Treating relapsed and refractory metastatic germ cell tumours with high-dose chemotherapy with carboplatin and etoposide and autologous haematopoietic stem cell transplantation.

INTRODUCTION AND AIM: To demonstrate the real-life data about patients who underwent AHSCT due to GCT. METHODS: Between November 2016 and April 2020, 64 patients who received CE as high-dose chemotherapy for AHSCT in the Gulhane Education and Research Hospital were included in the study. Sixty-one patients received one AHSCT with CE chemotherapy regimen. Survival data and clinical characteristics were evaluated retrospectively. RESULTS: The mean age of the patients were 31.9 ± 9 (min-max:18-55). With a median follow-up of 10.7 ± 8.7 months, the 1-year progression-free survival (PFS) rate was 57.8%, and the 1-year overall survival rate was 77.5%. Median overall survival (OS) and progression-free survival (PFS) times were 21.5 ± 1.8 (95% CI: 14.5-33.4) and 20 ± 2 months, respectively. The response rate was 72%. There were three treatment-related deaths. CONCLUSION: This sizeable single-centre study shows that patients with relapsed metastatic GCT are curable by CE as high dose chemotherapy plus AHSCT with reliable toxicity even for a single cycle.

Outcomes of bladder preservation therapy on survival in patients with muscle-invasive bladder cancer. / Resultados de preservación vesical en pacientes con tumor vesical musculoinfiltrante.

INTRODUCTION: The standard of care in muscle invasive bladder cancer is radical cystectomy; however; transurethral resection (TUR) followed by external radiotherapy and systemic chemotherapy demonstrates comparable results with radical cystectomy in terms of local control and survival rates. OBJECTIVES: To evaluate our results of multimodality bladder preservation therapy (BPT) in patients who had muscle-invasive bladder cancer and were reluctant to radical cystectomy. METHODS: The retrospective analysis of twenty-three patients with stage T2 transitional cell bladder cancer that were consecutively treated with BPT was performed. Treatment strategy included radical TUR followed by 3 cycles of cisplatin, gemcitabine combination, and radiotherapy of 64 Gy as adjuvant treatment. The Kaplan-Meier survival estimates and log rank were calculated. RESULTS: Median follow-up time was 58 (15-158) months. Disease-free survival (DFS) and five year overall survival (OS) rates for 23 patients were 55.9% and 63.9%, respectively. Cancer-specific OS was 67%. There were no grade 3 or higher complications. CONCLUSIONS: Our small patient group suggests that BPT can be safely applied in selected cases with bladder cancer or in patients that refused radical cystectomy.

INTRODUCCIÓN: El estándar de tratamiento en el CVMI es la cistectomía radical, aunque la RTUv + RTP+ quimioterapia sistémica demuestra resultados comparables a la cistectomía radical en términos de control local y supervivencia global. OBJETIVOS: Evaluar nuestros resultados en terapia trimodal en cáncer de vejiga músculo-invasivo que rechazan la cistectomía radical. MÉTODOS: Análisis retrospectivo de 23 pacientes con estadio T3 TVMI tratados con preservación vesical (RTUv +3 ciclos de gemcitabina, cisplatino+ 64Gy RTP adyuvante). KM estimados y log Rank fueron calculados. RESULTADOS: La mediana de seguimiento fue de 58 meses (15-158). El intervalo libre de enfermedad y la supervivencia global a los 5 anos fue de 56% y 64%, respectivamente. La Supervivencia cáncer especifica fue de 67%. No se objetivaron complicaciones grado 3 o más. CONCLUSIONES: Nuestra serie de tratamiento preservación vesical demuestra que el uso de este tratamiento en pacientes debidamente seleccionados que no quieren cistectomía radical es apropiado.

A Review of Allogeneic Hematopoietic Stem Cell Transplantation in Metastatic Breast Cancer.

