Aggressive Chemotherapy Regimens Research Articles

Pathology Consultation on Gene Mutations in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a rapidly fatal disease without the use of aggressive chemotherapy regimens. Cytogenetic and molecular studies are commonly used to classify types of AML based on prognosis, as well as to determine therapeutic regimens. Although there are several AML classifications determined by particular translocations, cytogenetically normal AML represents a molecularly, as well as clinically, heterogeneous group of diseases. Laboratory evaluation of AML will become increasingly important as new mutations with both prognostic and therapeutic implications are being recognized. Moreover, because many patients with AML are being treated more effectively, these mutations may become increasingly useful as markers of minimal residual disease, which can be interpreted in an individualized approach. Current laboratory studies of gene mutations in AML include analysis of NPM1, FLT3, CEBPA, and KIT. In addition to these genes, many other genes are emerging as potentially useful in determining patients' prognosis, therapy, and disease course. This article briefly reviews the current most clinically relevant gene mutations and their clinical and immunophenotypic features, prognostic information, and methods used for detection.

Plasmablastic Lymphoma of the Maxillary Sinus: Case Report of a Novel Treatment Approach of Concurrent Bortezomib and Intensity-Modulated Radiotherapy

Plasmablastic lymphoma (PBL) is an aggressive variant of diffuse large B-cell lymphoma and was initially described as affecting the oral cavity of patients with HIV. Recently, it has been better characterized through histopathology and case reports demonstrating that it may affect HIV-negative patients as well. In particular, elderly patients that have immunosenescence can develop PBL, and it may present in anatomic sites outside the oral cavity. Treatment typically consists of aggressive chemotherapy regimens, such as CHOP, EPOCH, or hyperCVAD; however, elderly patients may not be able to tolerate such intense regimens. We present a case of an elderly man with PBL of the maxillary sinus treated with a unique regimen of concurrent bortezomib and intensity-modulated radiotherapy (IMRT). This treatment produced a significant, durable tumor response and was well tolerated. Bortezomib with IMRT could be considered an alternative to more intense chemotherapy regimens, particularly in elderly patients with PBL, although prospective studies are needed to further test the safety and efficacy.

B-cell lymphomas with concurrent MYC and BCL2 abnormalities other than translocations behave similarly to MYC/BCL2 double-hit lymphomas

Large B-cell lymphomas with IGH@BCL2 and MYC rearrangement, known as double-hit lymphoma (DHL), are clinically aggressive neoplasms with a poor prognosis. Some large B-cell lymphomas have concurrent abnormalities of MYC and BCL2 other than coexistent translocations. Little is known about patients with these lymphomas designated here as atypical DHL. We studied 40 patients of atypical DHL including 21 men and 19 women, with a median age of 60 years. Nine (23%) patients had a history of B-cell non-Hodgkin lymphoma. There were 30 diffuse large B-cell lymphoma (DLBCL), 7 B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma, and 3 DLBCL with coexistent follicular lymphoma. CD10, BCL2, and MYC were expressed in 28/39 (72%), 33/35 (94%), and 14/20 (70%) cases, respectively. Patients were treated with standard (n=14) or more aggressive chemotherapy regimens (n=17). We compared the atypical DHL group with 76 patients with DHLand 35 patients with DLBCL lacking MYC and BCL2 abnormalities. The clinicopathologic features and therapies were similar between patients with atypical and typical DHL. The overall survival of patients with atypical double-hit lymphoma was similar to that of patients with double-hit lymphoma (P=0.47) and significantly worse than that of patients with DLBCL with normal MYC and BCL2 (P=0.02). There were some minor differences. Cases of atypical double-hit lymphoma more often have DLBCL morphology (P<0.01), less frequently expressed CD10 (P<0.01), and patients less often had an elevated serum lactate dehydrogenase level (P=0.01). In aggregate, these results support expanding the category of MYC/BCL2 DHL to include large B-cell lymphomas with coexistent MYC and BCL2 abnormalities other than concurrent translocations.

Ultra-Deep Sequencing Defines Stem Cell-Specific Diversity Patterns in Acute Myelogenous Leukemia

Acute myelogenous leukemia (AML) is a fatal disease with dismal outcomes. Despite aggressive chemotherapy regimens, most patients relapse and ultimately succumb to their disease. Relapse is thought to be driven by a surviving residual population of leukemia stem cells (LSCs) that remain quiescent and survive chemotherapy. Moreover, relapsed disease has been shown to be frequently more genetically complex, acquiring new mutations not seen in de novo disease. Since the acquisition of new mutations and survival of LSCs are both evident with relapse, we hypothesized that genetic diversity of LSCs is a likely contributor to disease outcomes. To assess diversity, we performed ultra-deep targeted next generation sequencing at up to 15000x non-duplicate depth of coverage, constructed local haplotypes, and performed subclonal variant analysis on AML samples across varying molecular and cytogenetic risk strata. The resulting high resolution molecular portrait enabled us to examine the clonal composition of both lymphocytes and leukemia, including LSCs.Consistent with previous reports, we detected established pre-leukemic mutations in DNMT3A(R882H) evident in both patient-matched sort-purified lymphocytes and leukemic cells. In this patient, the pre-leukemic acquisition of DNMT3A(R882H) observed in lymphocytes was followed by additional acquisition of NRAS(G13D) seen exclusively in the LSC and non-LSC compartments, but not the sorted lymphocyte compartment. Interestingly, we found that LSC populations frequently exhibited more complex clonal architecture and nucleotide diversity (p < 10-18) compared to non-stem matched patient counterparts. Because LSCs inherently resist chemotherapy, genetic lesions occurring in the surviving LSC pool are capable of supporting sustainable outgrowths of new drug resistant clones. Indeed, within this complex stem cell architecture, we identified deeply subclonal lesions in clinically relevant AML genes including FLT3. For example, in one high risk patient, the drug-resistant tyrosine kinase domain mutant FLT3(D835Y) was evident at below 0.25% allele frequency in the LSC compartment. This FLT3 allele demonstrated penetrance into the bulk tumor, but not into normal lymphocytes, indicating the AML-specific context of this subclonal variant.The data suggest that, in addition to surviving chemotherapy, LSCs represent a diverse reservoir of surviving residual cells that can support emergence of drug resistant mutants and refractory relapse. Moreover, ultra-deep sequencing of LSCs and bulk disease will enable improved precision medicine approaches to enhance AML outcomes via early detection of emergent and clinically impactful mutant alleles. DisclosuresNo relevant conflicts of interest to declare.

