Immune modulation properties of zoledronic acid on TcRγδ T-lymphocytes after TcRαβ/CD19-depleted haploidentical stem cell transplantation: an analysis on 46 pediatric patients affected by acute leukemia

TcRαβ/CD19-cell depleted HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) represents a promising new platform for children affected by acute leukemia in need of an allograft and lacking a matched donor, disease recurrence being the main cause of treatment failure. The use of zoledronic acid to enhance TcRγδ+ lymphocyte function after TcRαβ/CD19-cell depleted haplo-HSCT was tested in an open-label, feasibility, proof-of-principle study. Forty-six children affected by high-risk acute leukemia underwent haplo-HSCT after removal of TcRαβ+ and CD19+ B lymphocytes. No post-transplant pharmacological graft-versus-host disease (GvHD) prophylaxis was given. Zoledronic acid was administered monthly at a dose of 0.05 mg/kg/dose (maximum dose 4 mg), starting from day +20 after transplantation. A total of 139 infusions were administered, with a mean of 3 infusions per patient. No severe adverse event was observed. Common side effects were represented by asymptomatic hypocalcemia and acute phase reactions (including fever, chills, malaise, and/or arthralgia) within 24–48 h from zoledronic acid infusion. The cumulative incidence of acute and chronic GvHD was 17.3% (all grade I-II) and 4.8% (all limited), respectively. Patients given 3 or more infusions of zoledronic acid had a lower incidence of both acute GvHD (8.8 vs. 41.6%, p = 0.015) and chronic GvHD (0 vs. 22.2%, p = 0.006). Transplant-related mortality (TRM) and relapse incidence at 3 years were 4.3 and 30.4%, respectively. Patients receiving repeated infusions of zoledronic acid had a lower TRM as compared to those receiving 1 or 2 administration of the drug (0 vs. 16.7%, p = 0.01). Five-year overall survival (OS) and disease-free survival (DFS) for the whole cohort were 67.2 and 65.2%, respectively, with a trend toward a better OS for patients receiving 3 or more infusions (73.1 vs. 50.0%, p = 0.05). The probability of GvHD/relapse-free survival was significantly worse in patients receiving 1–2 infusions of zoledonic acid than in those given ≥3 infusions (33.3 vs. 70.6%, respectively, p = 0.006). Multivariable analysis showed an independent positive effect on outcome given by repeated infusions of zoledronic acid (HR 0.27, p = 0.03). These data indicate that the use of zoledronic acid after TcRαβ/CD19-cell depleted haploHSCT is safe and may result in a lower incidence of acute GvHD, chronic GvHD, and TRM

Outcome of children with acute leukemia given HLA-haploidentical HSCT after ab T-cell and B-cell depletion

Allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA-haploidentical relative (haplo-HSCT) is a suitable option for children with acute leukemia (AL) either relapsed or at high-risk of treatment failure. We developed a novel method of graft manipulation based on negative depletion of ab T and B cells and conducted a prospective trial evaluating the outcome of children with AL transplanted with this approach. Eighty AL children, transplanted between September 2011 and September 2014, were enrolled in the trial. All children were given a fully myeloablative preparative regimen. Anti–T-lymphocyte globulin from day 25 to 23 was used for preventing graft rejection and graft-versus-host disease (GVHD); no patient received any posttransplantation GVHD prophylaxis. Two children experienced primary graft failure. The cumulative incidence of skin-only, grade 1-2 acute GVHD was 30%; no patient developed extensive chronic GVHD. Four patients died, the cumulative incidence of nonrelapse mortality being 5%, whereas 19 relapsed, resulting in a 24% cumulative incidence of relapse. With a median follow-up of 46 months for surviving patients, the 5-year probability of chronic GVHD-free, relapse-free survival (GRFS) is 71%. Total body irradiation–containing preparative regimen was the only variable favorably influencing relapse incidence and GRFS. The outcomes of these 80 patients are comparable to those of 41 and 51 children given transplantation from an HLA-identical sibling or a 10/10 allelic-matched unrelated donor in the same period. These data indicate that haplo-HSCT after ab T- and B-cell depletion represents a competitive alternative for children with AL in need of urgent allograft. This trial was registered at www.clinicaltrials.gov as #NCT01810120

