Biomedical subjects

Jing Qin

Publications and source records attributed to Jing Qin.

At least 37 records · Page 2Linked to original sources

PubMed2004

Patterns of morphologic alteration in residual rectal carcinoma following preoperative chemoradiation and their association with long-term outcome.

Preoperative radiation (RT) and chemotherapy improve outcome in patients with locally advanced rectal adenocarcinoma and, therefore, have been used increasingly in patient management. The histopathologic alterations in postirradiated rectal adenocarcinoma and their prognostic significance have not been fully characterized. In this study, detailed analyses of morphologic alterations of stromal and tumor cells were performed in a series of 66 posttreatment rectal carcinomas, and the pathologic findings were correlated with long-term outcome. All tumors were locally advanced, with a bulky and/or tethered tumor or endorectal ultrasound or magnetic resonance imaging evidence of T3-4 and / or N1 disease. All patients were treated at one institution with preoperative RT to the pelvis (at least 4500 cGy) with or without concurrent 5-fluorouracil (5-FU)-based chemotherapy 4 to 7 weeks prior to surgical resection. Pathologic assessment showed some treatment response in all patients. Nine patients (13.4%) had complete response, and 8 (11.9%) had near-complete response (> 95% of the tumor replaced by fibroinflammatory tissue). Salient morphologic features included marked fibrosis with or without prominent inflammatory cells replacing neoplastic glands; lack of active tumor necrosis; increased mucin production and mucin pools; marked cytoplasmic eosinophilia, often in combination with marked nuclear atypia but without active mitoses in tumor cells showing treatment effect; endocrine tumor phenotype; and retention of mucosal adenoma in the presence of tumor regression within the bowel wall. With a median follow-up of 69 months, the estimated 5-year recurrence-free survival (RFS) for the entire group was 79%. By univariate analysis, the residual tumor stage (P < 0.05) and reduction of pretreatment T stage (P = 0.002) significantly correlated with RFS, as did pN stage (P = 0.002) and lymphovascular invasion (P = 0.008). The extent of treatment response did not correlate with RFS (P = 0.4). However, patients with a treatment response > or = 95% seemed to fare better than those with a treatment response < 95% (marginally significant difference in RFS, P = 0.057). Univariate and multivariate analyses identified the following morphologic patterns that were significantly associated with a reduced RFS independent of other risk factors: a fibrotic-type stromal response with minimal inflammatory infiltrates (P = 0.001) and absence of surface ulceration (P = 0.026). Our study represents the first detailed morphologic assessment of rectal carcinomas that have been subjected to long course preoperative RT and chemotherapy. Our results demonstrate distinct morphologic features in treated rectal carcinomas that are prognostically relevant.

Adenocarcinoma↗

PubMed2004

Adverse prognostic significance of CD20 positive Reed-Sternberg cells in classical Hodgkin's disease.

The prognostic significance of CD20 positive classical Hodgkin's disease (cHD) is uncertain. All cHD cases referred to the Memorial Sloan-Kettering Cancer Center (MSKCC) were retrospectively identified (5/92-11/00); the samples were immunostained, and clinical data ascertained. Cases were re-reviewed without knowledge of clinical outcome. Univariate and multivariate analyses were performed 248 patients had cHD: 28 CD20(+) (11%); 220 CD20(-). All clinical characteristics were comparable except haemoglobin level at presentation. With a median follow-up of 29.2 months, significant prognostic factors in multivariate analysis were: CD20 positivity, elevated white blood cell count (WBC) and low absolute lymphocyte count for time-to treatment failure (TTF); and for overall survival (OS), CD20 positivity, elevated WBC count, bone marrow involvement and age >/=45 years. TTF was significantly poorer for ABVD-treated patients with CD20(+) cHD as compared with CD20(-) cHD. Among 167 patients treated at MSKCC, both TTF (P < 0.0001) and OS (P = 0.017) were significantly decreased in CD20(+) patients as compared with CD20(-) cHD. CD20(+) cHD is a poor prognostic factor for TTF and OS. All cHD cases should be immunophenotyped for CD20. A large prospective trial is needed to confirm these findings.