Breast cancer (BC) has a high mortality rate and metastatic BC is almost incurable despite hormonal therapy and chemotherapy. The second and third lines of chemotherapies usually yield transient responses and the median survival is generally as low as 18-24 months. Autologous and allogeneic hematopoietic stem cell transplantation (HSCT) have been extensively investigated in this setting. The presence of immune mediated anti-tumor effects referred to as graft-versus-tumor (GvT) effects after allogeneic HSCT among patients with solid tumors have been clearly defined. The advantages of allogeneic HSCT over autologous HSCT for metastatic BC are i) cancer-free graft and ii) immune-mediated GvT effects mediated by human leukocyte antigen compatible donor T-cells. In conclusion, a GvT effect does exist against metastatic BC and play a key role in tumor response. This review aims to describe the background, rationale, and clinical results of allogeneic HSCT as a potential alternative treatment in metastatic BC.

Hematopoietic stem cell transplantation in patients with gain-of-function signal transducer and activator of transcription 1 mutations.

BACKGROUND: Gain-of-function (GOF) mutations in signal transducer and activator of transcription 1 (STAT1) cause susceptibility to a range of infections, autoimmunity, immune dysregulation, and combined immunodeficiency. Disease manifestations can be mild or severe and life-threatening. Hematopoietic stem cell transplantation (HSCT) has been used in some patients with more severe symptoms to treat and cure the disorder. However, the outcome of HSCT for this disorder is not well established. OBJECTIVE: We sought to aggregate the worldwide experience of HSCT in patients with GOF-STAT1 mutations and to assess outcomes, including donor engraftment, overall survival, graft-versus-host disease, and transplant-related complications. METHODS: Data were collected from an international cohort of 15 patients with GOF-STAT1 mutations who had undergone HSCT using a variety of conditioning regimens and donor sources. Retrospective data collection allowed the outcome of transplantation to be assessed. In vitro functional testing was performed to confirm that each of the identified STAT1 variants was in fact a GOF mutation. RESULTS: Primary donor engraftment in this cohort of 15 patients with GOF-STAT1 mutations was 74%, and overall survival was only 40%. Secondary graft failure was common (50%), and posttransplantation event-free survival was poor (10% by 100 days). A subset of patients had hemophagocytic lymphohistiocytosis before transplant, contributing to their poor outcomes. CONCLUSION: Our data indicate that HSCT for patients with GOF-STAT1 mutations is curative but has significant risk of secondary graft failure and death.

An overview of high dose chemotherapy with autologous stem cell rescue for germ cell tumors in current practice.

Testicular cancer is a frequent tumor of adolescent and young adult males. Chemotherapy has been reported to provide cure rates as high as 80% even in the presence of advanced testicular cancer. Studies regarding testicular cancer started after the advent of high dose chemotherapy (HDC) plus atologous stem cell rescue (ASCR) for the treatment of solid tumors in 1980s. Testicular cancer is highly responsive to HDC. Einhorn et al. have reported long-lasting remissions reaching up to 40% among patients with platinum-refractory disease. However, the present prospective randomized studies are heterogeneous in terms of patient characteristics and methodology, therefore superiority of HDC plus ASCR to conventional chemotherapies could not be proven. The results of the TIGER study, which is a recent prospective randomized study being conducted by the European Organisation for Research and Treatments in Cancer (EORTC) and the European Society for Blood and Marrow Transplantation (EBMT) aiming to compare HDC plus ASCR to conventional chemotherapy are eagerly expected. In this review, we will evaluate the current use of HDC plus ASCR in patients with relapsed or refractory germ cell tumors.

Comparison of the clinical features and hematopoietic stem cell transplantation outcomes of mediastinal malignant germ cell tumors with nonmediastinal extragonadal placements.

