Intralymphatic Spread is a Rare Finding Associated With Poor Prognosis in Diffuse Large B-Cell Lymphoma With Extranodal Involvements.

Intralymphatic spread is common in solid cancers, but has been rarely studied in lymphomas. Review of 635 extranodal specimens from 475 diffuse large B-cell lymphoma (DLBCL) patients revealed intralymphatic spread in 10 surgical resection specimens from 10 patients including 9 de novo DLBCLs and 1 Richter transformation. The prevalence in de novo DLBCL with extranodal involvements was 1.65%. The most common involved site of intralymphatic spread was the gastrointestinal tract, followed by the female genital tract and breasts. Lymphatic vessels, lined by D2-40-positive endothelial cells, were expanded by lymphoma cells, reminiscent of intravascular lymphoma or tumor emboli. None of the involved lymphatic vessels were located in the mucosa. Patients with intralymphatic spread had a trend of lower overall response rate and a trend of higher progressive disease than those without intralymphatic spread. Compared with patients without intralymphatic spread, those patients with intralymphatic spread had a shorter median overall survival (14.3 vs. 96.2 mo; P=0.004) and a shorter median progression-free survival (11.2 vs. 64.2 mo; P=0.01), respectively. Multivariate analyses showed that intralymphatic spread was an independent poor prognostic factor for overall survival (hazard ratio, 3.029; 95% confidence interval, 1.315-6.978; P=0.009), irrespective of the National Comprehensive Cancer Network-International Prognostic Index, B symptoms, and serum albumin levels. Among patients who underwent surgical resection, intralymphatic spread was still an independent prognostic factor. In conclusion, our study demonstrated extranodal intralymphatic spread in DLBCL. Inspiringly, this rare morphologic finding may serve as a new negative prognostic indicator in DLBCL with extranodal involvements.

CYP19 genetic polymorphism haplotype AASA is associated with a poor prognosis in premenopausal women with lymph node-negative, hormone receptor-positive breast cancer.

Given the critical role of CYP19 in estrogen synthesis, we investigated the influence of CYP19 gene polymorphisms on the clinical outcome of lymph node- (LN-) negative, hormone receptor- (HR-) positive early breast cancers. Genotyping for the CYP19 polymorphisms rs4646 (A/C), rs1065779 (A/C), CYP19 (TTTA)n (short allele/long (S/L) allele using the 7 TTTA repeat polymorphism as the cut-off), and rs1870050 (A/C) was performed on 296 patients with LN-negative, HR-positive breast cancers. All patients received adjuvant hormonal therapy. Associations were examined between these 4 genotypes and 6 common haplotypes of CYP19 and distant disease-free survival (DDFS), disease-free survival (DFS), and overall survival (OS). Patients were divided into the 6 subhaplotypes of CCLA (41.1%), AASA (17.1%), CASA (11.9%), CCLC (8.9%), CCSA (7.5%), AASC (8.9%), and others (4.6%). In premenopausal patients, haplotype AASA was significantly associated with a poor DDFS (adjusted hazard ratio (aHR), 3.3; P = 0.001), DFS (aHR, 2.5; P = 0.0008), and OS (aHR, 2.9; P = 0.0004) after adjusting for age, tumor size, tumor grade, estrogen receptor status, progesterone receptor status, chemotherapy, pathology, adjuvant hormone therapy, menopausal status, and radiotherapy. Furthermore, haplotype AASA remained a negative prognostic factor for premenopausal patients receiving adjuvant chemotherapy in terms of DDFS (aHR, 4.5; P = 0.0005), DFS (HR, 3.2; P = 0.003), and OS (HR, 6.4; P = 0.0009). However, in postmenopausal patients, haplotype AASA was not associated with a poor prognosis, whereas the AASC haplotype was significantly associated with a poor DFS (aHR, 3.1; P = 0.03) and OS (aHR, 4.4; P = 0.01). Our results indicate that, in patients with LN-negative, HR-positive breast cancers, genetic polymorphism haplotype AASA is associated with poor survival of premenopausal women but does not affect survival of postmenopausal women.

Inferior survival of advanced pancreatic cancer patients who received gemcitabine-based chemotherapy but did not participate in clinical trials.

BACKGROUND: Advanced pancreatic cancer, even when treated, is highly lethal. The best choice of gemcitabine-based therapy and the prognostic factors affecting the success of treatment remain uncertain. METHODS: We identified 159 of 1,475 patients with pancreatic cancer diagnosed in our institution and receiving gemcitabine-based chemotherapy between January 1995 and June 2007. Univariate and multivariate analyses were used to evaluate the prognostic significance of various clinical parameters for overall survival (OS). RESULTS: The median survival after gemcitabine-based therapy was 5.4 months; 89.9% (n = 143) had ductal adenocarcinoma, 55.3% (n = 88) with stage IV. Gemcitabine alone was given to 60 (38%) patients, and gemcitabine with high-dose infusional fluorouracil (5-FU) with (n = 25) or without (n = 39) oxaliplatin was given to 64 (40%) patients. All regimens correlated with OS (p = 0.042) but not with the response rate (RR; p = 0.3). The overall RR was 11.1%, and all responders had a good performance status (PS). The RRs to gemcitabine with infusional 5-FU, and gemcitabine with oxaliplatin and infusional 5-FU were 5.3 and 20.8%, respectively. In a multivariate analysis, old age, advanced stage, poor PS and no enrollment in clinical trials were associated with inferior survival. CONCLUSIONS: The outcome for patients who did not participate in clinical trials, regardless of gemcitabine-based treatment, is still bleak.