Adolescent↗

PubMed2004

Factors that affect final height and change in height standard deviation scores in survivors of childhood cancer treated with growth hormone: a report from the childhood cancer survivor study.

GH deficiency is a common late complication in survivors of pediatric malignancies, particularly those who are treated with radiation (RT) to the hypothalamic-pituitary region. Nonetheless, few reports have assessed final height outcomes in survivors treated with GH. In the present study, we investigated which patient and treatment variables correlate with final height and change in height sd score (SDS) in a large cohort of cancer survivors treated with GH. We previously identified 361 participants in the multicenter Childhood Cancer Survivor Study who were treated with GH. Final height data were available in 183 survivors (120 males). Diagnoses included: central nervous system tumors (n = 90), acute leukemia (n = 64), soft tissue sarcomas (n = 23), and miscellaneous (n = 6). The median age at diagnosis of the primary cancer was 4.6 yr, and the median age at start of GH treatment was 11.3 yr. Mean height SDS at start of GH therapy was -2.03 +/- 0.8, and the mean final height SDS was -1.48 +/- 0.10 (P < 0.001). Final height SDS was positively associated with target height and dose of GH but negatively associated with the presence of concomitant endocrinopathies and dose of spinal RT. Change in height SDS (start of GH-final height) was positively associated with male gender, younger bone age at start of GH, and dose of GH; presence of concomitant endocrinopathies and dose of spinal RT were negatively associated with change in height SDS. Risk factors associated with a final height of -2.0 sd or less included lower doses of GH and exposure to higher doses of spinal RT. Thus, to maximize final height, our findings emphasize the importance of beginning GH therapy at the earliest bone age that is clinically feasible; treating with conventional higher doses of GH; and, when possible, minimizing the dose of spinal RT.

Adolescent↗

PubMed2004

[Clinical significance of soluble selectins and matrix metalloproteinases-9 in patients after successful cardiopulmonary resuscitation].

OBJECTIVE: To investigate whether patients after successful cardiopulmonary resuscitation (CPR) exist elevated levels of soluble P-and E-selectin (sP-selectin, sE-selectin), matrix metalloproteinases-9 (MMP-9) and to evaluate the clinical significance of changes in these cytokine levels. METHODS: Plasma levels of sP-and sE-selectin, MMP-9 of 82 patients who survived >or=48 hours after CPR were determined on the second day after successful CPR. They were classified into different groups according to whether causing systemic inflammatory response syndrome (SIRS) and developing sepsis. Sixty-five non-critically ill patients were served as control group. RESULTS: Incidence of SIRS was 68.3% (56/82 cases) after successful CPR. Plasma levels of sP-selectin were higher in patients with SIRS compared with those in patients without SIRS or control group (all P<0.01). Plasma levels of sE-selectin and MMP-9 were not significantly different between patients with SIRS and without SIRS (all P>0.05), but were higher in both patient groups than those in the control group (all P<0.01) 43.9% of the patients developed sepsis within 1 week after CPR. Plasma levels of sP-selectin were higher in patients developing sepsis than those in patients without sepsis (P<0.05), but plasma levels of sE-selectin and MMP-9 were not significantly different between two groups (all P>0.05). Plasma levels of sE-selectin and MMP-9 were higher in nonsurvivors than those in survivors (both P<0.01), but plasma levels of sP-selectin were not significantly different between two groups (all P>0.05). CONCLUSION: SIRS is a frequent but unspecific finding after CPR with only minor impact on outcome. Determination of sP-and sE-selectin, MMP-9 early after CPR might help to identify patients at a high risk for sepsis or an adverse, respectively.

Adult↗

PubMed2003

Relationship between REL amplification, REL function, and clinical and biologic features in diffuse large B-cell lymphomas.

Although it has been suggested that REL is the critical target gene of 2p12-16 amplification in diffuse large B-cell lymphoma (DLBCL), little experimental evidence supports this notion. In the present study, we sought to evaluate the relationship between REL amplification and REL function in a panel of 46 newly diagnosed DLBCLs and to correlate with DLBCL subgroups as identified by gene expression profiles and clinical features. The results indicate that amplification of the REL locus is not associated with accumulation of the active form of REL, as evaluated by immunofluorescence analysis. Upon subgrouping of the DLBCL cases based on gene expression signatures, REL amplification was detected in all subgroups, while high levels of nuclear-located REL were more frequently detected in activated B-cell-like DLBCL. Correlative analyses of REL copy number and REL nuclear accumulation with clinical parameters did not reveal any significant associations. Together these results indicate that 2p12-16 amplification does not lead to abnormal REL activation, suggesting that REL may not be the functional target of the amplification event. Nonetheless, these data indicate that DLBCLs are heterogeneous with respect to REL and thus nuclear factor-kappaB (NF-kappaB) activity.