OBJECTIVE: Even though the primary mediastinal extragonadal germ cell tumors (EGCTs) are rare, they are noteworthy in the differential diagnosis of mediastinal masses. In this study, we aimed to identify the clinical features of mediastinal malignant GCTs and compare the results of hematopoietic stem cell transplantation between mediastinal and nonmediastinal malignant EGCTs. METHOD: Data of the patients with EGCT who were treated and underwent hematopoietic stem cell transplantation at our hospital between 1988 and 2015 were retrieved retrospectively. Results were compared between mediastinal and nonmediastinal EGCTs. RESULTS: Data of 65 patients diagnosed with EGCT (37 [56.92%] cases with mediastinal EGCT and 28 [43.07%] cases with nonmediastinal EGCT) were assessed. The clinical stages, frequency of pretransplant status, mean pretransplant time, and mean number of chemotherapy lines before hematopoietic stem cell transplantation were not significantly different between groups. Although the overall survival did not significantly differ between groups, the 5-year survival was significantly higher in mediastinal EGCTs (P=0.02). Yolk sac tumor was significantly more common in mediastinal EGCTs (P=0.05). Mortality rates were higher in seminomas and yolk sac tumors in all cases, higher in embryonal carcinomas in mediastinal EGCT group and higher in yolk sac tumors in nonmediastinal EGCT group. While choriocarcinomas had more aggressive courses in mediastinal EGCTs, seminomas and yolk sac tumors had poorer prognosis in nonmediastinal EGCTs. Short pretransplant time and persistence of elevated posttransplant ßhCG and AFP levels were the significant mortality risk factors both in mediastinal and nonmediastinal EGCTs. CONCLUSION: Mediastinal placement of EGCT was not a poor prognostic factor; furthermore, the 5-year survival was significantly higher in mediastinal EGCTs. According to our knowledge, this is the first study that compares the clinical outcomes of hematopoietic stem cell transplantation of mediastinal and nonmediastinal malignant EGCTs.

Review of allogeneic hematopoietic stem cell transplantation with reduced intensity conditioning in solid tumors excluding breast cancer.

Solid tumors in adults constitute a heterogeneous group of malignancy originating from various organ systems. Solid tumors are not completely curable by chemotherapy, even though some subgroups are very chemo-sensitive. Recently, oncologists have focused on the use of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with reduced intensity conditioning (RIC) for the treatment of some refractory solid tumors. After the demonstration of allogeneic graft-versus-leukemia effect in patients with hematological malignancies who received allo-HSCT, investigators evaluated this effect in patients with refractory metastatic solid tumors. According to data from experimental animal models and preliminary clinical trials, a graft-versus-tumor (GvT) effect may also be observed in the treatment of some solid tumors (e.g., renal cell cancer, colorectal cancer, etc.) after allo-HSCT with RIC. The use of RIC regimens offers an opportunity of achieving full-donor engraftment with GvT effect, as well as, a reduced transplant-related mortality. Current literature suggests that allo-HSCT with RIC might become a choice for elderly and medically fragile patients with refractory metastatic solid tumors.

Investigational tests and treatments performed in terminal stage cancer patients in two weeks before death: Turkish oncology group (TOG) study.

Although more palliative care is necessary for terminally ill cancer patients, excess investigational tests, invasive procedures, and treatments are given instead. Between November 2009 and December 2013, six hundred and twenty-four patients with end-stage cancer who were died at inpatient setting evaluated retrospectively. Patients' characteristics, sites of tumor and metastasis, tests and invasive procedures, treatments performed in the last 2 weeks before death were collected from the hospital files and analyzed. Median age of 624 patients was 58 (range 16-96) years. More than half of the patients (370, 59.3%) were men. The most frequent cancer sites were gastrointestinal (GI) system (32.2%), lung (24.0%), and breast (11.1%). Frequent metastatic sites were liver (34.8%), bone (31.5%), lung (23.3%), and/or brain (16.9%). Causes of death were respiratory failure, infections, and/or liver failure in 49.9, 23.9, and 19.4% of patients, respectively. Radiological tests performed in the last 2 weeks before death were ultrasonography, computed tomography, magnetic resonance imaging, bone scan in 25.6, 16.3, 11.4, and 3.8% of patients, respectively. Treatments received were intravenous (i.v) serum infusion, blood transfusion, total parenteral nutrition (TPN), human albumin infusion in 55.9, 44.1, 34.9, and 9.5% of patients, respectively. Invasive procedures such as invasive pain relief, terminal sedation, and chemotherapy performed in 12.6, 4.4, and 10.0% of patients, respectively. Central venous catheter application, paracentesis, thoracentesis, and GI endoscopy were applied in 41.7, 9.8, 5.6, and 3.4% of the patients, respectively. Radiological tests, invasive procedures, TPN, and human albumin transfusion were used excessively in terminal stage cancer patients in our medical oncology inpatient clinics. Invasive pain relief and terminal sedation were still underused in our cancer clinics. There is an urgent need in developing national palliative care program to improve the understanding of end-of-life care in our medical oncology clinics.

A rare presentation of follicular lymphoma: cerebellar involvement, successfully treated with a combination of radiotherapy and chemotherapy.

