Adjuvant Immunotherapy of Resected, Intermediate-Thickness, Node-Negative Melanoma With an Allogeneic Tumor Vaccine: Impact of HLA Class I Antigen Expression on Outcome

2002 ◽  
Vol 20 (8) ◽  
pp. 2067-2075 ◽  
Author(s):  
Jeffrey A. Sosman ◽  
Joseph M. Unger ◽  
P.-Y. Liu ◽  
Lawrence E. Flaherty ◽  
Min S. Park ◽  
...  
Keyword(s):  
Adjuvant Therapy ◽  
Stage Iv ◽  
Hla Class I ◽  
Antigen Expression ◽  
Hla Typing ◽  
Class I ◽  
Relapse Free Survival ◽  
Primary Tumor Site ◽  
Free Survival ◽  
Node Negative

PURPOSE: An association between expression of ≥ two of five HLA class I antigens (HLA-A2, HLA-A28, HLA-B44, HLA-B45, and HLA-C3; collectively called M5) and response to an allogeneic melanoma vaccine (Melacine; Corixa Corporation, Seattle, WA) has been described in stage IV melanoma. This study investigated whether class I antigen expression impacted relapse-free survival (RFS) after adjuvant therapy with this vaccine. PATIENTS AND METHODS: We performed class I (HLA-A, HLA-B, and HLA-C) serotyping on patients enrolled onto Southwest Oncology Group Trial 9035, a randomized, observation-controlled, phase III trial of adjuvant Melacine. All patients had clinically node-negative cutaneous melanoma (1.5 to 4.0 mm). Interactions between treatment and class I antigen expression were tested. Analyses involved all serotyped patients and were adjusted for tumor thickness, method of nodal staging, sex, ulceration, and primary tumor site. RESULTS: HLA typing was performed on 553 (80%) of the 689 enrolled patients (294 vaccinated and 259 observed). Expression of ≥ two M5 antigens was associated with a superior vaccine treatment effect. Among patients who matched ≥ two of the M5, the 97 vaccine-treated patients had improved RFS compared with the 78 observation patients (5-year relapse-free survival, 83% v 59%; P = .0002). The major components of this effect were contributed by HLA-A2 and HLA-C3. Among those who were HLA-A2–positive and/or HLA-C3–positive, the 5-year RFS for vaccinated patients was 77%, compared with 64% for observation (P = .004). There was no impact of HLA-A2 and/or HLA-C3 expression among observation patients. CONCLUSION: This prospective analysis indicates a highly significant benefit of adjuvant therapy with Melacine among patients expressing ≥ two of the M5 class I antigens, validating a prior observation in stage IV disease. HLA-A2 and HLA-C3 contributed most to this effect. Processed melanoma peptides found in Melacine may be presented by HLA-A2 and HLA-C3 and play a role in preventing relapse in vaccinated patients.

scholarly journals Adjuvant Vaccine Immunotherapy of Resected, Clinically Node-Negative Melanoma: Long-term Outcome and Impact of HLA Class I Antigen Expression on Overall Survival

2014 ◽  
Vol 2 (10) ◽  
pp. 981-987 ◽  
Author(s):  
William E. Carson ◽  
Joseph M. Unger ◽  
Jeffrey A. Sosman ◽  
Lawrence E. Flaherty ◽  
Ralph J. Tuthill ◽  
...  
Keyword(s):  
Overall Survival ◽  
Hla Class I ◽  
Antigen Expression ◽  
Class I ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Node Negative ◽  
Hla Class I Antigen ◽  
Adjuvant Vaccine

Factors influencing prognosis in node-negative breast carcinoma: analysis of 767 T1N0M0/T2N0M0 patients with long-term follow-up.

