Evren Ozdemir

Relationship between LYVE-1, VEGFR-3 and CD44 gene expressions and lymphatic metastasis in gastric cancer.

AIM To investigate the expression levels of lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), vascular endothelial growth factor receptor-3 (VEGFR-3) and CD44 genes and the relationship between their levels and clinicopathological parameters in gastric cancer. METHODS Tissue samples were obtained from 33 patients (8 females) with gastric cancer. mRNA levels of LYVE-1, VEGFR-3 and CD44 in normal and tumor tissues were quantitatively measured using real time polymerase chain reaction. The results were correlated with lymph node metastasis, histological type and differentiation of the tumor, T-stage, and presence of vascular, perineural and lymphatic invasions. The distribution of molecules in the tissue was evaluated using immunohistochemistry. RESULTS LYVE-1, CD44 and VEGFR-3 gene expression levels were significantly higher in gastric cancer than in normal tissue. While there was no correlation between gene expressions and clinicopathologic features such as histologic type, differentiation and stage, gene expression levels were found to be increased in conjunction with positive lymph node/total lymph node ratio and the presence of perineural invasion. A significant correlation was also found between LYVE-1 and CD44 over-expressions and perineural invasion and lymph node positivity in gastric cancers. When the distribution of LYVE-1 antibody-stained lymphatic vessels in tissue was evaluated, lymphatic vessels were located intra-tumorally in 13% and peri-tumorally in 27% of the patients. Moreover, lymph node metastases were also positive in all patients with LYVE-1-staining. CONCLUSION LYVE-1, VEGFR-3 and CD44 all play an important role in lymphangiogenesis, invasion and metastasis. LYVE-1 is a perfectly reliable lymphatic vessel marker and useful for immunohistochemistry.

The Lollipop with Strawberry Aroma May Be Promising in Reduction of Infusion-Related Nausea and Vomiting during the Infusion of Cryopreserved Peripheral Blood Stem Cells

Nausea and vomiting during the infusion of cryopreserved peripheral blood stem cells (PBSC) are common. The aim of this study was to explore the effect of lollipop with strawberry aroma on the infusion-related nausea and vomiting of cryopreserved autologous PBSCs. We compared 2 groups of adult patients receiving lollipop with strawberry aroma during cryopreserved PBSC infusions or not to assess the incidences of nausea and vomiting occurring during infusions. All patients received granisetron 3 mg i.v. twice a day, and lorazepam 1 mg every 4 hours orally for prophylaxis of the nausea and vomiting during conditioning phase and infusion day. Before infusion, all patients were premedicated with pheniramine maleate 45.5 mg i.v. and paracetamol 500 mg orally. The patients had no evidence of nausea or vomiting prior to cryopreserved PBSC infusions. The patients with ongoing nausea or vomiting owing to conditioning regimens and/or receiving additional antiemetics were excluded from the study. One hundred fifty-eight patients who consecutively underwent autologous stem cell transplantation for malignancy were included in the study. The first 110 patients (median age: 42.5, range: 17-75) were observed for the infusion related adverse effects only. The consecutive 48 patients (median age: 48, range: 18-80) were given a lollipop with strawberry aroma during cryopreserved PBSC infusions and observed for the infusion-related adverse effects. The 2 groups were comparable with respect to age, sex, diagnosis, stem cell collection methods, conditioning regimens administered, total mononuclear cell dose infused, number of total nucleated cells (TNCs) infused, number of CD34+ cells infused, number of bags infused, total volume infused, amount of dimethylsulfoxide (DMSO), and infusion rate. Patients who received a lollipop with a strawberry aroma during infusions had significantly less nausea (6.3%, n = 3 versus 21.8%, n = 24, P = .02) and vomiting (2%, n = 1 versus 13.6%, n = 15, P = .04) than the ones who did not (observation only group). Other infusion-related adverse events were as follows; hypoxia, cough, dyspnea, abdominal cramping, tachycardia, hiccup, fever, chills, chest pain, hypotension, hypertension, agitation, sore throat, and arrhythmia. Incidences of each of these adverse events were <5% in both groups and were comparable. The use of a lollipop with a strawberry aroma during infusion of cryopreserved autologous PBSCs may be promising in reduction of infusion-related nausea and vomiting, with an easy administration at a very cheap cost.