Phase II study of FOLFOXIRI plus panitumumab (pmab) followed by evaluation for resection, in patients (pts) with metastatic KRAS wild-type colorectal cancer (mCRC) with liver metastases only.

e14552 Background: Pts with liver-only mCRC who are not candidates for potentially curative resection may be converted to resectable with more aggressive chemotherapy regimens with higher response rates (RR). FOLFOXIRI has shown a higher RR and pts sent to resection than FOLFIRI. EGFR inhibitors improve RR by approximately 10%. This phase II, non-randomized, multicenter trial evaluated the RR of the combination of FOLFOXIRI plus pmab as first-line treatment for pts with KRAS wild-type mCRC with liver-only metastasis. Methods: Pts with liver-only KRAS wild-type mCRC received FOLFOXIRI (5-FU 3200 mg/m2 48-hour continuous IV; LV 200 mg/m2 IV; irinotecan 125 mg/m2 IV; oxaliplatin 85 mg/m2 IV) and pmab (6 mg/kg IV) day 1 of each 14-day cycle. Restaging occurred every 4 cycles. Surgical evaluation occurred at baseline and with each restaging. The primary endpoint was overall RR. Secondary endpoints included: rate of R0 resection, progression-free survival (PFS), overall survival (OS), and safety. Results: Fifte...

Treatment outcomes of patients with cervical cancer with complete metabolic responses after definitive chemoradiotherapy

We sought to evaluate failure patterns and prognostic factors predictive of recurrences and survival in cervical cancer patients who are treated with definitive chemoradiotherapy (ChRT), who have a subsequent complete metabolic response (CMR) with (18) F-fluorodeoxyglucose positron-emission tomography (FDG-PET) after treatment. The records of 152 cervical cancer patients who were treated with definitive chemoradiotherapy were evaluated. All patients underwent pre-treatment positron emission tomography (PET-CT), and post-treatment PET-CT was performed within a median of 3.9 months (range, 3.0-9.8 months) after the completion of ChRT. The prognoses of partial response/progressive disease (PR/PD) cases (30 patients, 18 %) and CMR cases (122 patients, %82) were evaluated. Univariate and multivariate analysis effecting the treatment outcome was performed in CMR cases. The median follow-ups for all patients and surviving patients were 28.7 (range, 3.3-78.7 months) and 33.2 months (range, 6.23-78.7 months), respectively. Four-year overall survival (OS) rate was significantly better in patients with CMR compared to patients with PR/PD (66.9 % vs. 12.4 %, p < 0.001, respectively). Patients with PR/PD had higher maximum standardized uptake value (SUVmax) of primary cervical tumor (26.4 ± 10.1 vs. 15.9 ± 6.3; p < 0.001) and larger tumor (6.4 cm ± 2.3 cm vs. 5.0 cm ± 1.4 cm; p < 0.001) compared to patients with CMR. Of the 122 patients with post-treatment CMRs, 25 (21 %) developed local, locoregional, or distant failure. In univariate analysis, tumor size ≥ 5 cm, 'International Federation of Obstetricians and Gynecologists' (FIGO) stage ≥ IIB, and pelvic and/or para-aortic lymph node metastasis were predictive of both overall survival (OS) and disease-free survival (DFS), while histology was predictive of only OS. In multivariate analysis, tumor size, stage and lymph node metastasis were predictive of OS and DFS. Although CMR is associated with better outcomes, relapses remain problematic, especially in patients with bulky tumors (≥ 5 cm), extensive stage (≥ IIB) or pelvic and/or para-aortic lymph node metastasis. These findings could support the need for more aggressive treatment or adjuvant chemotherapy regimens.