1993 ◽  
Vol 11 (11) ◽  
pp. 2090-2100 ◽  
Author(s):  
P P Rosen ◽  
S Groshen ◽  
D W Kinne ◽  
L Norton
Keyword(s):  
Breast Carcinoma ◽  
Adjuvant Therapy ◽  
Lobular Carcinoma ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Node Negative ◽  
Contralateral Carcinoma ◽  
Tumor Types ◽  
Favorable Group

PURPOSE This study was undertaken to define prognostically favorable and unfavorable subgroups of node-negative breast carcinoma patients by employing conventional pathologic data. PATIENTS AND METHODS Seven hundred sixty-seven women with T1N0M0/T2N0M0 breast carcinoma treated consecutively from 1964 through 1970 by modified or radical mastectomy without systemic adjuvant therapy were analyzed at a median follow-up duration of 18 years. RESULTS Size and histologic type of the carcinoma were crucial discriminants of prognosis. We defined a prognostically favorable group of 219 patients (29%) with infiltrating duct or lobular carcinoma < or = 1.0 cm in diameter or special tumor types < or = 3.0 cm. This group had a relapse-free survival rate of 91% at 10 years and 87% at 20 years. The less favorable group (548 patients, 71%) with infiltrating duct or lobular carcinoma greater than 1.0 cm and special tumor types greater than 3.0 cm had relapse-free survival rates of 73% and 68% at 10 and 20 years, respectively. The frequency of nonmammary malignant neoplasms (NMMN) was similar to that of contralateral carcinoma. Deaths due to NMMN were seven times more frequent than deaths due to contralateral carcinoma. CONCLUSION Nearly 30% of these node-negative patients, identified on the basis of tumor size and type, had an extremely favorable prognosis. There is insufficient evidence to warrant the routine use of adjuvant therapy in this group unless new forms of treatment prove to be less toxic and/or more effective in enhancing relapse-free survival. Early detection of NMMN should be an important part of the follow-up of node-negative breast carcinoma patients.

Improved Outcomes with Class I and II DNA-Based HLA Typing for Matched Unrelated Donor (MUD) Allogeneic Bone Marrow Transplant (ABMT) in Hematologic Diseases.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5181-5181 ◽  
Author(s):  
Ronald Sobecks ◽  
Edward J. Ball ◽  
Lisa Rybicki ◽  
Elizabeth Kuczkowski ◽  
Matt Kalaycio ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Hla Typing ◽  
Class I ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Improved Outcomes ◽  
Typing Methods

Abstract Class I and II DNA-based HLA typing has resulted in improved outcomes in MUD ABMT compared to that observed with HLA serologic typing methods. Since MUDs do not necessarily possess the same linkage of HLA genes on haplotypes as found in matched sibling donors (MSD) it is important to determine the specific alleles present through DNA-based methods in order to improve matching between recipients and donors. We analyzed 146 consecutive hematologic malignancy patients (pts) who underwent ABMT at our institution from 1/7/99–2/4/04, to compare outcomes of 41 MUD and 105 MSD pts. All pts were matched at HLA-A, B, C, and DRB1 by at least low to intermediate resolution using either PCR-sequence specific priming or PCR-sequence specific oligonucleotide probing using Class I and II DNA-based HLA typing. All pts received a busulfan/cyclophosphamide (Bu/Cy)-based preparative regimen. All MUD ABMTs were CD8+ T cell depleted while all MSD ABMTs were T cell replete. GVHD prophylaxis for MUD pts consisted of FK506 and methotrexate while MSD pts received cyclosporine and methotrexate or mycophenolate mofetil. There were no differences between MUD or MSD pts in terms of sex, age, race, prior radiation therapy, or donor-pt gender. Primary diagnoses were comparable except the MSD group had more CML pts (19 vs. 0) (p=0.01 for all diagnoses). There were no differences between MUD and MSD pts regarding infection, acute GVHD, acute grade 3–4 GVHD, chronic GVHD or extensive chronic GVHD. MUD pts as compared to MSD pts had higher graft failure rates (12% vs. 3%, p = 0.019); lower relapse-free survival (median 5.4 mos vs. 10.7 mos, p=0.037); higher 100-day mortality (37% vs. 21%, p=0.05), and lower overall survival (median 5.7 mos vs.13.6 mos, p=0.036). Deaths occurred in 30 (73%) of MUD pts and 61 (58%) of the MSD pts with disease relapse followed by GVHD as the most common causes of death. Since CML pts were only in the MSD group, we repeated the analysis excluding these pts and there were no longer any significant differences between the MUD and MSD pts in 100 day mortality (p=0.12), relapse-free survival (median 5.4 mos vs. 6.5 mos, p=0.22), or overall survival (median 5.7 mos vs. 10.0 mos, p=0.18). For further purposes of comparison, we also analyzed 112 consecutive ABMT pts (31 MUD, T cell depleted; 81 MSD, T cell replete; Bu/Cy-based preparative regimens for all pts) previously transplanted at our institution from 4/93–11/98 during which time only HLA serologic and Class II DNA-based typing was used. In this earlier pt cohort, the MUD pts had a significantly higher incidence of acute GVHD (p<0.001), lower 100-day mortality (52% vs. 12%, p<0.001), lower relapse-free survival (p=0.001) and lower overall survival (2.6 mos vs. 32.5 mos, p=0.001) than the MSD patients. We conclude that Class I and II DNA-based HLA typing is important and can improve outcome in MUD ABMT. Further investigation with high resolution HLA typing methods may continue to improve outcomes with MUD ABMT.