Adult↗

PubMed2003

Lymphoblastic lymphoma of childhood and the LSA2-L2 protocol: the 30-year experience at Memorial-Sloan-Kettering Cancer Center.

BACKGROUND: Until the 1970s, diffuse lymphoblastic lymphoma (DLBL) was considered incurable. With intensive multidrug regimens, the majority of patients can now be cured. In the current study, the authors present what to their knowledge is the longest follow-up presented to date (median, 20 years for survivors) of the largest group of DLBL patients treated with a single protocol at a single institution. METHODS: Between 1971-1990, a total of 95 consecutive patients (age < 21 years) with DLBL were treated with the LSA(2)-L(2) protocol at the Memorial Sloan-Kettering Cancer Center (MSKCC). Patients with Stage I-II disease were treated for 2 years. In 1980, the protocol was modified and patients with Stage III and IV disease were treated for 3 years. In addition, before the modification, patients with Stage IV disease received a cumulative dose of 15,600 mg/m(2) of cyclophosphamide for 3 years; after 1980, these patients received the same dosage as the other patients (i.e., 8400 mg/m(2) for 2 years). Radiation therapy initially was administered to all patients with bulky disease in the primary tumor site. Until 1977, the dose of radiation was 20-55 grays (Gy); from 1977 to 1989, the dose was 20 Gy. After the fifth year of completion of treatment, all patients were evaluated comprehensively every 2 years. RESULTS: The overall survival (OS) of the patients was 79% with a median follow-up of 20 years. The overall event-free survival (EFS) was 75% (71 of 95 patients). Seventeen patients developed a disease recurrence and 15 died of disease. The OS and EFS rates for patients with Stages I-II disease (n = 8) were 87% and 87%, respectively, and the OS and EFS rates for patients with Stage III disease (n = 41) were 90% and 85%, respectively. The OS and EFS for patients with Stage IVA disease (with bone marrow [BM] involvement of < 25%) (n = 19) were 79% and 73%, respectively, whereas the OS and EFS for patients with Stage IVB disease (BM involvement of > 25%) (n = 27) were 74% and 70%. Of the 29 patients with Stage IV disease who were treated with the original protocol, 7 died of disease (1 of 8 patients with Stage IVA disease and 6 of 21 patients with Stage IVB disease). Of the 17 patients with Stage IV disease who were treated with the modified protocol, 3 died of disease (2 of 11 patients with Stage IVA disease and 1 of 6 patients with Stage IVB disease). Six patients developed secondary malignancies, four of whom died. CONCLUSIONS: Long-term EFS can be achieved in the majority of patients with widely disseminated pediatric DLBL. Chemotherapy alone appears to be sufficient prophylaxis against disease recurrence in the central nervous system. No disease-related or treatment-related deaths were reported to occur > 4.5 years after diagnosis in the current study.

Adolescent↗

PubMed2003

Intensive chemotherapy with cyclophosphamide, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine (CODOX-M/IVAC) for human immunodeficiency virus-associated Burkitt lymphoma.