Light regulation of metabolic pathways in fungi

Light represents a major carrier of information in nature. The molecular machineries translating its electromagnetic energy (photons) into the chemical language of cells transmit vital signals for adjustment of virtually every living organism to its habitat. Fungi react to illumination in various ways, and we found that they initiate considerable adaptations in their metabolic pathways upon growth in light or after perception of a light pulse. Alterations in response to light have predominantly been observed in carotenoid metabolism, polysaccharide and carbohydrate metabolism, fatty acid metabolism, nucleotide and nucleoside metabolism, and in regulation of production of secondary metabolites. Transcription of genes is initiated within minutes, abundance and activity of metabolic enzymes are adjusted, and subsequently, levels of metabolites are altered to cope with the harmful effects of light or to prepare for reproduction, which is dependent on light in many cases. This review aims to give an overview on metabolic pathways impacted by light and to illustrate the physiological significance of light for fungi. We provide a basis for assessment whether a given metabolic pathway might be subject to regulation by light and how these properties can be exploited for improvement of biotechnological processes

[Role of radiotherapy in the treatment of seminoma of the testis].

From 1965 through 1988, 113 patients affected with testicular seminoma were treated at the Dept. of Radiotherapy, University "La Sapienza", Rome, Italy. Mean age of the patients was 38 years; in 70 cases tumor developed in the right testis and in 43 in the left one. In 9 patients underlying cryptorchidism was observed. All cases underwent radical orchiectomy. Histology diagnosed anaplastic seminoma in 5 cases and pure seminoma in all the other patients. Structures were involved in 7 cases. Eighty-four patients were in stage I, 20 in stage IIA, 4 in IIB, 4 in IIIA, and 1 in stage IIIB. All patients staged as I and IIA were treated with exclusive radiotherapy on paraaortic lymph nodes and inguinal and iliac lymph nodes of the involved sites (total doses: 28-35 Gy in stage I and 34-40 Gy in stage IIA). Before 1970 these patients underwent prophylactic irradiation of mediastinum and of left supraclavicular lymph nodes (total dose: 25-28 Gy). Patients in stage IIB were administered subdiaphragmatic lymph nodes irradiation with inverted-Y field (total dose: 36-45 Gy). Two cases were irradiated also on mediastinum and left supraclavicular lymph nodes, and 2 received two cycles of polychemotherapy (PVB) before irradiation. Patients in stage IIIA underwent sub-/supra-diaphragmatic irradiation (total dose: 40-45 Gy, and 40-42 Gy). The case in stage IIIB underwent palliation chemotherapy and local irradiation. All cases in stages I, IIA and IIB obtained complete remission. Three cases of the 4 in stage IIIA obtained complete remission (75%), while 1 (25%) progressed and died 8 months after diagnosis; the only case in stage IIIB progressed and died after 7 months of follow-up. Two cases in stage I recurred (2.4%), 1 in the mediastinum and 1 in the left supraclavicular lymph nodes. Both were cured with salvage radiation therapy. Toxicity related to treatment was low. Two cases in stage I developed secondary malignant neoplasms, at 4 and 34 months of follow-up, respectively

An unusual case of fatty liver in a patient with desmoid tumor

A desmoid tumor, also known as aggressive fibromatosis, is a rare benign neoplasm that arises from fascial or musculoaponeurotic tissues. It can occur in any anatomical location, most commonly the abdominal wall, shoulder girdle and retroperitoneum. The typical clinical presentation is a painless mass with a slow and progressive invasion of contiguous structures. It is associated with a high local recurrence rate after resection. Many issues regarding the optimal treatment of desmoid tumors remain controversial. Aggressive surgical resection with a wide margin (2-3 cm) remains the gold standard treatment with regard to preserving quality of life. Radiotherapy alone has been shown to be effective for the control of unresectable or recurrent lesions. Desmoid tumors tend to be locally infiltrative, therefore, the fields must be generous to prevent marginal recurrence. The radiation dose appropriate for treating desmoid tumors remains controversial. We present a 25-year-old Caucasian man with local recurrence of a desmoid tumor after repeated surgical resection, treated with radiotherapy. The patient achieved complete tumor regression at 4 mo after radiotherapy, and he is clinically free of disease at 12 mo after the end of treatment, with an acceptable quality of life. The patient developed short bowel syndrome as a complication of second surgical resection. Consequently, radiotherapy might have worsened an already present malabsorption and so led to steatohepatitis

Primary mediastinal large B cell lymphoma with sclerosis: A clinical study of 92 patients treated at a single institution with macop-B and radiotherapy