High dose sequential chemotherapy and autologous stem cell transplantation in patients with relapsed/refractory lymphoma

Although high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) has become the standard approach for patients with relapsed/refractory Hodgkins disease (HD) or non-Hodgkins lymphoma (NHL), more than 50% of patients will experience relapse following ASCT. High-dose sequential chemotherapy (HDSC) can intensify the conventional salvage treatment and improve the outcome of ASCT by maximal debulking of the tumor load with the use of non-cross resistant drugs, each at their maximal tolerated doses. We conducted a phase II study in 40 patients with relapsed/refractory HD (n = 18) and NHL (n = 22) using HDSC followed by ASCT. Only patients sensitive to salvage chemotherapy were eligible for the protocol, consisting of three phases. Phase I consisted of cyclophosphamide (4.5 g/m2) followed by G-CSF and peripheral blood stem cell (PBSC) collection. Phase II consisted of etoposide (2 g/m2). The transplant phase consisted of mitoxantrone (60 mg/m2) and melphalan (180 mg/m2) followed by PBSC infusion. Eleven out of nineteen patients with B-cell lymphoma received rituximab. Prior to HDSC, 45% of the patients were in complete remission (CR) and 55% were in partial remission (PR). After completion of all phases of the protocol, 35 out of 39 evaluable patients achieved CR (90%) and this was durable in 30 (75%) patients with a projected progression-free survival (PFS) rate at 4 years of 71.7%. Treatment-related mortality rate at day +100 was 2.5% (n = 1). At a median follow-up of 32 months (range, 3 – 61), nine patients relapsed/progressed and eleven patients died. The estimated 4-year PFS and overall survival (OS) were 72.2% and 47.6% in HD patients and 70.3% and 69.4% in NHL patients, respectively. Factors predicting OS were response to conventional salvage therapy and stage prior to salvage therapy. When compared to patients achieving PR, patients who attained CR prior to HDSC had a significantly higher probability of 4-year OS (78.4% vs 31.3%, p = 0.02). Three prognostic subgroups were defined according to the score determined by stage prior to initiation of salvage chemotherapy, remission duration prior to salvage (refractory/early relapse vs. late relapse) and response to salvage. Prognostic score was found to predict OS, PFS and event free survival (EFS). In conclusion, HDSC followed by ASCT is an effective salvage therapy with acceptable toxicity, allowing further consolidation of response attained by conventional salvage therapy.

Hyper-CVAD regimen in routine management of adult acute lymphoblastic leukemia: a retrospective multicenter study.

Treatment of acute lymphoblastic leukemia is unsatisfactory in adults due to disease and patient-related factors and probably because adult chemotherapy regimens are weaker than pediatric protocols. Worries about inadequacy of adult regimens urged many hematologists, including us, to reconsider their routine treatment practices. In this retrospective multicenter study, we aimed to evaluate results of hyper-CVAD treatment in comparison to other intensive protocols. All patients aged ≤65 years who were commenced on intensive induction chemotherapy between 1999 and 2011 were included in the study. Sixty-eight of 166 patients received hyper-CVAD, 65 were treated with CALGB-8811 regimen and 33 with multiple other protocols. Limited number of patients who were treated with other intensive protocols and mature B-acute lymphoblastic leukemia cases who were mostly given hyper-CVAD were eliminated from the statistical analyses. In spite of a favorable complete remission rate (84.2%), overall (26.3 vs. 44.2% at 5 years, p = 0.05) and disease-free (24.9 vs. 48.2%, p = 0.001) survival rates were inferior with hyper-CVAD compared to CALGB-8811 due to higher cumulative nonrelapse mortality risk (29.7 vs. 5.9%, p = 0.003) and no superiority in cumulative relapse incidence comparison (45% for both arms, p = 0.44). Hyper-CVAD, in its original form, was a less favorable regimen in our practice.

Successful treatment of relapsed/refractory Hodgkins lymphoma with nivolumab in a heavily pretreated patient with progressive disease after both autologous and allogeneic stem cell transplantation