BACKGROUND: In the era of highly active antiretroviral therapy (HAART), standard-dose chemotherapy for human immunodeficiency virus (HIV)-associated diffuse large B-cell lymphoma is becoming the standard of care. In contrast, the safety and efficacy of intensive regimens have not been established for Burkitt lymphoma (BL), a highly aggressive lymphoma for which moderate-dose chemotherapy is substandard in the HIV-negative population. METHODS: To evaluate the feasibility of intensive chemotherapy in HIV-associated BL, the authors retrospectively reviewed 14 HIV-positive adults with BL treated at their center between 1988 and 2000. Eight patients were treated between 1996 and 2000 with cyclophosphamide, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine (CODOX-M/IVAC), one of the currently preferred intensive-dose chemotherapy regimens for BL. Six received other chemotherapy. Outcomes were compared with those of 24 HIV-negative adult patients with BL who had similar patient characteristics and were treated concomitantly (13 with CODOX-M/IVAC; 11 with other regimens). RESULTS: Of the 14 HIV-positive patients, 63% had a complete response after CODOX-M/IVAC treatment, compared with 67% of patients receiving other chemotherapy. The 2-year event-free survival (EFS) rates were 60% and 60% after CODOX-M/IVAC or other regimens, respectively. Similar outcomes were seen despite the fact that 88% of CODOX-M/IVAC-treated HIV-positive patients had Stage IV disease, compared with one-third of HIV-positive patients treated with other chemotherapy. HIV status did not adversely affect long-term EFS independent of the treatment regimen (P = 0.88). When EFS was evaluated according to chemotherapy regimen independent of HIV status, CODOX-M/IVAC was found to be associated with improved EFS (P = 0.05) in all patients, and particularly those at high risk. HIV-positive patients treated with CODOX-M/IVAC tolerated chemotherapy well with similar rates of myelosuppression and infectious complications as HIV-negative patients. CONCLUSIONS: The current nonrandomized retrospective study suggested that intensive chemotherapy with CODOX-M/IVAC is feasible and well tolerated in HIV-positive adults with BL. In the post-HAART era, intensive chemotherapy such as CODOX-M/IVAC may be appropriate in all adult patients with BL, and especially those with poor prognostic factors, regardless of HIV status.

Adult↗

PubMed2003

Long-term event-free survival after intensive chemotherapy for Ewing's family of tumors in children and young adults.

PURPOSE: To improve the long-term event-free survival of patients with Ewing's family of tumors (EFTs) using high-dose, short-term chemotherapy. PATIENTS AND METHODS: P6 was a prospective study of previously untreated patients with newly diagnosed EFTs. Patients received seven cycles of chemotherapy. Cycles 1, 2, 3, and 6 consisted of cyclophosphamide 2,100 mg/m2/d on days 1 and 2, and a 72-hour continuous infusion of doxorubicin 75 mg/m2 and vincristine 2 mg/m2 starting day 1. Cycles 4, 5, and 7 consisted of 5 consecutive days of ifosfamide 1,800 mg/m2/d and etoposide 100 mg/m2/d. RESULTS: Sixty-eight patients were enrolled from 1991 to 2001 (median age, 18.7 years; range, 3.7 to 39.9 years). At diagnosis, 44 patients had local-regional disease, and 24 had distant metastases. The 4-year event-free survival (EFS) rate for patients with local-regional disease is 82%; overall survival (OS) is 89%. The 4-year EFS rate for patients with distant metastases is 12%; the OS rate is 17.8%. All events occurred within 51 months of diagnosis. Four patients with distant metastases had progressive disease during therapy, and no patient with local-regional disease experienced disease progression during therapy. CONCLUSION: Sustained EFS and OS can be achieved with intensive chemotherapy in children and young adults with local-regional EFTs. This therapy is relatively ineffective in the treatment of metastatic EFTs.

Adolescent↗

PubMed2003

Genome-wide analysis of gene expression associated with MYCN in human neuroblastoma.

Molecular mechanisms through which MYCN expression contributes to the malignant phenotype of neuroblastoma are unknown. We performed a genome-widegene expression analysis of 40 well-characterized neuroblastic tumors and 12 cell lines to identify genes and biological pathways associated with MYCN expression. Gene expression was validated by reverse transcription-PCR and immunohistochemistry using tissue arrays. Two hundred twenty-two of 62,839 oligonucleotide probe sets detected expression of genes that were strongly associated with MYCN expression. Differentially expressed genes included examples of known oncogenes, genes associated with neural differentiation, and genes related to cell proliferation. Expression of a subset of these genes was altered after transfection of a neuroblastoma cell line, SK-N-ER, with a MYCN expressing gene construct when protein synthesis was inhibited and have consensus MYCN binding E-box sequences in their promotor regions, suggesting they represent direct targets. Several novel genes/expressed sequences were identified as overexpressed and most likely coamplified with MYCN in a subset of cases. A classification model to identify neuroblastomas with high levels of MYCN expression was developed based on expression profiles. The identification of coexpressed and coamplified genes associated with MYCN overexpression in neuroblastoma suggests biochemical pathways that contribute to the malignant behavior of these tumors and forms a basis for molecular classification.

