistochemical assays.ResultsWe identified two subgroups of tumors according to their expression profiles, probably related with cancer progression. Ten genes, unexpressed in normal tissue, were turned on in some tumors. We found consistent high expression of Bik gene in 14/15 tumors with predominant cytoplasmic distribution.ConclusionRecently, the product of the Bik gene has been associated with tumoral reversion in different neoplasic cell lines, and was proposed as therapy to induce apoptosis in cancers, including breast tumors. Even though a relationship among genes, for example those from a particular pathway, can be observed through microarrays, this relationship might not be sufficient to assign a definitive role to Bik in development and progression of the neoplasia. The findings herein reported deserve further investigation.

Second Lethal Events Associated with Treatment for Hodgkin's Disease: A Review of 2980 Patients Treated in a Single Mexican Institute

Presence of second neoplasms and cardiac toxicity has been recognized as potential late lethal second events in patients treated for Hodgkins disease. However, most reports analyze these association independently. We reviewed 2980 cases of patients treated during 1970-1995 with long-term follow-up (> 4 years) in an attempt to identity all late events in Hodgkins disease secondary to the treatment or those which are unrelated. Three hundred and ten patients died, and of these 156 were secondary to relapse and tumor progression. Death associated second tumors and cardiac events were increased 37 fold and 29 fold respectively compared to the general population. The risk factors for this complications did not differ to previous reports and included alkylating agents and/or radiotherapy for second neoplasms and anthracycline therapy and radiotherapy for cardiac toxicity. Moreover, 61 patients died secondary to non-related events. Nevertheless, at 20-years overall survival was 90% (95% confidence interval (CI): 78% to 97%) and event free surviva1 was 88% (95% CI: 76% to 96%) for these patients. Thus, second events, fatal in most cases, should be considered as an expected risk to the treatment in patients with Hodgkins disease; the proposed modifications of therapy may indeed be useful to avoid or diminish these complications in the future.

Colorectal sarcoma: analysis of failure patterns.

Background and Objectives: Colorectal sarcomas (CRS) are rare and their treatment remains controversial, especially for those located in the rectum. The aim of this paper is to evaluate our experience, with special emphasis on the failure pattern after surgical therapy alone or combined with postoperative radiotherapy.

Lack of Prognostic Factors in Follicular Lymphoma

We performed a retrospective analysis of prognostic factors in patients with stage III and IV and high-tumor burden follicular lymphoma (FL) treated with uniform schedules and with a long term follow-up. Eight-hundred and ten patients treated with intensive, anthracycline-based, chemotherapy and adjuvant radiotherapy to sites of initial bulky nodal disease were the basis of this analysis. Age >60 years, presence of B symptoms, bulky disease, >2 extranodal sites involved, high levels of LDH and the presence of serous effusions all identified as worse prognostic factors in univariate analysis were subject to multivariate analysis. Three factors remained significant: age >60 years old, presence of B symptoms and >2 extranodal sites involved and these were found to influence overall survival (OS) and progression-free survival (PFS). We developed a score system and only two groups (score 0 and 1 and score 2 and 3) showed statistical significance in OS. When the International Prognostic Index was applied to these patients, no statistical differences were observed in OS and PFS between the four groups. Comparison of our results with multiple previous studies showed a lack of uniform prognostic factors and adequate prognostic classification could not be performed. In conclusion, it is mandatory for multicentric international clinical analysis to define prognostic factors and search for a clinical classification, as in diffuse large B cell lymphoma, so as to define groups of FL for more aggressive or conservative therapy.