Incidence and Risk Factors of Bisphosphonate-Related Osteonecrosis of the Jaw in Multiple Myeloma Patients Having Undergone Autologous Stem Cell Transplantation

Background: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a severe complication of bisphosphonate therapy. Due to their long survival and subsequently high cumulative doses of bisphosphonates, multiple myeloma patients have the highest risk of developing BRONJ of all patients treated with bisphosphonates. The purpose of the present study was to evaluate the incidence and risk factors for BRONJ in multiple myeloma patients after high-dose chemotherapy and autologous stem cell transplantation (ASCT). Patients and Methods: We retrospectively analyzed the data of 120 multiple myeloma patients after high-dose chemotherapy and ASCT treated with bisphosphonates and assessed the incidence and risk factors of BRONJ. Results: Of the 120 patients, 23 (19%) developed BRONJ. 6 patients suffered several BRONJ events, resulting in a total incidence of 23%. The risk for BRONJ was significantly higher for patients with rheumatism and recent dental manipulations. Furthermore, the number of previous bisphosphonate rotations, the duration of bisphosphonate therapy, and the type and cumulative dose of bisphosphonate used were associated with the incidence of BRONJ. Conclusion: Our study is the first to determine the risk of BRONJ in a homogeneous group of multiple myeloma patients treated with high-dose chemotherapy and ASCT

GLS following high-dose chemotherapy

Background Cardiac amyloidosis (CA) is a secondary form of cardiomyopathy where abnormal accumulation of amyloid protein in the myocardial interstitium causes cardiac hypertrophy and myocardial fibrosis. If primary CA advances to heart failure, most patients do not survive for very long after the diagnosis. Case summary A 40-year-old man was admitted to our hospital for dyspnoea, progressive anaemia, and decreased appetite. He has diagnosed with amyloid light-chain (AL) amyloidosis. Although BD treatment (bortezomib + dexamethasone) and medical treatment were started, there was no sign of improvement. Then, high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (auto-PBSCT) was initiated. Pretreatment echocardiography revealed typical findings of CA, such as ventricular wall thickening, valvular thickening, diastolic dysfunction, and pericardial effusion. Global longitudinal strain (GLS) was significantly reduced, and bull's-eye mapping showed typical apical sparing. After auto-PBSCT, GLS gradually improved and was almost normal after 2 years. Other echocardiographic parameters, functional status, and laboratory data also showed that there was significant regression of CA. Discussion Although the prognosis in primary CA is extremely poor, we achieved long-term survival in a patient with effective high-dose chemotherapy and auto-PBSCT. Global longitudinal strain may be a useful marker of prognosis, regression, and recovery

Therapeutic sequences in patients with grade 1−2 neuroendocrine tumors (NET): an observational multicenter study from the ELIOS group

Purpose: Many different treatments are suggested by guidelines to treat grade 1−2 (G1−G2) neuroendocrine tumors (NET). However, a precise therapeutic algorithm has not yet been established. This study aims at identifying and comparing the main therapeutic sequences in G1−G2 NET. Methods: A retrospective observational Italian multicenter study was designed to collect data on therapeutic sequences in NET. Median progression-free survival (PFS) was compared between therapeutic sequences, as well as the number and grade of side effects and the rate of dose reduction/treatment discontinuation. Results: Among 1182 patients with neuroendocrine neoplasia included in the ELIOS database, 131 G1–G2 gastroenteropancreatic, lung and unknown primary NET, unresectable or persistent/relapsing after surgery, treated with ≥2 systemic treatments, were included. Four main therapeutic sequences were identified in 99 patients: (A) somatostatin analogs (SSA) standard dose to SSA high dose (n = 36), (B) SSA to everolimus (n = 31), (C) SSA to chemotherapy (n = 17), (D) SSA to peptide receptor radionuclide therapy (PRRT) (n = 15). Median PFS of the second-line treatment was not reached in sequence A, 33 months in sequence B, 20 months in sequence C, 30 months in sequence D (p = 0.16). Both total number and severity of side effects were significantly higher in sequences B and C than A and D (p = 0.04), as well as the rate of dose reduction/discontinuation (p = 0.03). Conclusions: SSA followed by SSA high dose, everolimus, chemotherapy or PRRT represent the main therapeutic sequences in G1−G2 NET. Median PFS was not significantly different between sequences. However, the sequences with SSA high dose or PRRT seem to be better tolerated than sequences with everolimus or chemotherapy