Cell Nucleus↗

PubMed2003

A secreted high-affinity inhibitor of human TNF from Tanapox virus.

A class of secreted poxvirus tumor necrosis factor (TNF)-binding proteins has been isolated from Tanapox-infected cell supernatants. The inhibitor bound to a TNF-affinity column and was identified as the product of the 2L gene. Sequence analysis of 2L family members from other yatapoxviruses and swinepox virus yielded no sequence homology to any known cellular gene. The expressed Tanapox virus 2L protein bound to human TNF with high affinity (K(d) = 43 pM) and exhibits an unusually slow off-rate. However, 2L is unable to bind to a wide range of human TNF family members. The 2L protein can inhibit human TNF from binding to TNF receptors I and II as well as block TNF-induced cytolysis. Thus, Tanapox virus 2L represents an inhibitor of human TNF and offers a unique strategy with which to modulate TNF activity.

Amino Acid Sequence↗

PubMed2003

Age-adjusted International Prognostic Index predicts autologous stem cell transplantation outcome for patients with relapsed or primary refractory diffuse large B-cell lymphoma.

Second-line chemotherapy followed by high-dose therapy (HDT) with autologous stem cell transplantation (ASCT) cures less than half of the patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Prognostic models capable of predicting outcome are essential. In 3 sequential clinical trials, conducted from January 1993 to August 2000, we treated 150 patients with relapsed or primary refractory DLBCL with ifosfamide, carboplatin, and etoposide (ICE) chemotherapy followed by HDT/ASCT for patients with chemosensitive disease. We evaluated the age-adjusted International Prognostic Index at the initiation of second-line therapy (sAAIPI) as a predictor of progression-free survival (PFS) and overall survival (OS). At a median follow-up of 4 years, the PFS and OS are 28% and 34% by intention to treat and 39% and 45% for only those patients with chemosensitive disease. Three risk groups with different PFS and OS were identified by the sAAIPI: low risk (0 factors), 70% and 74%; intermediate risk (1 factor), 39% and 49%; and high risk (2 or 3 factors), 16% and 18% (P <.001 for both PFS and OS). The sAAIPI also predicts the PFS and OS for patients with ICEchemosensitive disease: low risk, 69% and 83%; intermediate risk, 46% and 55%; and high risk, 25% and 26% (P <.001 PFS and OS). The sAAIPI predicts outcome for patients with relapsed or primary refractory DLBCL in both intent-to-treat and chemosensitive populations. This powerful prognostic instrument should be used to evaluate new treatment approaches and to compare results of different regimens.

Adolescent↗

PubMed2003

CHOP with high dose cyclophosphamide consolidation versus CHOP alone as initial therapy for advanced stage, indolent non-Hodgkin's lymphomas.

The role of high dose therapy, including autologous stem cell transplantation (ASCT) in indolent non-Hodgkin's lymphomas remains controversial. We evaluated a dose intense regimen of CHOP induction followed by high dose cyclophosphamide consolidation (CHOP-HC) versus CHOP alone in a prospective comparison to assess intensified therapy without ASCT. Twenty-five patients with previously untreated advanced stage indolent NHL were enrolled: follicular lymphoma, grade 1 (11 patients) and grade 2 (8 patients); small lymphocytic lymphoma (5 patients); and lymphoplasmacytic lymphoma (1 patient). All patients were treated as clinically indicated. The median age was 47 years (21-70). There were 15 males, and 10 females. Three patients had intra-abdominal stage II, 2 patients with stage III, and 20 patients with stage IV disease. All patients received induction with CHOP for 4 cycles (weeks 1, 4, 7, 10): cyclophosphamide 750 mg/m2 i.v., doxorubicin 50 mg/m2 i.v., vincristine 1.4 mg/m2 i.v. (2 mg capped dose) and prednisone 100 mg p.o. x 5 days. Following induction, responding patients were given consolidation with either high dose cyclophosphamide @ 3 gm/m2 i.v. for 3 doses with G-CSF (weeks 13, 15, 17) or 2 additional cycles of CHOP (weeks 13, 16), stratified by stage and bulk of disease. The overall response rate to CHOP was 92% (3 CR, 8 PR) and to CHOP-HC was 93% (4 CR, 8 PR). The overall response, complete response and partial response rates were comparable in both arms. Median progression free survival for CHOP was 15.9 and 23.0 months for CHOP-HC. At 74.3 months median follow-up, all patients in the CHOP arm have recurred; 3 patients in the CHOP-HC arm (3 CR) have not recurred. The median overall survival has not been reached (at 5 years, 77% OS for CHOP-HC versus 83% OS for CHOP alone]. Greater hematologic toxicity was observed with CHOP-HC resulting in an increased number of hospitalizations for sepsis. There were no treatment-related deaths. No myelodysplasia or acute leukemia has been seen to date. With no obvious improvement in CR and with greater hematologic toxicity than CHOP, CHOP-HC is not recommended for treatment of indolent non-Hodgkin's lymphomas.