Profiles Of De Novo CD25-Positive Mature B-Cell Lymphomas

BackgroundInterleukin 2 (IL-2) is an important cytokine that controls the proliferation and differentiation of not only T- but also B-lymphocytes. Recently, we reported that CD25 (IL-2 receptor alpha chain, IL-2R) is expressed in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), and high expression of CD25 in the two types of lymphoma is correlated with a poor prognosis following chemotherapy regimens containing rituximab (ASH annual meeting, 2011 118:2666, 2012 120:1543). We evaluated the clinical significance of CD25 expression in a larger series of different mature B-cell lymphomas (BCL). Patients and MethodsFour hundred and thirty-seven newly diagnosed patients who were admitted to our hospital between 2002 and 2013 were retrospectively evaluated. Lymph node or related tissue biopsy samples of BCL were analyzed using flow cytometry, as follows: 182 patients, DLBCL; 92, FL; 48, chronic lymphocytic leukemia (CLL); 21, mantle cell lymphoma (MCL); 23, marginal zone lymphoma (MZL); 8, Burkitt lymphoma (BL); 18, B-cell lymphoma unclassifiable with features intermediate between BL and DLBCL (BL/DLBCL); 5, lymphoplasmacytic lymphoma (LPL); and 39, reactive lymphadenopathy with sufficient B-cells. CD25-positivity was defined as >20% of clonal B-cells in a gated region. ResultsCD25 expression in patients with MCL, CLL, MZL, and DLBCL was significantly higher than that in patients with reactive lymphadenopathy (P<0.001,<0.001, =0.019, and <0.001, respectively). BL and FL, which were derived from germinal center B-cells, did not express CD25. These results indicate that pre- or post- germinal center-derived B-cells, activated by IL-2/IL-2R signaling, may give rise to CD25+ BCL such as CD25+ MCL, CLL, MZL, and DLBCL.The highest median CD25 expression (41.5%) was observed in MCL. CD25 expression was higher in MCL than CD5+ BCL (CLL and CD5+ DLBCL) (median, 41.5 vs. 16.9%, respectively; P<0.001). With a cut-off value of 60% CD25-positivity, patients with CD25-high (>60%) MCL (n=9) were not treated with aggressive chemotherapy regimens such as Hyper-CVAD due to their age and characteristics, compared with those with CD25-low (<60%) MCL (n=12) (11.1 vs. 72.7%, respectively, P=0.021).In patients with CLL, the range of CD25 expression was wide (0.4-90.7%), and 29 patients (60%) showed CD25-positivity (CD25+ CLL). CD25+ CLL showed higher soluble IL-2R (sIL-2R) levels and an inferior overall survival (OS) than CD25- CLL (median sIL-2R, 2,195 vs. 706 U/ml P=0.047; 5-year OS, 62.7 vs. 100%; P=0.037). There was a significant correlation between levels of CD25 and sIL-2R (r=0.53, P=0.0053).It is clinically important to distinguish between DLBCL and BCL involving MYC oncogene rearrangement (BL and BL/DLBCL, MYC+ BCL). The former showed higher CD25 expression than the latter (median, 10.2 vs. 2.1%, respectively, P=0.04). The progression-free survival rate (PFS) after rituximab containing chemotherapy was inferior in patients with CD25+ DLBCL (n=72) than those with CD25- DLBCL (n=110) and MYC+ BCL (5-year PFS, 49 vs. 70.4, 66.3%, respectively). In patients with DLBCL, central nerve system (CNS) involvement was observed in 15 patients (7 at diagnosis and 8 at relapse). CD25+ DLBCL showed a higher frequency of CNS involvement than CD25– DLBCL (13.8 vs. 4.5%, respectively, P=0.049).Regarding MZL, CD25 was highly expressed in nodal MZL, but it showed a low expression in splenic MZL. Regarding the sites of extranodal MZL, CD25 expression was lower in the thyroid than at other sites (median, 5.1 vs. 21.2%, respectively, P=0.37). There were some differences between CD25+ (n=9) and CD25- (n=14) MZL concerning the presence of B symptoms (33.3 vs. 0%, respectively) and advanced stage (66.6 vs. 35.7%, respectively). ConclusionCD25 expression using flow cytometry can potentially provide diagnostic and prognostic implications on BCL patient. The high expression of CD25 in MCL and CLL suggests the possibility of targeted anti-CD25 immunotherapy. These findings may shed light on the role of CD25 expression in B-cell lymphomagenesis. Disclosures:No relevant conflicts of interest to declare.

Co-Existent Hyperdiploidy Does Not Abrogate The Poor Prognosis Associated With Adverse Cytogenetics In Myeloma