Cisplatin-based chemotherapy of testicular cancer - Two decades after a major breakthrough

Two decades ago the introduction of cisplatin-based combination chemotherapy has dramatically improved the prognosis of patients with metastatic testicular cancer, At present 3 cycles of cisplatin, etoposide and bleomycin are considered as standard treatment for good-risk metastatic disease. Outside of clinical trials patients in the intermediate and poor prognosis categories should receive 4 cycles of this standard regimen, Clinical trials currently evaluate the role of high-dose chemotherapy in first-line treatment of high-risk patients and in the salvage setting, Post-chemotherapy resection of tumor residuals remains an important part of therapy. Attention should be focused on long-term toxicity of therapy and the occurrence of late relapse

High-dose chemotherapy with autologous peripheral blood stem cell support for recurrent primary AFP-producing intracranial germinoma

We report of a 34-year old man with second intracranial relapse of a suprasellar germinoma. Despite of extensive pretreatment with radiation and conventional chemotherapy relapse occurred and was treated with sequential high-dose chemotherapy followed by transfusion of autologous peripheral stem cells. The high-dose chemotherapy course was complicated by refractory derailment of pineal gland insufficiency. The patient achieved a complete remission after high dose chemotherapy which lasted for 13 months. Subsequently, he developed a third relapse and died

High dose sequential chemotherapy with autologous transplantation versus dose-dense chemotherapy MegaCEOP as first line treatment in poor-prognosis diffuse large cell lymphoma: an Intergruppo Italiano Linfomi randomized trial

Background and Objectives. Poor prognosis diffuse large cell lymphoma (DLCL) responds poorly to standard chemotherapy. Randomized studies comparing high-dose chemotherapy with autologous stem-cell transplantation (ASCT) against standard chemotherapy have produced conflicting results. Dose-dense chemotherapy with granulocyte colony-stimulating factor (G-CSF) support seems to hold promise. The purpose of this multicenter, randomized trial was to compare failure-free and overall survival in patients with poor prognosis DLCL treated with high-dose sequential (HDS) chemotherapy followed by ASCT or an outpatient dose-dense chemotherapy regimen (MegaCEOP). Design and Methods. Between 1996 and 2001, 130 DLCL patients, aged <= 60 years, with intermediate-high or high-risk disease, according to the International Prognostic Index score, and/or bone marrow involvement were enrolled. Sixty were randomized to HDS chemotherapy plus high-dose mitoxantrone and melphalan with ASCT (arm A) and 66 to the MegaCEOP regimen (6-8 courses of an escalated dose of cyclophosphamide and epirubicin plus vincristine and prednisone with G-CSF every 2-weeks) (arm B); 4 patients were considered ineligible. Results. The complete remission rate was 59% in arm A and 70% in arm B (p=0.18). After a median follow-up of 78 months, the 6-year failure-free survival was 45% in arm A and 48% in arm B (hazard ratio=1.15, 95% confidence intervals =0.72-1.84, p=0.56). The 5-year overall survival was 49% in arm A and 63% in arm B (hazard ratio=1.67, 95% confidence interval=0.98-2.85, p=0.06). Two cases of secondary acute myeloid leukemia were observed after treatment in group A. Interpretations and Conclusions. HDS and ASCT as initial therapy for patients with poor-prognosis DLCL does not provide a benefit over that of outpatient dose-dense MegaCEOP chemotherapy

Safety and preliminary efficacy of vorinostat with R-EPOCH in high-risk HIV-associated non-Hodgkin\u27s lymphoma (AMC-075)