Adult↗

PubMed2003

Value of histopathology in predicting microsatellite instability in hereditary nonpolyposis colorectal cancer and sporadic colorectal cancer.

Identification of colorectal carcinomas with high levels of DNA microsatellite instability (MSI-H) is important because of the suggested prognostic and therapeutic significance associated with MSI. The role of histology in identifying MSI-H colorectal carcinomas has been suggested by some studies but not confirmed by others. Furthermore, previous studies assumed that hereditary nonpolyposis colorectal cancer (HNPCC)-associated MSI-H tumors and sporadic MSI-H tumors have similar histology. This assumption, however, has been challenged by more recent studies. In this report, we first analyzed the value of various histologic features in predicting MSI-H in a series of 218 colorectal carcinomas containing mixed HNPCC and sporadic cases [77 tumors (35%) were MSI-H by polymerase chain reaction (PCR) method]. Then, we evaluated the various histologic features comparatively in two groups extracted from the 218 cases. Group A was composed of 84 tumors from 82 patients obtained based on a strong family history (HNPCC/HNPCC-like group) (male to female ratio, 42:40; age range, 23-80 years, median, 53.5 years). Thirty-one of the 84 tumors (41.7%) were MSI-H by PCR, and all 31 cases were HNPCC by Amsterdam criteria. Group B was composed of 109 patients with no family history of colorectal cancer or HNPCC-associated cancer, obtained from surgical clinics (sporadic group) (male to female ratio, 65:69; age range, 31-84 years, median, 65 years). Thirty-five of the 109 tumors (32.1%) were MSI-H by PCR. Our results showed that, overall, poor tumor differentiation, medullary type, mucinous type, signet-ring cell component, histologic heterogeneity, and increased tumor-infiltrating lymphocytes (TILs) were features more commonly seen in MSI-H tumors than in non-MSI-H tumors. Comparative analyses showed that the overall TIL count was significantly higher in HNPCC/HNPCC-like group, and mucinous type appeared to be more frequent in HNPCC MSI-H tumors than in sporadic MSI-H tumors. However, there was no significant difference in the odds ratio for predicting MSI-H status for any of the analyzed histologic features between HNPCC/HNPCC-like group and sporadic group, indicating that differences between HNPCC and sporadic MSI-H tumors did not significantly impact on the informative value of histology in predicting MSI in the two different clinical settings. TIL counts followed by histologic heterogeneity provided the greatest sensitivity and specificity in predicting MSI status in both HNPCC/HNPCC-like and sporadic cases. Using a stepwise logistic regression model, a formula was generated that could be used to calculate the probability of a colorectal carcinoma being MSI-H based on morphologic features.

Adaptor Proteins, Signal Transducing↗

PubMed2003

MUC-1 mucin protein expression in B-cell lymphomas.