AbstractThe development of the cytogenetic abnormalities hyperdiploidy or a translocation involving the immunoglobulin heavy chain are initiating events in the pathogenesis of myeloma. Previous studies have shown that hyperdiploidy is associated with a more favorable outcome whilst the presence of specific translocations (4;14), (14;16) and (14;20) are associated with poor clinical outcomes especially when they occur in association with other high risk features such as del17p and 1q+. While it has been generally accepted that these events are mutually exclusive, review of a number of clinical datasets shows that they occur together in a significant proportion of cases. This raises the mechanistic issue of which cytogenetic abnormality occurs first as well as the more practical issue of what it means for prognosis. In order to address these important questions we have investigated these cases with interphase FISH (iFISH) as well as determining their outcome in the Myeloma IX study.Myeloma IX is a large study (1960 newly diagnosed myeloma patients) that has been extensively described. iFISH results with a complete data set for hyperdiploidy, adverse IgH translocations, 1q+ and del17p were available for 847 patients with a median follow up of 5.9 years. 58% of patients (499/847) had hyperdiploidy and had a significantly improved survival compared with non-hyperdiploid patients (Median OS 49.7 vs 42.8 months, p=0.016 and PFS 18.8 vs 16.3 months, p=0.028).Hyperdiploid patients were divided into those who had one or more of the adverse lesions t(4;14), t(14;16), t(14;20), del17p and 1q+ (61%, 304/499) and their outcome was compared to those with none (39%, 195/499). The overall and progression free survival was significantly worse for those with hyperdiploidy plus an adverse lesion compared to those with hyperdiploidy alone (Median OS 60.9 vs 35.7 months, p<0.001, median PFS 23 vs 15.4 months, p<0.001). These results remained significant on multivariate analysis. When subdivided into those patients with hyperdiploidy plus: del17p alone, 1q+ alone, an adverse translocation alone or >1 adverse lesion, there remained a significant detrimental effect on survival (OS and PFS) for the del17p, 1q+ and >1 lesion groups and a trend towards worse survival for those with an adverse translocation (numbers too small to prove significance) when compared to those with hyperdiploidy and no adverse lesion. (table 1)Table 1HD = HyperdiploidyNo. of patientsPFS (months)OS (months)HD, no adverse lesions3042360.9HD plus del 17p2019.1 (p=0.019)35.2 (p=0.003)HD plus 1q+14215.4 (p<0.001)38.1 (p<0.001)HD plus adverse translocation915.4 (p=0.272)40.1 (p=0.180)HD plus >1 lesion2412.1 (p<0.001)19.9 (p<0.001)The converse situation was also examined by taking each population with an abnormal lesion and dividing them by the presence or absence of hyperdiploidy. 409/847 (48%) of patients had at least one adverse lesion and they had a significantly worse outcome within the whole data set than those without any adverse lesions (OS 60.6 vs 33.7 months, p<0.001, PFS 23.3 vs 15 months, p<0.001). When the impact of hyperdiploidy within the high-risk population (195/409 hyperdiploid, 214/409 non-hyperdiploid) was examined there was no difference in survival, (OS 35.7 vs 33.6 months p=0.64, PFS 15.4 vs 14.5 months, p=0.58). This remained true across each adverse lesion when individually analysed.A group of patients with hyperdiploidy and a (4;14) translocation were analysed at a single-cell level using iFISH. Within each case the percentage of cells with a translocation was consistently high, whereas the frequency of individual chromosomal trisomies varied. This suggests that the translocation event may occur earlier. Single cell genetic analysis using the Fluidigm technology is ongoing in order to confirm this finding.In conclusion, patients with co-existent hyperdiploidy and adverse cytogenetics have worse outcomes than those with hyperdiploidy alone. The progression of their disease is not different to those patients with adverse cytogenetics alone and our data suggests that the presence of hyperdiploidy is not able to abrogate or even ameliorate this adverse prognostic feature. It is important that this is recognised when designing treatment strategies for this group of patients as they should be treated with more aggressive chemotherapy regimens to maximize their response and control disease. Disclosures:No relevant conflicts of interest to declare.

The Role Of PET Imaging For Predicting Treatment Failure In Primary Mediastinal B-Cell Lymphoma

IntroductionPrimary mediastinal B-cell lymphoma (PMBL) is a distinct clinicopathologic subtype of diffuse large B-cell lymphoma (DLBCL). The optimal management of PMBL remains controversial. While R-CHOP with or without radiation therapy (RT) is established as a potentially curative regimen in this setting, there have been concerns about a subgroup of PMBL patients (pts) who are refractory to R-CHOP (Soumerai et al, Leuk Lymphoma, 2013). Efforts to improve outcomes led to the use of aggressive chemotherapy regimens such as dose-adjusted R-EPOCH despite the lack of a randomized trial demonstrating benefit (Dunleavy et al, N Engl J Med., 2013). Identifying early predictors of R-CHOP treatment failure may inform risk-adapted treatment strategies in PMBL. 18F-fluorodeoxyglucose-positron-emission tomography fused with CT (PET-CT) has been used as a predictor of treatment failure in Hodgkin lymphoma and DLBCL, but the role in PMBL has not been well described. MethodsWe conducted a retrospective analysis using our institutional database of PMBL pts treated with R-CHOP with or without RT. Overall survival (OS) and progression-free survival (PFS) for the entire cohort and for those with positive versus negative interim and post-treatment PET-CT were calculated by Kaplan Meier method (STATA version 12). PET-CT scans were graded as positive or negative based on the consensus criteria from the International Harmonization Project (IHP) (Juweid et al, J Clin Oncol, 2007). We also determined positive predictive value (PPV) and negative predictive value (NPV) for interim and post-treatment PET-CTs. ResultsWe identified 26 pts with PMBL treated with R-CHOP at our institution between 11/2001 and 5/2013. The median age at diagnosis was 36 years (range 18-57 years). Eight pts had stage I, 15 had stage II, 0 had stage III and 3 had stage IV PMBL. At diagnosis, IPI was low-risk in 21, low-intermediate in 2 and high-intermediate in 3 pts. LDH level was elevated in 18 pts (69%). Thirteen pts (50%) had bulky disease (> 10 cm). After R-CHOP, 19 pts (73%) underwent consolidative RT. At a median follow-up of 35.7 months, median OS was 94.7% (95%CI: 68.1-99.2%) and PFS was 75.3% (95%CI: 52.9-88.1%) for the entire cohort. The PFS and OS at 1 year was 75.3% and 100%, respectively. Six pts (23%) had progressive disease (PD): 5 progressed during or immediately following treatment with R-CHOP (prior to RT). Four pts with PD underwent high dose chemotherapy and autologous stem cell transplantation (ASCT) and all achieved complete response (CR). Only 1 of 26 pts died of progressive PMBL. Two patients required steroids for radiation pneumonitis which resolved.Twenty-two pts (85%) underwent an interim PET-CT following 2 cycles of R-CHOP (N=12), 4 cycles of R-CHOP (N=20) or at both time points (N=10). The PFS at 1 year for pts who had a positive interim PET-CT after either cycle 2 or cycle 4 (N=17) versus pts who had negative interim PET-CT (N=5) was 68.9% vs. 100%, respectively. The NPV of interim PET-CT was 100%, but the PPV was low at 43%. Fifteen pts (58%) underwent a PET-CT at the completion of therapy. Nine (60%) had a negative scan and did not relapse. Six (40%) had a positive scan at the completion of therapy: 3 pts with PD were treated with salvage therapy, one underwent a biopsy that was negative and has not relapsed, and 2 underwent sequential PET-CT scans until resolution of the abnormality. The PFS at 1 year for pts who had a positive post-treatment PET-CT (N=6) versus pts who had a negative post-treatment PET-CT (N=9) was 50% vs. 100% respectively. The NPV for a post-treatment PET-CT was 100% and the PPV was 50%. ConclusionIn our cohort, pts with PMBL had excellent outcomes using R-CHOP with or without RT. Those who failed primary therapy were salvaged with ASCT. There were no relapses after 6 months of completing primary therapy. Negative interim or negative post-treatment PET-CT identified patients who achieve long term remission. However, positive PET-CT in this setting is of limited clinical value in predicting treatment failure. Distinctive characteristics of this DLBCL subtype, including bulky presentation, localization to mediastinum, and necrosis, probably contribute to the high false positive rate, limiting the utility of IHP criteria. We are actively studying other factors (pathological, clinical, and radiographic) which would allow early prediction of therapeutic outcome and the ability to tailor first line therapy for PMBL. Disclosures:No relevant conflicts of interest to declare.