The central nervous system (CNS) is an important area of involvement for both high-grade, aggressive primary and secondary lymphomas. Although follicular lymphoma represents a low-grade histology, it may rarely present with CNS involvement. Here, we describe a patient diagnosed with follicular lymphoma who was presented with cerebellar involvement.

HLA-haploidentical transplantations for primary immunodeficiencies: a single-center experience.

SCID is characterized by profound deficiencies of T and B lymphocytes. HSCT is the only curative treatment for children with SCID. The clinical characteristics and outcome of 30 HLA-haploidentical transplantations in 18 patients (15 SCID, two Omenn syndrome, and one MHC Class II deficiency) are reported here. The age of patients at diagnosis ranged from one and half to nine months (median: four months). The median time was one month between the diagnosis and the time of the initial transplantation. Infused CD34+ stem cell dose was ranged between 7 and 94.2 × 10(6) /kg. Nine of 18 patients were found to be positive for CMV antigenemia at diagnosis; therefore, none of them received a conditioning regimen. The most common complication was graft failure (61%), so repeated transplantations (two to four) were performed in seven patients. The mean time of lymphoid engraftment was 17.5 days (median: 16, range: 11-29 days). Ten of 15 SCID (67%) patients survived with a stable complete donor chimerism. However, all three non-SCID patients died. In conclusion, in the absence of a matched family donor, HLA-haploidentical transplantation from parental donors represents a readily available treatment option especially for patients with SCID, offering a high chance of cure.

Selective intraarterial radionuclide therapy with Yttrium-90 (Y-90) microspheres for hepatic neuroendocrine metastases: initial experience at a single center.

BACKGROUND/AIM: Selective intraarterial radionuclide therapy (SIRT) with Yttrium-90 (Y-90) microspheres is also known as radioembolization and delivers high doses of radiation to hepatic tumors with minimum healthy liver exposure. The aim of this study was to present our preliminary experience in the role of liver directed radiotherapy with Y-90 microspheres for the treatment of unresectable hepatic metastases from neuroendocrine tumors (NET). METHODS: The results of SIRT in 10 patients (5 males, 5 females; mean age 48.7 years; age range 24-73 years) with metastatic liver disease from NETs during the period from April 2008 through August 2010 were reviewed. All patients had meticulous pre- and post-imaging studies as a part of their work-up procedure, as well as serologic tests of liver function to determine the extent of liver function damage. The patients who were eligible for SIRT had pretreatment visceral angiography to define and occlude non-target arteries. RESULTS: The mean +/- SD administered SIR-Spheres activity was 1.49 +/- 0.42 GBq (range 0.72-2.21 GBq) in all the patients. These treatments delivered a dose of 99.73 +/- 66.36 Gy (range 49-420.8 Gy) to the target tumors. The estimated dose to the lungs and normal liver was 4.45 +/- 1.95 Gy (range 2.4-8.5 Gy) and 26.73 +/- 14.19 Gy (range 5-58.9 Gy), respectively. Overall response rate of 90% and patient tolerance was satisfactory for most patients. CONCLUSION: From our limited experience, we can conclude that SIRT with Y-90 microspheres is a safe and efficacious treatment option for patients with liver metastasis of NET without any serious side effects.

Efficacy of melatonin, mercaptoethylguanidine and 1400W in doxorubicin- and trastuzumab-induced cardiotoxicity.

Doxorubicin (DOX) and Trastuzumab (TRAST) are effective agents for the treatment of many neoplastic diseases. Cardiotoxicity is a major side effect of these drugs and limit their use. In this study, the possible protective effects of melatonin (MEL), mercaptoethylguanidine (MEG), or N-(3-(aminomethyl) benzyl) acetamidine (1400W) against the cardiotoxicity of DOX and TRAST were tested. Male Sprague-Dawley rats received an injection of DOX (20 mg/kg) alone or in combination with TRAST (10 mg/kg) to induce cardiotoxicity; daily treatments with MEL (10 mg/kg × 2), MEG (10 mg/kg × 2), or 1400W (10 mg/kg × 2) were begun 36 hr before and continued for 72 hr after DOX and TRAST administration. Oxidant/antioxidant indices of the cardiac tissue, namely, malondialdehyde, superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), as well as serum levels of creatine phosphokinase (CK-MB) were measured. Additionally, the injury scores were evaluated histopathologically. Malondialdehyde levels were significantly higher, while SOD and GSH-Px activities were significantly reduced in rats with DOX- or DOX+TRAST-induced cardiotoxicity compared to normal values. All three treatment agents significantly reversed oxidative stress markers. Serum CK-MB levels were significantly increased after treatment with DOX and DOX+TRAST; these changes were also reversed by each of the treatments and resulted in near normal levels. Both the DOX- and DOX+TRAST-treated rats presented similar histopathologic injuries; in the animals treated with the protective agents, histologic protection of the cardiac tissue was apparent. These results suggested that MEL, MEG, as well as 1400 W are effective in preventing DOX- or DOX+TRAST-induced cardiotoxicity.