scholarly journals Abnormalities in HLA Class I Antigen Expression by Melanoma Cells: Structural Characterization and Functional Implications

1993 ◽  
Vol 100 (2) ◽  
pp. S226-S230 ◽  
Author(s):  
Sebastiano Gattoni-Celli ◽  
Lidio Calorini ◽  
Hugh Randolph Byers ◽  
Takafumi Etoh ◽  
Zhigang Wang ◽  
...  
Keyword(s):  
Structural Characterization ◽  
Hla Class I ◽  
Antigen Expression ◽  
Melanoma Cells ◽  
Class I ◽  
Hla Class I Antigen ◽  
Functional Implications

Evidence for HLA-related susceptibility for stroke in children with sickle cell disease

Blood ◽  
2000 ◽  
Vol 95 (11) ◽  
pp. 3562-3567 ◽  
Author(s):  
Lori A. Styles ◽  
Carolyn Hoppe ◽  
William Klitz ◽  
Elliott Vichinsky ◽  
Bertram Lubin ◽  
...  
Keyword(s):  
Linkage Disequilibrium ◽  
Cerebral Infarction ◽  
Sickle Cell ◽  
Hla Class I ◽  
Class Ii ◽  
Hla Typing ◽  
Class I ◽  
Increased Risk ◽  
Mri Scans ◽  
Comparison Of The Results

Abstract Cerebral infarction occurs in one quarter of all children with sickle cell anemia (SCA). There is an increased risk of stroke in siblings with SCA, suggesting genetic factors may influence risk of stroke. The authors investigated whether HLA type was associated with risk of stroke in children with SCA. Fifty-three patients with SCA underwent complete HLA typing at both HLA class I (HLA-A, B) and HLA class II (HLA-DR, DQ, DP) loci. Of the 53 patients, 22 had magnetic resonance imagining (MRI)–documented evidence of cerebral infarction, and the remaining 31 patients had negative MRI scans. Comparison of the results of HLA typing between the SCA patients with a positive and those with a negative MRI documented that the 2 groups differed with respect to the class I HLA-B (P = .012), and the class II HLA-DRB1 (P = .0008) and DQB1 (P = .029). Susceptibility associations at the HLA-DRB1 locus included both DR3 alleles, where DRB1*0301 and *0302 were both associated with an increased risk of stroke. Protective associations were found in the DR2 group, where DRB1*1501 was protective for stroke. DQB1*0201, which is in linkage disequilibrium with DRB1*0301, was also associated with stroke. Similarly, DQB1*0602, in linkage disequilibrium with DRB1*1501, was protective. Specific HLA alleles may influence the risk of stroke in children with SCA. HLA typing may prove useful in identifying SCA patients at higher risk for stroke.