Granulocyte Transfusion Therapy

Bacterial and fungal infections continue to be a major cause of morbidity and mortality in severely neutropenic patients undergoing aggressive chemotherapy regimens or hematopoietic stem cell transplantation. Traditional granulocyte transfusion therapy, a logical approach in treating these infections, has been available for many years, and several controlled studies have shown this therapy to be useful. However, granulocyte transfusion therapy fell out of favor because the results were not clinically impressive, and adverse results were reported. These disappointing results were felt to be, in part, because of the low doses of granulocytes provided. More recent studies have attempted to increase the numbers of transfused cells by stimulating normal granulocyte donors with G-CSF (+/-corticosteroids). With these techniques, the number of granulocytes transfused can be increased 3-4 fold. The cells have been shown to circulate in recipients, and daily transfusions are capable of maintaining normal or near-normal blood neutrophil counts in previously severely neutropenic patients. The cells appear to function normally by a variety of in vitro and in vivo tests. Clinical benefit, as defined by survival or clearance of infection, has not been definitively determined. Results of an ongoing randomized controlled clinical trial should be available in the near future.

A case of long-term survival after repeated response to oxaliplatin-based chemotherapy and repeated thermoablation of liver metastases from colorectal cancer. Should we introduce the concept of oxaliplatin-resistant tumors?

The management of advanced colorectal cancer patients differs among cancer centers. International guidelines recommend offering all the recognized active regimens in order to obtain survival advantage, but little information is given about the sequence and combination in which such regimens should be administered. We report the case of a man with multiple liver metastasis from colorectal cancer followed for more than 78 months at our Institution. Repeated response to the same oxaliplatin, 5-fluorouracil and folinic acid chemotherapy schedule was achieved, and repeated radiofrequency ablation of liver metastases was performed until progression of lung and brain disease at 50 and 72 months, respectively, after the diagnosis of advanced disease. Although the tumor became oxaliplatin and chemo-resistant after the onset of extra-hepatic disease, a more aggressive chemotherapy regimen, including a doublet with a biological, halted tumor growth. The patient survived for more than 78 months without experiencing a major impact on his quality of life. This case reflects the importance of following tumor biology in the therapeutic decision-making process, reintroducing oxaliplatin whenever possible, and adopting a more aggressive strategy when the tumor becomes oxaliplatin-resistant.

Response evaluation following neoadjuvant treatment of pancreatic cancer patients

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human neoplastic entities, with a very poor prognosis characterized by a high mortality rate and short survival. This is due both to its aggressive biological behaviour and the high incidence of locally advanced stages at the time of the initial diagnosis. The limits of resectability and the role of neoadjuvant (radio) chemotherapy for PDAC management are still unclear. A recently published article by Kats et al compared the radiological, surgical and histopathological results of 129 patients with borderline resectable tumors undergoing neoadjuvant treatment followed by surgery. Although post-neoadjuvant treatment imaging implied a low response rate, a high rate of complete resections was achieved. This seems to confirm that, though radiology has made a significant progress in defining locally advanced PDAC, there is place for further improvement. In particular, the differentiation between radiotherapy-induced scarring/fibrosis and cancer-associated desmoplasia remains a clinical/radiological challenge. Though selection of patients with occult systemic disease is possible with neoadjuvant treatment, downstaging does not seem to occur frequently. Thus, development of novel, more aggressive (radio) chemotherapy regimens is required to improve prognosis of patients with locally unresectable but not systemically micro-metastasized tumors.

