Ulas Darda Bayraktar

Primary ocular adnexal mucosa‐associated lymphoid tissue lymphoma (MALT): single institution experience in a large cohort of patients

Extranodal marginal zone B‐cell lymphoma is the most common orbital tumour. We conducted a retrospective analysis to examine: (i) the impact of initial presentation and staging on outcome and (ii) response to various treatment modalities and the effect of the latter on recurrence. Ninety patients with primary ocular adnexal marginal zone lymphoma (POAML) diagnosed at our institution between 1984 and 2009 were studied. POAML was associated with monoclonal gammopathy (13%) at presentation. Most POAML patients (86%) presented with Ann‐Arbor stage I disease. Radiotherapy led to excellent local control, but relapses occurred in 18% of Ann‐Arbor stage I patients during a median follow‐up of 5 years. Local relapses, including secondary central nervous system (CNS) involvement, were observed in patients receiving radiation doses <30·6 Gy. No differences in relapse rate and survival were observed between patients who did or did not undergo staging bone marrow biopsy. Ann‐Arbor stage II–IV disease and high lactate dehydrogenase levels were associated with shorter freedom from progression. In conclusion, POAML is an indolent lymphoma with continuous risk for relapse. Radiation doses of at least 30·6 Gy should be given in Ann‐Arbor stage I disease, since lower doses may be more frequently associated with relapses, including CNS relapses.

Does delay of adjuvant chemotherapy impact survival in patients with resected stage II and III colon adenocarcinoma

It is unclear whether delays in commencing adjuvant chemotherapy after surgical resection of colon adenocarcinoma adversely impact survival.

Vitamin D receptor upregulation in alloreactive human T cells

Vitamin D deficiency is adversely associated with diseases characterized by inflammation. The combination of the high incidence of vitamin D deficiency in patients undergoing allogeneic stem cell transplants (SCT) and the potential role of vitamin D deficiency in influencing graft-versus-host disease led us to further characterize the expression of VDR on alloreactive T cells. We hypothesized that vitamin D receptor expression may directly regulate alloreactive T cell responses. To overcome existing limitations in measuring VDR in bulk cellular populations, we developed a flow cytometric assay to measure cytoplasmic VDR in human T cells. Upon stimulation, VDR was expressed extremely early and exhibited sustained upregulation with chronic stimulation. VDR expression was also coupled to cytokine production, proliferation, and ERK1/2 phosphorylation. In addition, VDR exhibited a maturation stage-specific pattern of expression, with greatest expression on cells known to mediate GVHD, naïve and early memory T cells. Alloreactive T cells upregulated VDR, whereas the nonreactive T cells did not. Finally, repletion of vitamin D in vitro was sufficient to significantly reduce alloreactive T cell responses. These data suggest that vitamin D effects on T cells may be important in reducing graft versus host disease (GVHD) in the allogeneic stem cell transplant setting.

Zidovudine-based lytic-inducing chemotherapy for Epstein - Barr virus-related lymphomas

Abstract Treatment of Epstein–Barr virus (EBV)-related lymphomas with lytic-inducing agents is an attractive targeted approach for eliminating virus-infected tumor cells. Zidovudine (AZT) is an excellent substrate for EBV-thymidine kinase: it can induce EBV lytic gene expression and apoptosis in primary EBV+ lymphoma cell lines. We hypothesized that the combination of AZT with lytic-inducing chemotherapy agents would be effective in treating EBV+ lymphomas. We report a retrospective analysis of 19 patients with aggressive EBV+ non-Hodgkin lymphoma, including nine cases of acquired immune deficiency syndrome-associated primary central nervous system lymphoma (AIDS-PCNSL) treated with AZT-based chemotherapy. Our results demonstrate that high-dose AZT–methotrexate is efficacious in treating highly aggressive systemic EBV+ lymphomas in the upfront setting. In primary EBV+ lymphoma cell lines, the combination of AZT with hydroxyurea resulted in synergistic EBV lytic induction and cell death. Further, AZT–hydroxyurea treatment resulted in dramatic responses in patients with AIDS-PCNSL. The combination of AZT with chemotherapy, especially lytic-inducing agents, should be explored further in clinical trials for the treatment of EBV-related lymphomas.