The programmed death-1 (PD-1) regulatory pathway is active in several tumors and a potent immunotherapeutic target with PD-1 inhibitors. Nivolumab is an anti-PD-1 monoclonal antibody that is approved for melanoma and squamous cell lung cancer.[1,2] It has also been shown that nivolumab has a profound therapeutic activity in patients with relapsed/refractory Hodgkin lymphoma, a disease with a genetic basis for PD-1 ligand overexpression and a marked but ineffective inflammatory and immune-cell infiltrate.[3] However, very little is known on its potential activity and safety after allogeneic stem cell transplantation (SCT), mainly because of the concerns that PD-1 blockage may increase the risk of graft versus host disease (GVHD). As allogeneic SCT remains potentially curative option for the treatment of younger patients with advanced classical Hodgkin lymphoma (cHL), these patients have limited treatment options if they fail allogeneic transplant.[4] We describe our experience with nivolumab in a patient with relapsed/refractory Hodgkin lymphoma who had progressive disease after both autologous and allogeneic SCT. 30-year-old male was diagnosed with cHL (nodular sclerosing type), stage IIIB, on November 2010. He received 6 cycles of adriamycin (doxorubicin), bleomycin, vinblastine and dacarbazine (ABVD) and achieved a clinical complete remission (CR), however, he relapsed on October 2011. Subsequently, he was given 2 cycles of ICE and achieved a clinical partial response (PR). He underwent high-dose chemotherapy followed by autologous SCT on February 2012 and achieved a clinical CR. Unfortunately, he had relapsed disease on September 2012. He received 3 cycles of Gemcitabine and Oxaliplatin (GemOx) but had progressive disease. He was given 4 cycles of Paclitaxel and achieved a clinical PR. Subsequently, he underwent an allogeneic SCT using reduced intensity conditioning (FþM) from his full-match mother by high resolution HLA typing on May 2013. However, he had clinical and radiographic evidence of disease progression by day 100 with full donor chimerism and no evidence of GVHD or GVL. Progression continued despite withdrawal of immunosuppression. On September 2013, he was started on brentuximab vedotin (BV), achieved a clinical PR and received a total of 16 cycles. BV was stopped after 16th cycle due to grade III motor and peripheral neuropathy. He was started on pregabalin and his neuropathy resolved completely within 3 months. He progressed on September 2014 and was given Bendamustin for 3 cycles with further progression. He was then given oral PECC (prednisone, etoposide, chlorambusil, CCNU) for 6 cycles with a brief clinical PR, however, progressed again on December 2015. The patient presented with weakness, nonproductive cough, and weight loss on December 2015. His physical examination revealed a large palpable mass at epigastric area. A PET-CT confirmed progressive disease (Figure 1(A)). Given the lack of any meaningful treatment option, we decided to treat the patient with off-label nivolumab. We obtained a written informed consent and nivolumab treatment was started at the dose of 3mg/kg every 2 weeks on January 2016. His treatment course was uneventful except that the patient experienced an intense abdominal pain radiating to his back within an hour of the first injection of nivolumab that eventually disappeared in hours. He was feeling very well with a significant decrease of his cough before the second injection and his examination revealed no evidence of palpable mass at his epigastric area. A PET-CT obtained after the 6th cycle of the nivolumab treatment showed complete resolution of his disease (Figure 1(B)). His biweekly maintenance nivolumab therapy is ongoing, after the 14th cycle of the treatment, he has a good allograft function and full donor chimerism with no evidence of drugrelated toxicity and GVHD so far. We have described successful treatment of a patient with highly refractory cHL with nivolumab after failing multiple lines of therapy including autologous and

Comparative outcome of reduced intensity and myeloablative conditioning regimen in HLA identical sibling allogeneic hematopoietic stem cell transplantation for acute leukemia patients: A single center experience

Due to the high transplant related morbidity and mortality (TRM), relatively younger acute leukemia patients that have a good performance status and no comorbidity are eligible for myeloablative conditioning (MAC) followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT). The outcomes of 84 consecutive adult patients with ALL (n=38) or AML (n=46) who underwent allo-HSCT from their HLA-identical siblings were evaluated retrospectively. The median age at transplantation was 34 (17-58 years) for the whole patient population. Of these, 24 patients received a MAC and 60 patients received a fludarabine-based reduced intensity conditioning regimen (RIC). After a median follow-up of 32 months (range, 1-119), for the entire group, the 3-year estimated overall survival (OS) was 57.5% and the disease-free survival (DFS) was 51.5%. The OS for ALL and AML patients were 53.9% vs 62.1%: and DFS were 50.5% and 53.4%, respectively. The 3-year estimated OS for RIC and MAC patients were 63.2% and 41.7%; and DFS were 57.1% and 34.7%, respectively. In ALL patients, conditioning regimens (RIC vs MAC) led to similar OS and DFS; however, in AML patients both OS (70.1% vs 21.4%) and DFS (59.3% vs 42.9%) were found to be higher in RIC patients compared to MAC recipients. Overall, the TRM at day 100 was 1.7% and has increased up to 5.1% at 1st year. In multivariate analysis, the diagnosis (p=0.03) and RIC regimen (p=0.027) were the prognostic variables for prolonged OS in all patients; and RIC regimen (p=0.031) was the only prognostic factor for prolonged OS in AML patients. The first complete remission (CR1) was correlated with a prolonged DFS as an independent variable for all patients (p=0.09). Eleven of the RIC patients (18.3%) and 6 of the MAC patients (25%) developed acute graft-versus-host disease (GvHD). Seventeen of the RIC patients (33.3%) and 4 of the MAC patients (16.7%) developed chronic GvHD. In conclusion, RIC conditioning regimens may provide a longer OS and DFS, especially in patients with AML who are in first CR, not eligible for MAC conditioning.