We have recently shown that MUC1, mapped to the chromosomal band 1q21, is rearranged or amplified in 15% of B-cell lymphomas and that rearrangement led to over-expression of MUC-1 mucin in a case of diffuse large B-cell lymphoma (DLBCL). To determine the incidence of MUC-1 mucin expression and its clinical significance in B-cell lymphomas, we investigated a panel of 113 cases by immunohistochemistry (IHC). MUC-1 mucin expression was detected in the majority of cases (92.9%), with moderate to high levels noted in 50.4% of all histologic subsets comprising DLBCL (82 cases), follicular lymphoma (FL) (15 cases), FL with transformation to DLBCL (4 cases), and other B-cell lymphomas (12 cases). No statistically significant correlation was found between MUC-1 mucin expression and MUC1 genomic status (amplification/rearrangement) evaluated by Southern blot analysis, and 1q21 abnormality by karyotypic analysis. For all cases, MUC-1 mucin expression correlated with a previous history of lymphoma (p=0.003).

Blotting, Southern↗

PubMed2003

Complete genomic sequence and comparative analysis of the tumorigenic poxvirus Yaba monkey tumor virus.

The Yatapoxvirus genus of poxviruses is comprised of Yaba monkey tumor virus (YMTV), Tanapox virus, and Yaba-like disease virus (YLDV), which all have the ability to infect primates, including humans. Unlike other poxviruses, YMTV induces formation of focalized histiocytomas upon infection. To gain a greater understanding of the Yatapoxvirus genus and the unique tumor formation properties of YMTV, we sequenced the 134,721-bp genome of YMTV. The genome of YMTV encodes at least 140 open reading frames, all of which are also found as orthologs in the closely related YLDV. However, 13 open reading frames found in YLDV are completely absent from YMTV. Common to both YLDV and YMTV are the unusually large noncoding regions between many open reading frames. To determine whether any of these noncoding regions might be functionally significant, we carried out a comparative analysis between the putative noncoding regions of YMTV and similar noncoding regions from other poxviruses. This approach identified three new gene poxvirus families, defined as orthologs of YMTV23.5L, YMTV28.5L, and YMTV120.5L, which are highly conserved in virtually all poxvirus species. Furthermore, the comparative analysis also revealed a 40-bp nucleotide sequence at approximately 14,700 bases from the left terminus that was 100% identical in the comparable intergene site within members of the Yatapoxvirus, Suipoxvirus, and Capripoxvirus genera and 95% conserved in the Leporipoxvirus genus. This conserved sequence was shown to function as a poxvirus late promoter element in transfected and infected cells, but other functions, such as an involvement in viral replication or packaging, cannot be excluded. Finally, we summarize the predicted immunomodulatory protein repertoire in the Yatapoxvirus genus as a whole.

Amino Acid Sequence↗

PubMed2003

mRNA expression levels of E2F transcription factors correlate with dihydrofolate reductase, reduced folate carrier, and thymidylate synthase mRNA expression in osteosarcoma.

Previous studies have shown that decreased expression of the reduced folate carrier (RFC) and increased expression of dihydrofolate reductase (DHFR) are associated with intrinsic and acquired methotrexate resistance, respectively, in osteosarcoma (OS). It has also been shown in colorectal cancer that E2F-1 expression correlates with thymidylate synthase (TS) and, to a lesser extent, DHFR expression. To begin to investigate the regulation of DHFR and RFC expression in OS samples, mRNA expression of E2F-1 and E2F-4 were measured in OS tumor samples and related to DHFR, RFC, and TS mRNA expression. Using fluorescent quantitative real-time PCR, 112 human OS patient samples were investigated for potential E2F-1/E2F-4:DHFR, E2F-1/E2F-4:RFC, and E2F-1/E2F-4:TS correlations. The expression ranges for each gene are as follows: DHFR, 0.02-33.13 (median = 0.20); RFC, 0.02-229.13 (median = 1.91); TS, 0.01-9.99 (median = 0.15); E2F-1, 0.05-69.07 (median = 0.52); and E2F-4, 0.24-52.35 (median = 1.45). Spearman correlation coefficients (r(s)) for E2F-1:DHFR, E2F-1:RFC, E2F-1:TS, E2F-4:DHFR, E2F-4:RFC, and E2F-4:TS were calculated to be 0.53, 0.63, 0.60, 0.41, 0.58, and 0.33, respectively (P < 0.001). On the basis of this data, moderate correlations exist between E2F-1/E2F-4 and DHFR, RFC, and TS. These results suggest E2F-1/E2F-4 may play a role in the regulation of RFC expression, which has not been reported previously. The E2F transcription factors are also related to DHFR and TS expression in OS samples, suggesting a possible involvement in methotrexate resistance. Although E2F mRNA levels correlate with DHFR, RFC, and TS mRNA expression, additional experiments are necessary to determine the direct effects of these transcription factors and identify other proteins that may influence this relationship.