Drug resistant MCF-7 cells exhibit epithelial-mesenchymal transition gene expression pattern.

PURPOSE: Multidrug resistance is resistance to structurally unrelated anticancer agents. Large-scale expression analysis by using high-density oligonucleotide microarrays may provide information about new candidate genes contributing to MDR. This study demonstrates alterations in expression levels of several genes related to epithelial-mesenchymal transition (EMT) in paclitaxel, docetaxel, and doxorubicin resistant MCF-7 cells. METHODS: Resistant sublines were developed from sensitive cells by selective paclitaxel, docetaxel, and doxorubicin applications in dose increments. cDNA microarray analysis was performed for sensitive and resistant cells. Genes having statistically significantly altered expression levels more than two-folds compared to the sensitive MCF-7 cells were considered. Genes encoding the determinants of the EMT were evaluated. Immunostaining was performed for relevant protein expressions. RESULTS: Key elements of EMT were transcriptionally activated in paclitaxel, docetaxel and doxorubicin resistant sublines. One of the upregulated genes was Slug, a transcription factor of E-cadherin, occludin repression, and N-cadherin, vimentin activation. Decreased estrogen receptor-α (ER) levels in cells might have stimulated Slug expression. Increased expression levels of TGF-beta receptor2 (TGFBR2) together with SMAD3 might have stimulated EMT in resistant cells. Immunocytochemistry results confirmed loss of ER and E-cadherin, together with high vimentin levels. CONCLUSIONS: EMT was induced in multidrug resistant MCF-7 cells indicating a relationship of this process and drug resistance. However, the relationship of each specific component of EMT with drug resistance requires further analysis.

Oral metastasis of the mediastinal germ cell tumor (yolk sac).

A yolk sac tumor is a rare malignant tumor of germ cell origin. It most commonly arises from the testes and ovaries in young adults, but extragonadal sites of origin are reported in 10% to 15% of the cases. Yolk sac tumors are malignant, tend to recur locally, and may present with widespread metastases at the time of diagnosis. Involvement of the head and neck is uncommon. In this study, we present the case of a 23-year-old man presenting with mandibular and adjacent gingival metastasis of a mediasatinal yolk sac tumor. Thus, the patient has already undergone chemotherapy; no additional treatment was provided. In this case report, clinical and histopathologic features of the oral metastases of a yolk sac tumor were briefly discussed.

Factors affecting engraftment time in autologous peripheral stem cell transplantation.

BACKGROUND: Rapid hematological engraftment at autologous peripheral stem cell transplantation (APSCT) is a significant factor in reduction of early transplant-related complications and costs. For this reason, it is important to determine influences on hematological recovery. METHODS: This study was designed to evaluate factors affecting leukocyte and platelet engraftment times after high dose chemotherapy following APSCT. A total of 228 patients (131 males and 97 females) were enrolled. RESULTS: There were statistically significant differences between patients with CD34+ cell doses ≥ 2.5 x 106/kg (n=180) and < 2.5 x 106/kg (n=48), regarding leukocyte engraftment at 11 and 12 days, respectively (p<0.02), between G-CSF (n=167) and GM-CSF (n=61) posttransplant regarding median leukocyte engraftment times (p=0.005), and between with (n=75) or without (n=153) history of pretransplant radiotherapy for both leukocyte and platelet engraftment times (p<0.001). CONCLUSIONS: For leukocyte engraftment, a history of pretransplant radiotherapy, type of growth factor used and number of CD34+ cells infused, and for platelet engraftment, a history of pretransplant radiotherapy were found to be independent variables on multivariate analysis with the Cox regression method.