E2A-positive gastric MALT lymphoma has weaker plasmacytoid infiltrates and stronger expression of the memory B-cell-associated miR-223: possible correlation with stage and treatment response.

Extranodal marginal-zone lymphoma of mucosa-associated lymphoid tissue of the stomach (gastric MALT lymphoma) is derived from memory B cells of the marginal zone. Normal memory B cells do not express markers of germinal-center B cells, such as E2A (immunoglobulin enhancer-binding factor E12/E47), B-cell chronic lymphocytic leukemia/lymphoma 6 (BCL6), or activation-induced cytidine deaminase (AID). E2A is a transcription factor that induces somatic hypermutations and blocks plasma cell differentiation. In 50 stage-I(E)/II(E1) gastric MALT lymphomas, we confirmed that all cases were BCL6(-)/AID(-), but a subset (50%, 25/50) was E2A(+). As E2A(-) and E2A(+) gastric MALT lymphomas had similar numbers of somatic hypermutations without intraclonal variations, which implied an origin from memory B cells, the expression of E2A was best regarded as a marker of aberrant follicular differentiation. Although the status of somatic hypermutation was not affected by E2A, E2A(+) gastric MALT lymphoma showed less plasmacytoid infiltrates and higher expressions of miRNA-223, a microRNA associated with memory B cells. Clinically, E2A(+) gastric MALT lymphomas were more likely to spread to perigastric lymph nodes and were less responsive to Helicobacter eradication therapy than were E2A(-) gastric MALT lymphomas. Taken together, aberrant E2A expression is a diagnostic feature of a subtype of gastric MALT lymphoma with weaker plasmacytoid infiltrates and stronger miR-223 expression. A prospective study would be necessary to verify the association between E2A expression and a poor response to Helicobacter eradication therapy.

The CYP19 TTTA repeat polymorphism is related to the prognosis of premenopausal stage I-II and operable stage III breast cancers.

PURPOSE: Given the critical role of the CYP19 gene, encoding aromatase, in estrogen synthesis and the association of the estrogen level with its TTTA repeat polymorphism, the potential influence of this polymorphism on breast cancer survival, and hence management, deserves further study. METHODS: Genotyping for the CYP19 TTTA repeat polymorphism was performed on 482 stage I-II and operable stage III Taiwanese breast cancer patients. Patients with more than seven TTTA repeats in either allele of CYP19 were defined as having the long allele. We correlated clinical variables and CYP19 genotypic polymorphism with outcome. RESULTS: In hormone receptor (HR)-positive breast cancers, premenopausal patients with the long allele of the CYP19 polymorphism had a significantly higher overall survival (OS) rate (8-year, 89% versus 68%; p= .003) than those without it. This difference was further demonstrated by a multivariate analysis (OS hazard ratio, 1.53; p= .041). In postmenopausal women or patients with HR-negative breast cancer, there was no significant difference in OS between patients with or without the long allele. In premenopausal women with HR-positive cancers, adequate intensity adjuvant chemotherapy did not achieve a greater OS rate than suboptimal chemotherapy in patients with the long allele, but it resulted in a significantly higher OS rate (p= .011) than suboptimal chemotherapy in women without the long allele. CONCLUSIONS: The CYP19 TTTA repeat polymorphism is associated with survival in premenopausal women, but not in postmenopausal women, with HR-positive breast cancers. Premenopausal women with the long allele have a greater survival rate and may not gain benefit from adjuvant chemotherapy.

Phase II study of weekly paclitaxel and 24-hour infusion of high-dose 5-fluorouracil and leucovorin in the treatment of recurrent or metastatic gastric cancer.

To investigate the efficacy and safety of combining weekly paclitaxel with weekly 24-hour infusion of high-dose 5-fluorouracil (5-FU) and leucovorin (LV, folinic acid) in the treatment of patients with advanced gastric cancer. Patients with histologically confirmed recurrent or metastatic gastric cancer were studied. Paclitaxel 80 mg/m2 3-hour intravenous infusion was given on days 1, 8, and 15, and high-dose 5-FU 2,600 mg/m2 plus LV 300 mg/m2 24-hour intravenous infusion (HDFL) was given on days 2, 9, and 16, repeated every 4 weeks. Between August 1997 and August 2003, 30 patients were enrolled. The median age was 58 years (range: 37-70). Eighteen patients (60.0%) had recurrent or metastatic disease and 12 patients had de novo metastatic disease. Among the 27 patients evaluable for tumor response, 2 achieved complete response and 9 achieved partial response, with an overall response rate of 40.7% (95% confidence interval, CI: 22-61%). Eleven of the 21 patients without prior exposure to HDFL-containing regimens responded (response rate: 52.4%, 95% CI: 29-74%), while none of the 6 patients who had previously failed HDFL-containing regimens responded (p value = 0.054 by Fisher's exact test). All 30 patients were evaluated for survival and toxicities. Median time to progression and overall survival were 6 and 10 months, respectively. Major grade 3-4 toxicities were neutropenia in 12 patients (40.0%), diarrhea in 10 patients (33.3%), and stomatitis in 3 patients (10.0%). Grade 1-2 and 3-4 paclitaxel-related neuropathy developed in 16 (53.3%) and 2 (6.7%) patients, respectively. None of the patients discontinued protocol treatment because of paclitaxel-related neuropathy or developed HDFL-related hyperammonemic encephalopathy. This paclitaxel-HDFL regimen is effective and well tolerated in the treatment of advanced gastric cancer.