Potential drug interactions and side effects in an outpatient oncology clinic: a retrospective descriptive study

Objective To identify potential drug interactions and side effects in an oncology outpatient clinic. Method The study was undertaken at an oncology outpatient clinic during November 2012 in Turkey. The information regarding patient demographics, drug treatments and side effects were collected retrospectively through the patient care records and potential drug interactions were identified. Side effects due to chemotherapy were assessed by using determined criteria of the National Cancer Institute Common Toxicity Criteria version 2. Results A total number of side effects assessed in 347 patients was 9080, of those 1526 (16.96%) were graded as ‘≥1’, which accounts for 4.4 side effects per patient. The top three categories of side effects were gastrointestinal (32.30%), neurological (23.91%) and fatigue (16.12%). Men experienced more side effects than women, and there was a correlation between the number of side effects and patients age. There were 229 drug–drug interactions identified in 126 patients (1.8 interactions per patient). There was no correlation between the number side effects and drug interactions. An estimated prevalence (36%; in 126 out of 347 patients) of drug interactions found in this study was similar to the previous studies. Conclusions Identification of potential drug-related problems in the clinic may improve the patient monitoring process and maintain effective drug treatment in oncology settings. There is a potential role for a clinical pharmacist to be integrated into the outpatient clinic.

Late relapse of a light-chain myeloma as extramedullary plasmacytoma of the thyroid gland after second allogeneic stem-cell transplantation.

Abstract:  We present a rare experience with a myeloma patient who had a late relapse as isolated extramedullary plasmacytoma of the thyroid gland after a second allogeneic transplantation. We give PET/CT scan findings at diagnosis and during follow up of the disease after subsequent management. The possible pathogenesis of the late extramedullary relapse of myeloma after allogeneic stem‐cell transplantation and management options are discussed.

The effect of granulocyte colony stimulating factor receptor gene missense single nucleotide polymorphisms on peripheral blood stem cell enrichment

Granulocyte-colony stimulating factor (G-CSF) has become the most effective agent supporting hematopoietic stem cell transplantation (HSCT). The cognate interaction between G-CSF and its specific receptor, G-CSFR, induces the mobilization of HSCs and increases their pool in the peripheral blood. G-CSFR has a highly conserved structure which may be functionally modulated by the presence of missense single nucleotide polymorphisms (SNPs). In this study, we asked whether the missense SNPs in G-CSFR could affect the response to G-CSF in HSCT patients and donors. Here, for the first time, G-CSFR missense SNPs were screened and minor allele frequencies were determined in a specific population with Turkish racial background. Five (rs3917991, rs3918001, rs3918018, rs3918019, and rs146617729) out of 16 missense SNPs screened were determined with minor allele frequencies lower than 0.04. Subsequent association analyses indicated potential impact of rs3918001, rs3918018, and rs3918019 minor alleles on peripheral blood CD34(+) cell enrichment. Although their frequency is rather low, certain missense SNPs, especially which are placed in the conserved regions of G-CSFR may possess the capacity to influence the response to G-CSF treatment.

Successful Treatment of Autoimmune Hemolytic Anemia with Steroid, IVIg, and Plasmapheresis in a Haploidentical Transplant Recipient.

Autoimmune hemolytic anemia (AIHA) is a rare, but clinically significant complication following hematopoietic stem cell transplantation (HSCT). It is characterized by hemolysis due to antibodies produced by the donor’s immune system against donor red cell antigens. The 3-year cumulative incidence of AIHA is 4.44% in adults; however, 75% of patients develop AIHA during the first post-HSCT year [1]. AIHA after allogeneic HSCT has been associated with a variety of conditions, including chronic graft-versus-host disease (GVHD) [2], T-cell depletion [3], and unrelated donor transplants [4]. HSCT from unrelated donors and the development of chronic extensive GVHD were the only independent factors associated with AIHA [1]; however, the incidence of and risk factors for AIHA, as well as its prognosis and response to treatment remain unclear.