Pepsinogen C is a new prognostic marker in primary breast cancer.

1995 ◽  
Vol 13 (1) ◽  
pp. 54-61 ◽  
Author(s):  
F Vizoso ◽  
L M Sánchez ◽  
I Díez-Itza ◽  
A M Merino ◽  
C López-Otín
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Multivariate Analysis ◽  
Prognostic Value ◽  
Survival Duration ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Node Negative ◽  
Pepsinogen C ◽  
Node Positive

PURPOSE Here we evaluate in breast cancer patients the prognostic value of pepsinogen C, a proteolytic enzyme involved in the digestion of proteins in the stomach that is also synthesized by a significant percentage of breast carcinomas. PATIENTS AND METHODS Pepsinogen C expression was examined by immunoperoxidase staining in a series of 243 breast cancer tissue sections, and results obtained were quantified using the HSCORE system, which considers both the intensity and the percentage of cells staining at each intensity. Evaluation of the prognostic value of pepsinogen C was performed retrospectively in corresponding patients by multivariate analysis that took into account conventional prognostic factors. The mean follow-up period was 48.5 months. RESULTS A total of 113 carcinomas (46.5%) stained positively for this proteinase, but there were clear differences among them with regard to the intensity and percentage of stained cells. Pepsinogen C values were significantly higher in well differentiated (grade I, 89.1) and moderately differentiated (grade II, 88.5) tumors than in poorly differentiated (grade III, 27.7) tumors (P < .001). Similarly, significant differences in pepsinogen C content were found between estrogen receptor (ER)-positive tumors and ER-negative tumors (85.9 v 41.2, respectively; P < .05). Moreover, results indicated that low pepsinogen C content predicted shorter relapse-free survival duration and overall survival duration (P < .0001). Separate Cox multivariate analysis for relapse-free survival and overall survival in subgroups of patients as defined by node status showed that pepsinogen C expression was the strongest factor to predict both relapse-free survival and overall survival in node-positive patients (P < .0001 for both) and node-negative patients (P < .005 and P < .01, respectively). CONCLUSION Pepsinogen C is a new prognostic factor for early recurrence and death in both node-positive and node-negative breast cancer. In addition, and in contrast to most studies that concern the prognostic significance of proteolytic enzymes in cancer, pepsinogen C production by breast cancer cells is associated with lesions of favorable evolution.

scholarly journals Mislabeled units of umbilical cord blood detected by a quality assurance program at the transplantation center

Blood ◽  
2009 ◽  
Vol 114 (8) ◽  
pp. 1684-1688 ◽  
Author(s):  
Jeffrey McCullough ◽  
David McKenna ◽  
Diane Kadidlo ◽  
David Maurer ◽  
Harriett J. Noreen ◽  
...  
Keyword(s):  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Hla Typing ◽  
Class I ◽  
Quality Assurance Program ◽  
Cord Blood Unit ◽  
Transplantation Center

Abstract We instituted procedures to check the identity of cord blood unit provided for transplantation by carrying out ABO and human leukocyte antigen (HLA) typing of the thawed units before transplantation. ABO typing is done using standard techniques. Rapid HLA class I serology is with monoclonal antibody trays (One Lambda Inc) using standard incubations. One mislabeled umbilical cord blood (UCB) unit was detected on the day of intended transplantation by repeat ABO typing of the thawed unit at our transplantation center. Because ABO typing will not detect all labeling errors, the rapid serologic class I HLA typing procedure was done on thawed units just before transplantation for all units without an attached segment. This procedure identified a second mislabeled unit. In a 6-year period, 2 of 871 (0.2%) cord blood units sent to us for transplantation were mislabeled and potentially would have been transplanted incorrectly. This error rate of 1 per 249 (0.4%) patients could have potentially devastating consequences.