Achieving the Best of Both Worlds

Achieving the Best of Both Worlds

Analysis of Prognostic Factors in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma and Skeletal Involvement: A Novel Simple Prognostic Score Identifies a Large Group of Low Risk Patients with an Excellent Prognosis

AbstractAbstract 1590 Background:Skeletal involvement (SI) is observed at low prevalence in patients with diffuse large B-cell lymphoma (DLBCL). Although extranodal lymphoma sites are generally regarded a risk factor, as reflected in the international prognostic index (IPI), there is limited data on prognostic factors further differentiating outcome in patients with DLBCL and SI due to the rareness of this particular entity. Whether there is a need for intensification of chemotherapy or combination with radiotherapy in all of these patients is a matter of debate. Methods:Medical charts of the Department of Hematology and Oncology from the University of Heidelberg Hospital were retrospectively reviewed in regard to patient characteristics, treatment and outcome. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The impact on PFS and OS of variables was evaluated by univariate log-rank tests. Results:A total of 812 patients with DLBCL were treated between January 2000 and December 2011. Of these, 75 patients (9.2%) were found to have presented with SI at initial diagnosis. Median age of patients with DLBCL and SI was 53.6 years [range 16–83]; 51 patients were male. 2 year (y) PFS was 76% and 2y OS was 81%. According to IPI, 18 (24%) were low risk (IPI 0–1), 35 (47%) intermediate risk (IPI 2–3) and 16 (21%) high risk (IPI 4–5); 6 patients had a missing IPI score. Of the five IPI components, only Ann Arbor stage III-IV was significantly associated with both reduced PFS and OS (p < 0.001). In contrast, neither ECOG > 1 nor extranodal sites > 1 were significantly associated with PFS or OS. We additionally analysed the impact of a higher number of extranodal sites, multilocular SI as well as of elevated serum calcium and serum AP levels (both thought to be indicative of increased bone metabolism) on patients’ survival. We found that more than 3 extranodal sites as well as hypercalcemia were significantly associated with both reduced PFS and OS (p < 0.001 and p < 0.01, resp.), whereas elevated serum AP and multilocular SI had no impact.In a next step, we developed a novel prognostic score taking into account the presence of hypercalcemia, extranodal sites > 3 and Ann Arbor stage III-IV (one point each). According to this score, 32 (43%) were low risk (0 points), 23 (31%) intermediate risk (1 point) and 13 (17%) high risk (> 1 point); 7 patients had no evaluable score due to missing variable. 2y PFS for score 0, 1, and > 1 was 100%, 71% and 36%, resp.; 2y OS was 97%, 81% and 39%, resp. (figure 1). No significant difference in regard to first-line treatment modalities was noticeable between different score groups. Patients in the low risk group (score 0) had an excellent outcome independently of addition of rituximab, escalation of standard CHOP chemotherapy to a more aggressive regimen or additional radiotherapy. In contrast, patients with score > 0 showed improved outcome with the addition of rituximab (2y PFS 61% vs 33%, p < 0.01; 2y OS 68% vs 33%, p = 0.06) as well as a trend to benefit from a more aggressive chemotherapy regimen than CHOP (2y PFS 73% vs 50%, p = 0.17; 2y OS 82% vs 56%, p = 0.14). Radiotherapy did not seem to have a significant impact. Conclusions:Patients with DLBCL and SI are a very heterogeneous population. A novel prognostic score comprising hypercalcemia, extranodal sites > 3 and Ann Arbor stage III-IV allows the identification of a large proportion of low risk patients with excellent outcome independently of treatment modalities. In contrast, patients with a higher risk score seem to benefit from the addition of rituximab as well as from a more aggressive chemotherapy regimen than standard CHOP. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Surgical Palliation of Pancreatic Cancer

The surgical palliation of pancreatic cancer remains an important component of the treatment of this disease. The introduction of a new aggressive and effective chemotherapy regimen (FOLFIRINOX), interdisciplinary palliative care, and minimally invasive approaches for providing palliation are all factors that expand the role of the surgeon in the care of patients with unresectable disease. Currently, the role of the surgeon in the palliation of pancreatic cancer is (1) to identify patients with incurable disease (either preoperatively or intraoperatively), (2) to determine the optimal palliative technique to optimize results and preserve resources, and (3) to perform palliation of symptoms with low morbidity and mortality. The 3 most common symptoms of pancreatic cancer requiring surgical palliation are obstructive jaundice, gastric outlet obstruction, and tumor-associated pain. It is important that the surgeon recognizes the full range of surgical and nonoperative techniques available and contributes to the decision making as to the most appropriate method for each individual patient.