Outcome of patients with relapsed/refractory acquired immune deficiency syndrome-related lymphoma diagnosed 1999–2008 and treated with curative intent in the AIDS Malignancy Consortium

Abstract No comparative studies exist for relapsed/refractory (rel/rfr) acquired immune deficiency syndrome (AIDS)-related lymphoma (ARL). To determine practices over the last decade and to assess the outcomes of salvage chemotherapy with curative intent and autologous stem cell transplant (ASCT), we retrospectively evaluated treatment outcomes in patients with rel/rfr ARL who were treated in 13 national AIDS Malignancy Consortium (AMC) sites between 1999 and 2008 (n = 88). The most commonly used second-line therapies were ICE (ifosfamide/carboplatin/etoposide, n = 34), dose adjusted EPOCH (etoposide/prednisone/vincristine/cyclophosphamide/doxorubicin, n = 17) and ESHAP (etoposide/methylprednisolone/cytarabine/cisplatin, n = 11). The odds of achieving a response were lower for those with non-Hodgkin lymphoma (NHL) than for those with HL and for those with primary refractory disease than for those with relapse. Overall survival (OS) was significantly longer for those with relapsed disease compared to those with refractory disease and for those with non-Burkitt NHL compared to those with Burkitt. OS was longer in patients who underwent ASCT compared to those who did not (1-year OS: 63.2% vs. 37.2%). However, among 32 patients (36%) who achieved a complete or partial reponse (CR/PR) after second-line therapy, 1-year OS was not different between the two groups (87.5% for ASCT vs. 81.8% for non-ASCT). Long-term survival in some patients with rel/rfr ARL may be possible without transplant, although transplant remains the standard of care for chemotherapy sensitive disease.

Azacitidine combined with gemtuzumab ozogamicin in patients with relapsed/refractory acute myeloid leukemia

Relapsed/refractory acute myeloid leukemia (AML) is associated with a poor prognosis and a median overall survival of less than 1 year [1]. Allogeneic hematopoietic stem cell transplant (HSCT) remains the standard of care in this setting. For those patients without available donors or with significant contraindications to transplant, therapeutic options are limited. Many of the chemotherapy regimens for relapsed/refractory AML are dose-intensive and cannot be easily applied in heavily pretreated patients. Azacitidine was demonstrated to significantly prolong survival over conventional care regimens in patients with intermediate-2/high-risk myelodysplastic syndrome and in elderly patients with AML, in two phase III trials [2,3]. Gemtuzumab ozogamicin (GO) is an anti-CD33 antibody linked to calicheamicin that showed promising results in elderly patients with relapsed AML [4]. Recently, its commercial marketing was voluntarily discontinued in the USA after the post-approval trial (S0106) failed to demonstrate any improvement in response rates when GO was added to standard induction therapy in previously untreated patients with de novo non-M3 AML [5]. Azacitidine and GO have acceptable tolerability profiles and non-cross-resistant mechanisms of action, rendering their combination a viable option in heavily pretreated patients with AML. Furthermore, an overall response rate of 70% was reported in previously untreated elderly patients with AML treated with the combination of azacitidine and GO [6]. Following presentation of the preliminary results of this trial [7], a number of patients with relapsed or refractory AML have been treated with azacitidine followed by GO in our institution as a bridge to HSCT or to improve survival while preserving patients’ quality of life. After approval by our institutional review board, we identified eight patients with relapsed/refractory AML who were treated with the azacitidine–GO combination between 2005 and 2009 at Jackson Memorial Hospital and Sylvester Comprehensive Cancer Center through the institutional tumor registry and medical record searches. All patients were documented to have CD33þ AML by flow cytometry on peripheral blood or bone marrow aspirate. All patients received the institutionally standardized azacitidine–GO regimen that included azacitidine 75 mg/m intravenously or subcutaneously on days 1–7 and GO 3 mg/m on day 8. The rest period between cycles was at the discretion of the treating physician and varied between 2 and 8 weeks. Complete remission (CR) was defined as (i) absence of blasts in the peripheral blood, (ii) normal marrow with 5% blasts, (iii) neutrophil count of 41.06 10/L, and (iv) platelet count of 41006 10/L. Patients who met all CR criteria but for whom a repeat bone marrow biopsy was not performed after azacitidine–GO therapy were defined to have a clinical response. Toxicity data were gathered from physician notes according to the Common Terminology Criteria for Adverse Events (CTCAE v4.0).