Introduction: Primary mediastinal large B cell lymphoma (PMLBCL) represents a distinct clinicopathological entity of large B cell lymphoma occuring preferentially in young females with a bulky mediastinal mass. Methods: Between 1991 and April 2004, 92 consecutive untreated patients (pts) with PMLBCL were diagnosed and treated at our institution. The median age was 33 years (range 15–61), 68/92 (74%) were females,72 pts had stage II and 20 stage IIE, 43(47%) presented B symptoms, LDH was increased in 68(74%), 81(88%) had a bulky mass and 47(51%) had a superior vena cava syndrome. According to age-adjusted IPI score 52 pts had an IPI = 0–1 and 40 pts IPI = 2–3. All pts were treated with standard MACOP-B chemotherapy (CHT) and 86 pts underwent mediastinal radiation therapy (RT) at dose of 30–36 Gy. Six (7%) pts did not receive RT (refusal = 3, progression = 2, death = 1). The response was evaluated in all pts after CHT and at the end of RT. Results: After MACOP-B regimen the response rate was: CR/CRu = 72(78%), PR = 18 (20%), NR = 1(1%), toxic death = 1(1%). Six (6%) PR pts underwent to intensification therapy with high dose therapy and ASCT. After RT pts achieved CR/CRu = 78 (91%), PR = 3(3%), NR = 5(6%).After CHT 67 Gallium scan was positive in 51/60 (85%) while after RT was positive in 12/53(23%) P <0.0001.After a median follow-up of 58 months (1–165) relapse was observed in 9 pts. Five of the 9 relapsed pts are alive in CR after second line therapy with ASCT. Five not responding pts had progressive disease and died. To date 82 (90%) pts are currently in continuous CR. Projected 5-years OS and PFS are 88% and 84%, respectively. The 5 years OS was better for pts with IPI = 0–1 compared to IPI = 2–3 (96% vs 76% P = 0.006). Conclusions: Combined modality treatment using the MACOP-B regimen and mediastinal RT induces high response and survival rates. Radiation therapy plays an important role in the achievement of these results

MACOP-B +/- RITUXIMAB FOLLOWED BY INVOLVED MEDIASTINAL RADIOTHERAPY IS A SAFE AND HIGH EFFECTIVE THERAPY FOR PRIMARY MEDIASTINAL LARGE B CELL LYMPHOMA (PMBL): LONG TERM RESULTS AND LATE TOXICITY FROM A SINGLE ITALIAN CENTER

Background: Primary Mediastinal B cell lymphoma is a distinct subtype of diffuse large B cell lymphoma that is more common in younger female age. Combined regimen of chemotherapy (CT) with involved field radiotherapy (IFRT) is considered the mainstay of treatment. In the pre-Rituximab era third generation regimens as MACOP-B has improved survival in PMBL patients (pts) over CHOP, but the current combination of Rituximab with CHOP regimen equalize this difference. The real need of consolidation mediastinal IFRT is still debated for the risk of secondary cancer and cardiac disease. We report the long term results on a large series of PMBL treated at our institute. Method: 107 pts with PMBL were treated between June 1991 and September 2006; 80 pts had stage II and 27 stage IIE-IV, 75% had elevated LDH, bulky disease was in 95 pts including 58 (55%) with clinical evidence of superior vena cava obstruction. Median age was 34 yrs (15-61), 71% were females. The IPI score was 0-1 in 60 pts and 2-3 in 47. Ninety-two pts were treated with standard MACOP-B regimen and 15 received a Rchemotherapy since March 2004. Overall 94% received IFRT at dose of 30-36 Gy. The response was evaluated at the end of CT and of IFRT. Results: At the end of the program, the CR/CRu was obtained in 76 pts (71%), PR in 23(21%), NR 1(1%), 7 pts were not evaluable: 6 pts received an early intensification for progressive disease and 1 died for toxicity by CT. At the end of the program: 14 of PR pts obtained a CR/CRu after IFRT with an overall CR/CRu rate of 89%; 9 pts relapsed within 10 months and 4 of them died of progressive disease. At a median follow-up of 111 months (1-238) the 10-yrs OS, PFS and EFS were 88%, 85% and 83% respectively. No statistically significant difference was recorded with MACOP-B +/- Rituximab in order to survival end-points. Pts with IPI 0-1 have significant better PFS p=0.020. In our experience 1/107 pt developed a secondary cancer (acute myeloid leukemia) after 164 months from the end of therapy and no breast cancer occurred. Four/107 (4%) presented late severe cardiotoxicity: 3 congestive heart failure and 1 sudden arrhythmic death. Conclusions: This is the largest reported series of PMBL treated at single center. MACOP-B +/- Rituximab plus IFRT is highly effective and devoid of a severe long term toxicity. Future randomized trials should evaluate the real need of a mediastinal IFRT in pts who obtained a PET negative CR after a R-chemotherapy regimen