Prognostic significance of RACGAP1 mRNA expression in high-risk early breast cancer: a study in primary tumors of breast cancer patients participating in a randomized Hellenic Cooperative Oncology Group trial

RACGAP1 is a Rac GTPase-activating protein involved in cell growth regulation, cell transformation and metastasis. The aim of the present study was to explore the prognostic and/or predictive significance of RACGAP1 mRNA expression on disease-free survival (DFS) and overall survival (OS) in high-risk early breast cancer patients and compare it to that of Ki67 protein expression and to the Nottingham prognostic index (NPI). A total of 595 high-risk breast cancer patients were treated in a two-arm trial evaluating postoperative dose-dense sequential chemotherapy with epirubicin followed by CMF with or without paclitaxel. RNA was extracted from 314 formalin-fixed paraffin-embedded primary tumor tissue samples followed by one-step quantitative RT-PCR for assessing RACGAP1 mRNA expression. High RACGAP1 mRNA expression (above the median) was associated with poor DFS (log-rank, p = 0.002) and OS (p < 0.001). High histological grade, as well as high Ki67 protein expression, was more frequent in the high-expression group of RACGAP1. Results of the Cox multivariate regression analysis revealed that high RACGAP1 mRNA expression independently predicted poor overall survival (Wald's p = 0.008). High Ki67 protein expression was also an adverse prognostic factor for death (p = 0.016), while high NPI score values were not. High RACGAP1 mRNA expression, as assessed by qRT-PCR, was found to be of adverse prognostic significance in high-risk early breast cancer patients treated with dose-dense sequential chemotherapy. The utility of RACGAP1 mRNA expression in patient selection for treatment with aggressive chemotherapy regimens should be further explored and validated in larger cohorts.

Hodgkin’s disease and HIV infection (HD-HIV): Prognostic factors in 596 patients (pts) within the group of European Cooperation on AIDS and Tumors (GECAT).

8058 Background: Hodgkin’s disease (HD) is the most common non-AIDS defining tumour diagnosed in HIV setting. The introduction of highly active antiretroviral therapy (HAART) has opened a new prospective in the treatment of pts with HD-HIV as the better control of the underlying HIV infection allows the use of more aggressive chemotherapy regimens, including high dose chemotherapy. However, up to now prognostic factors on overall survival (OS) or time to treatment failure (TTF) have not yet been identified. Methods: In order to identify prognostic factors, we analyzed data on 596 pts with HD-HIV diagnosed and treated in 90 different Institution of 6 European countries from October 1983 to March 2010. All factors were analyzed for OS and TTF. Results: 86% of pts were male and the median CD4 cell count was 224/dl (range 3-1274); 52% of pts had mixed cellularity subtype, stages III-IV were diagnosed in 72% of cases and 55% of pts had extranodal involvement (bone marrow 35%, spleen 21%, liver 14%). The table summarizes the results of multivariate analysis. Conclusions: We identified a new “European Score” for HD-HIV able to predict different outcomes in these patients. This score should be considered for future prospective studies. [Table: see text]

The influence of age plus standard clinical approach with or without comprehensive geriatric assessment (CGA) on treatment decisions in older cancer patients: Final results.

9035 Background: The aim of this prospective study was to examine how age and standard clinical approach with and without CGA results determine treatment decisions in older cancer patients (pts). Methods: This study,conducted in 2 Belgian university hospitals, included pts ≥ 70 years with a malignant tumor (breast, colorectal, ovarian, lung, prostate and hematological) if a new cancer therapy was considered. All pts underwent a uniform CGA. Results were communicated to the treating physician. After the treatment decision, an interview with the treating physician was performed, using a predefined questionnaire: 1/ What would be your oncological treatment proposal in case the pt was 55y without other comorbidity? 2/ Is this different from your treatment proposal for this pt according to age and standard clinical approach without CGA results? 3/ Is this different from your treatment proposal for this pt with CGA results? Results: From October 2009 till July 2011, 937 pts were included in the study. Median age was 76y (range 70-95) and 63.5% was female. A total of 902 (96.3%) questionnaires were completed and 56.2% of the physicians were aware of the CGA results at treatment decision. In 381 pts (42.2%; 95%CI 39.0-45.5) age and standard clinical approach led to a different treatment decision compared to younger pts without comorbidity. This influence was most prominent for chemotherapy decisions: 309 patients did not receive standard chemotherapy (reduced dose (13), less toxic regimen (163), less toxic regimen at reduced dose (5) or no chemotherapy (128)). When the physician was aware of the CGA, these results influenced their treatment in 6.7% (95%CI: 4.5-8.9), mostly concerning chemotherapy. In 8 pts CGA results encouraged the treating physician to choose a more aggressive chemotherapy regimen and in 11 pts CGA results led to a decision of palliative care. Conclusions: Based on this prospective trial, we conclude that physicians use adapted treatment regimens in older versus younger pts, only based on age and standard clinical approach. CGA results change the treatment decision in 6.7% and sometimes trigger the use of a more aggressive treatment.