High-dose glucocorticoids improve renal failure reversibility in patients with newly diagnosed multiple myeloma.

One-fifth of the newly diagnosed multiple myeloma (MM) patients present with renal failure (RF) [1-3]. Glucocorticoids (GCs) may improve RF in MM by (1) rapid reduction of paraprotein production, (2) lessening inflammation and fibrosis in renal parenchyma, and (3) decreasing serum calcium level. We hypothesized that lower dose GCs may be less effective in restoring renal function and retrospectively compared the RF reversibility between the newly diagnosed MM patients who were treated with GCs equivalent to ≥160 mg DX over 4 days (high-dose GC group, n = 16) versus those who were treated with <160 mg (low-dose/no GC group, n = 8). There was no difference in age, baseline calcium, and creatinine levels between the two groups. Renal function was restored in seven patients in the high-dose GC group (44%) and in none of the patients in the low-dose/no GC group (P = 0.026). The only other factor found to impact the RF reversibility was the delay of GC initiation. Four and 1 patients developed a severe infection in the high- and low-dose/no GC groups, respectively. The use of higher dose GCs in the newly diagnosed MM patients who present with RF increases the likelihood of renal function restoration.

Timing of Adjuvant and Neoadjuvant Therapy in Colorectal Cancers

Surgery remains the only curative therapy for colorectal cancer (CRC); however, several studies have proved that adjuvant chemotherapy improves the curative rate. A growing body of evidence indicates that significant deviations from recommended treatment plans are frequent. Patients may experience delays in the administration of adjuvant chemotherapy that can reduce its survival benefit. To date, few studies have examined factors associated with the timing of adjuvant chemotherapy or have described the effects of delayed therapy on overall survival. In this review, we discuss the extent and predictors of delay in administration of adjuvant chemotherapy as well as the relationship between timing and outcomes in CRC.

Comparison of Cancer Care and Outcomes between a Public Safety- Net Hospital and a Private Cancer Center

We compared the cancer outcomes and care-associated service defects between Jackson Memorial Hospital (ABC), a large public safety-net hospital, and Sylvester Comprehensive Cancer Center (XYZ), a private not-for-profit cancer center in patients with stage II–III colorectal cancer (CC) who received adjuvant chemotherapy (AC) and in patients with diffuse large B cell lymphoma (DLBCL). Colorectal cancer patients treated at ABC were more likely to have undergone urgent surgery. While in the CC cohort, three-year overall survival and relapse-free survival rates were significantly higher among patients treated at XYZ compared with those treated at ABC, there was no significant difference between patients treated for DLBCL in the two hospitals. Colorectal cancer patients treated at ABC were more likely to have undergone urgent surgery, to have delays before surgery or during chemotherapy, and to experience a system/patient-related service defect; whereas were less likely to complete a full course of AC.

Simultaneous measurement of ERα, HER2, and PhosphoERK1/2 in breast cancer cell lines by flow cytometry

The activation of human epidermal growth factor receptor-2 (HER2) results in the activation of the mitogen-activated protein kinase (MAPK) cascade that may lead to the resistance to anti-estrogen therapy in estrogen receptor (ERα) expressing breast cancer by means of phosphorylation of ERα in the N-terminal region by phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) and by means of decreasing ERα expression. Immunohistochemistry is the most widely used technique for the detection of ERα and HER2 in breast cancer specimens, however, is inadequate in its ability to assess the relationship between ERα, HER2, and MAPK cascade at the single cell level. To clear this major hurdle, we devised a novel flow cytometric method to quantify the expression of ERα, HER2, and the activation of MAPK cascade simultaneously in single cells. The method was validated by concurrent Western blotting in established cell lines: MDA-231 (ERα and HER2-negative), MCF-7 (ERα-positive, HER2-negative), MCF-7 cells overexpressing ERα after long-term incubation in estrogen-free medium, and HER2 transfected MCF7 cells. Using the flow cytometry method, we confirmed the previous finding that ERα expression is down-regulated upon epidermal growth factor mediated ERK1/2 phosphorylation in EGFR/MCF-7 cells. To our knowledge, this is the first such assay to incorporate simultaneous single cell measurement for all of these pathways, which may prove useful to determine the intratumoral heterogeneity in breast tumors or the receptor status in circulating tumor cells.