We performed a phase I trial of vorinostat (VOR) given on days 1 to 5 with R-EPOCH (rituximab plus etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin hydrochloride) in patients with aggressive HIV-associated non-Hodgkin lymphoma. VOR was tolerable at 300 mg and seemingly efficacious with chemotherapy with complete response rate of 83% and 1-year event-free survival of 83%. VOR did not significantly alter chemotherapy steady-state concentrations, CD4+ cell counts, or HIV viral loads. Vorinostat (VOR), a histone deacetylase inhibitor, enhances the anti-tumor effects of rituximab (R) and cytotoxic chemotherapy, induces viral lytic expression and cell killing in Epstein-Barr virus-positive (EBV+) or human herpesvirus-8-positive (HHV-8+) tumors, and reactivates latent human immunodeficiency virus (HIV) for possible eradication by combination antiretroviral therapy (cART). We performed a phase I trial of VOR given with R-based infusional EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin hydrochloride) (n = 12) and cART in aggressive HIV-associated B-cell non-Hodgkin lymphoma (NHL) in order to identify safe dosing and schedule. VOR (300 or 400 mg) was given orally on days 1 to 5 with each cycle of R-EPOCH for 10 high-risk patients with diffuse large B-cell lymphoma (1 EBV+), 1 EBV+/HHV-8+ primary effusion lymphoma, and 1 unclassifiable NHL. VOR was escalated from 300 to 400 mg using a standard 3 + 3 design based on dose-limiting toxicity observed in cycle 1 of R-EPOCH. The recommended phase II dose of VOR was 300 mg, with dose-limiting toxicity in 2 of 6 patients at 400 mg (grade 4 thrombocytopenia, grade 4 neutropenia), and 1 of 6 treated at 300 mg (grade 4 sepsis from tooth abscess). Neither VOR, nor cART regimen, significantly altered chemotherapy steady-state concentrations. VOR chemotherapy did not negatively impact CD4+ cell counts or HIV viral loads, which decreased or remained undetectable in most patients during treatment. The response rate in high-risk patients with NHL treated with VOR(R)-EPOCH was 100% (complete 83% and partial 17%) with a 1-year event-free survival of 83% (95% confidence interval, 51.6%-97.9%). VOR combined with R-EPOCH was tolerable and seemingly efficacious in patients with aggressive HIV-NHL

Novel schedule for treatment of inflammatory breast cancer

Inflammatory breast cancer (IBC) is the most aggressive form of this tumor, with the clinical and biological characteristics of a rapidly proliferating disease. This tumor is always diagnosed at advanced stages, atleast stage IIIB (locally advanced), so its management requires an integrated multidisciplinary approach with a systemic therapy followed by surgery and radiation therapy. Patients with IBC usually have a worse prognosis but the achievement of a pathologic complete response after neoadjuvant chemotherapy may have good rates of overall survival. We present the case of a 47 year old women with IBC, luminal B and with high proliferative index; she was successfully treated with a sequential schedule of chemotherapy (anthracyclines dose-dense/carboplatin+ taxane/Cyclophosphamide Methotrexate Fluorouracil), hormone-therapy, complementary radiotherapy and finally surgery until the achievement of a complete clinical and pathological response. Luminal B inflammatory breast cancer with high proliferation index can benefit from sequential schedules of neoadjuvant chemotherapy and hormonal treatment and this can result in pathological complete response

Long-term outcome and treatment-related toxicity in patients with breast and testicular cancer

Heart muscle impairment on ultrasound is linked to the administered dose of anthracycline chemotherapy in women who have been treated for early breast cancer. That is the conclusion of the HARBOR study, a collaborative effort of the UMCG and AVL included in this thesis. The 569 participating women had been treated with radiotherapy and/or chemotherapy over five years ago. Of note, about half of the participants was overweight, a quarter had high blood pressure and/or high cholesterol, and 15% smoked – targets of interest to manage the risk of heart and blood vessel disease in these patients after cancer treatment.In addition, this thesis contains long-term follow-up of a nationwide trial that compared high-dose to normal-dose chemotherapy in 885 women with breast cancer that had spread to four or more armpit lymph nodes. This N4+ study was conducted between 1993 and 1999 in ten Dutch hospitals. In the follow-up study, high-dose chemotherapy did not appear to improve survival. However, specifically in women with ten or more affected lymph nodes, 15% more patients were still alive twenty years after treatment with high-dose compared to normal-dose chemotherapy. To address long term outcome in male cancer patients, this thesis also addresses adverse effects of the treatment of testicular cancer. The protein INSL3 was investigated in relation to the decreased testosterone production found in some patients. Furthermore, analysis of the genetic makeup of 375 patients provided clues why some patients with testicular cancer get heart or blood vessel disease after treatment, and others do not