666 A NOVEL RISK STRATIFICATION SYSTEM FOR CHEMOTHERAPY FAILURE IN TESTICULAR GERM CELL TUMOR

You have accessJournal of UrologyPenis/Testis/Urethra: Benign & Malignant Disease I1 Apr 2012666 A NOVEL RISK STRATIFICATION SYSTEM FOR CHEMOTHERAPY FAILURE IN TESTICULAR GERM CELL TUMOR Jessica Lubahn, Nicholas Cost, Mehrad Adibi, Adam Romman, Ganesh Raj, Arthur Sagalowsky, and Vitaly Margulis Jessica LubahnJessica Lubahn Dallas, TX More articles by this author , Nicholas CostNicholas Cost Dallas, TX More articles by this author , Mehrad AdibiMehrad Adibi Dallas, TX More articles by this author , Adam RommanAdam Romman Dallas, TX More articles by this author , Ganesh RajGanesh Raj Dallas, TX More articles by this author , Arthur SagalowskyArthur Sagalowsky Dallas, TX More articles by this author , and Vitaly MargulisVitaly Margulis Dallas, TX More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.747AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The initial management of testicular germ cell tumor (T-GCT) is tailored by TNMS staging to surveillance, retroperitoneal lymph node dissection (RPLND), platinum-based chemotherapy (CT), or radiation. Risk stratification according to the International Germ Cell Collaborative Group classification (IGCCG) determines the CT regimen. We present a novel classification system, which can be easily used to predict CT failure (CT-F). METHODS We reviewed an institutional T−GCT database and selected patients who had undergone any CT. CT-F was defined as tumor marker elevation following normalization, receiving any salvage CT, or presence of active GCT in post-CT RPLND. CT-F patients were compared to those successfully treated with CT (CT-S). Factors predictive of CT-F on univariate analysis were used to develop a risk scoring system (RSS). One point was allotted to each risk factor and summed into an overall score. The prognostic ability of the RSS was compared to the IGCCG by constructing Receiver Operating Curves (ROC). RESULTS 205 patients were reviewed (153 CT-S, 52 CT-F). Factors predictive of CT-F included post-orchiectomy AFP and HCG, number of metastatic sites, N and M status. Non-significant factors included histology (seminoma v non-seminoma), initial treatment modality, and T stage. The RSS, derived from the mean tumor marker values in the CT-F group, consisted of the following criteria: AFP>3000, HCG>50,000, LDH>800, N3, non-pulmonary visceral metastasis, and >3 metastatic sites. The RSS distribution was obtained for CT-S and CT-F (p=0.00) respectively: 0: 101(89.4%) vs. 12(10.6%), 1:39(71.0%) vs. 16(29.0%), 2: 4(30.8%) vs. 9(69.2%), >3: 2(14.3%) vs. 12(85.7%). The hazard ratios for scores 1,2, and >3 were 2.53, 6.62, and 22.2 respectively (p=0.00). The figure depicts time to CT-F, stratified by RSS. The calculated ROC for our RSS had an Area Under the Curve (AUC) of 0.78±0.04 (p=0.001) compared with the AUC of 0.72±0.48 (p=0.001) for the IGCCG classification. CONCLUSIONS This novel RSS more accurately predicts CT-F than the IGCCG criteria. It may be used to easily identify patients who would benefit from more aggressive CT regimens and to aid in risk-stratification for future study development. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e271-e272 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jessica Lubahn Dallas, TX More articles by this author Nicholas Cost Dallas, TX More articles by this author Mehrad Adibi Dallas, TX More articles by this author Adam Romman Dallas, TX More articles by this author Ganesh Raj Dallas, TX More articles by this author Arthur Sagalowsky Dallas, TX More articles by this author Vitaly Margulis Dallas, TX More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

B-cell lymphomas with MYC/8q24 rearrangements and IGH@BCL2/t(14;18)(q32;q21): an aggressive disease with heterogeneous histology, germinal center B-cell immunophenotype and poor outcome

B-cell lymphomas with MYC/8q24 rearrangement and IGH@BCL2/t(14;18)(q32;q21), also known as double-hit or MYC/BCL2 B-cell lymphomas, are uncommon neoplasms. We report our experience with 60 cases: 52 MYC/BCL2 B-cell lymphomas and 8 tumors with extra MYC signals plus IGH@BCL2 or MYC rearrangement plus extra BCL2 signals/copies. There were 38 men and 22 women with a median age of 55 years. In all, 10 patients had antecedent/concurrent follicular lymphoma. Using the 2008 World Health Organization classification, there were 33 B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma (henceforth referred to as unclassifiable, aggressive B-cell lymphoma), 23 diffuse large B-cell lymphoma, 1 follicular lymphoma grade 3B, 1 follicular lymphoma plus diffuse large B-cell lymphoma, 1 B-lymphoblastic lymphoma, and 1 composite diffuse large B-cell lymphoma with B-lymphoblastic lymphoma. Using older classification systems, the 33 unclassifiable, aggressive B-cell lymphomas most closely resembled Burkitt-like lymphoma (n=24) or atypical Burkitt lymphoma with BCL2 expression (n=9). Of 48 cases assessed, 47 (98%) had a germinal center B-cell immunophenotype. Patients were treated with standard (n=23) or more aggressive chemotherapy regimens (n=34). Adequate follow-up was available for 57 patients: 26 died and 31 were alive. For the 52 patients with MYC/BCL2 lymphoma, the median overall survival was 18.6 months. Patients with antecedent/concurrent follicular lymphoma had median overall survival of 7.8 months. Elevated serum lactate dehydrogenase level, ≥2 extranodal sites, bone marrow or central nervous system involvement, and International Prognostic Index >2 were associated with worse overall survival (P<0.05). Morphological features did not correlate with prognosis. Patients with neoplasms characterized by extra MYC signals plus IGH@BCL2 (n=6) or MYC rearrangement with extra BCL2 signals (n=2) had overall survival ranging from 1.7 to 49 months, similar to patients with MYC/BCL2 lymphomas. We conclude that MYC/BCL2 lymphomas are clinically aggressive, irrespective of their morphological appearance, with a germinal center B-cell immunophenotype. Tumors with extra MYC signals plus IGH@BCL2 or MYC rearrangement plus extra BCL2 signals, respectively, appear to behave as poorly as MYC/BCL2 lymphomas, possibly expanding the disease spectrum.