High Resolution HLA Typing by Sequencing for HLA-A, B, C, DR, DQ in 115 Unrelated Cord Blood/Patient Pairs- Does It Improve Outcomes after Cord Blood-Transplantation?.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 973-973 ◽  
Author(s):  
Gesine Koegler ◽  
Juergen Enczmann ◽  
Vanderson Rocha ◽  
Eliane Gluckman ◽  
Peter Wernet
Keyword(s):  
High Resolution ◽  
Cord Blood ◽  
Cord Blood Transplantation ◽  
Hla Class I ◽  
Hla Typing ◽  
Class I ◽  
Published Data ◽  
Number Of Patients ◽  
The Impact ◽  
Grade Iii

Abstract The CB Bank Düsseldorf has provided to date (July 2004) 224 CB units (216 unrelated and 8 related, 29% adults, 71% children) to transplant centers worldwide. Until now no correlation could be detected between the number of HLA-mismatches based on low resolution (LR) typing for HLA-A and-B and high resolution typing (HR) for DRB1 and the incidence of aGvHD as published previously by us and other groups. The lack of correlation between aGvHD occurrence and donor/recipient HLA diversity in patients given an unrelated CBT could be explained by the fact that some mismatches for HLA class I antigens (A, B and C) are not detected by LR typing. In order to determine the impact of HLA high resolution typing with outcomes, mainly aGvHD after UCBT we analysed DNA samples of 115 CB recipients (86 children; 29 adults; 66 male, 49 female; diagnosis ALL=43, AML=19, SecAL =1, MDS=5, CML=10, NHL=5, Hodgkin=1, AA=7, genetic and metabolic diseases= 24) and their unrelated CB grafts were HLA-typed for HLA-class I (A, B, C) and HLA-class II (DRB1 and DQB1) by sequencing. The transplant centers used their own protocols for GvHD prophylaxis, the most commonly used was the combination of CsA and steroids alone (60%), CsA alone (15%), or the combination with MTX (6%). 55 of 115 patients did not develop aGvHD (grade 0= 48%), 26 patients developed grade I (23%), 12 patients developed grade II (10%), 10 patients grade III (9%) and 12 patients grade IV (10%). When mismatches (MM) were analysed for HLA-A, B based on LR-typing and -DRB1 based on HR-typing in concordance with all published data so far, the following mismatch situation resulted: No MM (16 pairs, 13.9%), one MM (47 pairs, 40.9%), two MM (41 pairs, 35.7%), three MM (5 pairs, 4.3%), four MM (3 pairs, 2.6%). If the MM for A and B alleles detected by HR-typing were included, the situation was as follows: 0 MM (6 pairs, 5.2%), 1 MM (35 pairs, 30.4%), 2 MM (54 pairs, 47%), 3MM (14 pairs, 12.2%), 4 MM (5 pairs, 4.3%), 5 MM (1 pair, 0.9%). If analysing A, B, C, DR and DQ based on HR typing a high additional frequency of MM occurred: No MM (4 pairs, 3.5%), 1 MM (13 pairs, 11.3%), 2 MM (19 pairs, 16.5%), 3 MM (24 pairs, 20.9%), 4 MM (30 pairs, 26.1%), 5 MM (14 pairs, 12.2%), 6 MM (6 pairs, 5.2 %), 6 MM (6 pairs, 5.2%), 7 MM (3 pairs, 2.6%), 8 MM (2 pairs, 1.7%). There was no significant correlation between the number of MM (also analysed in GvHD or rejection direction) using high-resolution level for HLA-A, B and DRB1 as well as for HLA-A, B, C, DRB1 and DQB1 and the development of aGvHD grade III-IV. More interestingly, we have not found any significant correlation between numbers of MM with 2-year survival probability. Although the heterogeneity and number of patients analysed, it shows that the degree of mismatching is even higher than expected, also in comparison to unrelated BMT. It also shows that additional subtyping for HLA-A, B, C and DQ, not performed on a routine basis at present, does not improve the 2-year survival rate.

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