Modified outpatient dexamethazone, cytarabine and cisplatin regimen may lead to high response rates and low toxicity in lymphoma.

OBJECTIVE: Our purpose was to investigate the efficacy of and establish a toxicity profile for a modified regimen of dexamethasone, cytarabine and cisplatin (DHAP) for lymphoma outpatients. SUBJECTS AND METHODS: Fifty-one lymphoma patients, 26 with Hodgkin's disease and 25 with non-Hodgkin's lymphoma, were included. The patients' median age was 32 years (range: 17-61). Twenty had progressive/refractory disease and 31 relapsed disease. Twenty-five were in clinical stage I/II and 26 in clinical stage III/IV before the initiation of salvage chemotherapy. DHAP consisted of dexamethasone (40 mg i.v. on days 1-4), cytarabine (2 g/m(2) i.v. as 3-hour infusion on days 2 in the evening and 3 in the morning) and cisplatin (35 mg/m(2) as 2-hour infusion on days 1-3) were administered every 21 days. A total of 154 cycles of modified DHAP were administered, with a median of 3 cycles per patient (range: 2-4). RESULTS: The main toxicity was myelosuppression. WHO grade III-IV neutropenia and grade III-IV thrombocytopenia were observed in 27 (52.9%) and 21 (41%) patients, respectively. The overall response rate (85% for Hodgkin's disease and 95% for non-Hodgkin's lymphoma) was 88.3% (39.2% complete response and 49.1% partial response). CONCLUSION: The results showed that this outpatient schedule of DHAP was well tolerated and an effective salvage regimen.

Meningeal carcinomatosis: an extremely rare involvement of urinary bladder carcinoma.

Meningeal carcinomatosis (MC) is a rare presentation of solid tumors, particularly breast cancer, lung cancer, and malignant melanoma. Recently, the incidence of MC has been reported to be increasing. It has a bad prognosis despite aggressive therapy. The usual clinical presentation is multifocal involvement of the neuraxis, with headache and radicular pain being the most common initial symptoms. The most frequent signs are motor deficits, altered mental status, and cranial nerve involvement. The treatment of MC remains controversial and no straightforward guidelines exist in the literature. MC from urinary bladder tumors is rare. In this case report, we present a 52-year-old male patient with meningeal metastasis from a primary urinary bladder carcinoma along with a review of the related literature. Free full text available at www.tumorionline.it

Gene expression analysis of drug-resistant MCF-7 cells: implications for relation to extracellular matrix proteins.

PURPOSE: Since multidrug resistance is a multifactorial phenomenon, a large-scale expression analysis of drug-resistant cells by using high-density oligonucleotide microarrays may provide information about new candidate genes contributing to resistance. Extracellular matrix (ECM) is responsible for many aspects of proliferation and invasive/metastatic behavior of tumor cells. This study demonstrates alterations in gene expression levels of several ECM components, matrix metalloproteinases (MMPs), adamalysins (ADAMs and ADAMTSs) and tissue inhibitors of metalloproteinases (TIMPs) in paclitaxel, docetaxel, vincristine and doxorubicin-resistant MCF-7 cells. METHODS: Resistant MCF-7 cells were developed by stepwise selection of cells in increasing concentrations of drugs. Affymetrix GeneChip Human Genome U133 Plus 2.0 Array was used for hybridizations. Statistical significance was determined by independent sample t test. The genes having altered expression levels in drug-resistant sublines were selected and filtered by volcano plots. RESULTS: Genes up/downregulated more than twofolds were selected and listed. Expression of 25 genes encoding ECM proteins (including collagen, finronectin and syndecan) and integrin receptor subunits were found to be upregulated in drug-resistant cells. In addition, expression levels of, 13 genes encoding MMPs, ADAMs, ADAMTSs and TIMPs (including MMP1, MMP9, ADAM9 and TIMP3) were found to be altered in drug-resistant sublines when compared with sensitive MCF-7. CONCLUSIONS: Based on the expression analysis profiles, this report provides a preliminary insight into the relationship between drug resistance and ECM components, which are related to invasion and metastasis. Correlation of each specific ECM component with drug resistance requires further analysis.