Adolescent↗

PubMed2002

Evolving significance of prognostic markers associated with treatment improvement in patients with stage 4 neuroblastoma.

BACKGROUND: With recent improvements in the treatment and outcome of patients with neuroblastoma (NB), the authors reassessed the prognostic importance of clinical and biologic markers in patients with Stage 4 NB who were treated at the Memorial Sloan-Kettering Cancer Center (MSKCC). METHODS: The authors analyzed 84 patients with Stage 4 NB who were treated on the N5, N6, or N7 protocols at MSKCC from 1987 to 1999. The impact on survival of clinical factors (age, serum ferritin, and lactate dehydrogenase [LDH] levels), histopathology (International Neuroblastoma Pathology Classification [INPC]), and tumor biologic markers (MYCN; ploidy; loss of heterozygosity [LOH] at 1p36, 1p22, 11q23, 14q12-q32, 9p21, and 19q13; and gain at 17q) were analyzed in univariate and multivariate models. RESULTS: Forty-six of 84 patients were alive at the time of this report (55%), with a median follow-up of 41 months from the time of diagnosis. In the univariate analysis, there was no prognostic impact on survival by age, serum ferritin and LDH levels, MYCN, 1p36 LOH, 14q32 LOH, or 17q gain. LOH at 11q23 was associated significantly with superior progression free survival (P = 0.04) and survival (P = 0.04) in the univariate analysis. In the multivariate analysis, it was found that 11q23 status was the most significant variable associated with overall survival (hazard ratio, 0.50; 95% confidence interval, 0.26-0.99). LOH at 11q23 and LOH at 1p22 were highly correlated (P = 0.02). It was found that 11q23 status and INPC score were the most significant variables associated with progression free survival. CONCLUSIONS: Because patient survival improves with more effective therapy, traditional prognostic markers, such as age, MYCN amplification, and elevated serum LDH levels, have become less important for patients with Stage 4 NB. In the current study, less common chromosomal abnormalities (LOH at 1p22 and 11q23) appeared to assume new importance.

Age Factors↗

PubMed2002

Spectral karyotyping identifies new rearrangements, translocations, and clinical associations in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL), a histologically well-defined subset of non-Hodgkin lymphoma, is clinically and genetically heterogenous. By G-banding, most cases showed complex hyperdiploid karyotypes and diverse cytogenetic abnormalities that included recurring and nonrecurring translocations, deletions, duplications, and marker chromosomes. While G-banding provided valuable leads to identification of specific rearrangements that enabled gene discovery and clinical correlations, many aberrations remained uncharacterized because of their complexity. The molecular cytogenetic technique spectral karyotyping (SKY), on the other hand, enables complete characterization of all aberrations in a tumor cell karyotype and, hence, precise quantitation of chromosome instability. We report here, for the first time, SKY analysis of a panel of 46 DLBCL cases previously analyzed by G-banding, ascertained at the Memorial Sloan-Kettering Cancer Center. This analysis provided a cytogenetic profile of DLBCL that was characterized by a higher level of instability, qualitatively as well as quantitatively, compared with G-banding. Thus, 551 breakpoints were detected by SKY, in contrast to the 295 by G-banding. Several new recurring breakpoints, translocations, and regions of gain and loss were identified, which included 13 breakpoints not previously identified by G-banding, 10 breakpoints that were underrepresented by G-banding, and 4 previously unrecognized translocations: der(14)t(3;14)(q21;q32), t(1;13)(p32;q14), t(1;7)(q21;q22), and der(6)t(6;8)(q11;q11). We identified new clinical associations involving recurring breakpoints detected by SKY. These studies emphasize the value of SKY analysis for redefinition of chromosomal instability in DLBCL to enhance gene discovery as well as clinical correlation analysis.

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