Isrid Sturm

Bisphosphonate-induced osteonecrosis of the jaws: Prospective study of 80 patients with multiple myeloma and other malignancies

A prospective study was performed in 80 patients receiving bisphosphonates in order to determine frequency of occurrence, risk factors, clinical presentation, radiology, pathology and proper treatment of osteonecrosis of the jaw (ONJ). Of 80 patients, 22 (28%) developed ONJ. There were 11 male and 11 female patients. Median age was 65 years. Ten patients (46%) had multiple myeloma (MM), 5 (23%) had breast cancer and 7 (32%) had other malignancies. Of 22 patients with ONJ, 14 patients (64%) received zoledronate, 3 (14%) received pamidronate, 4 (18%) received pamidronate later followed by zoledronate and 1 patient received ibandronate later followed by zoledronate. The median time of exposure in ONJ group was 32 months compared with 27 months in patients without ONJ. The mean induction time until bone exposure was 26 months for patients who received zoledronate, 54 months for pamidronate and 48 months for pamidronate followed by zoledronate. Thirteen patients (59%) had ONJ with bone exposure of mandible, 6 (27%) of maxilla and 3 (14%) of both jaws. ONJ occurred spontaneously in 5 patients (23%) and in 17 patients (77%) occurred after tooth extractions and surgical tooth removals (P<0.001). Nine patients (41%) had previous extractions of molars, 6 (27%) of premolars and 2 (9%) of front teeth. The cumulative hazard is significantly higher in zoledronate group (P=0.015). It was 3.48 times higher than the other group (pamidronate alone; pamidronate followed by zoledronate; ibandronate alone; etidronate alone; ibandronate followed by pamidronate; ibandronate followed by zoledronate; ibandronate followed by pamidronate and zoledronate). There was no association of ONJ with age, sex, use of high-dose or conventional chemotherapy or the use of corticosteroids, thalidomide or bortezomib (P>0.05). Patients diagnosed with multiple myeloma and breast cancer were found significantly associated with ONJ (P=0.001 and P=0.014, respectively). Long-term use of bisphosphonates (>2.5 years) increases the risk for development of ONJ. Intravenous application of zoledronate and previous dental extractions or surgical tooth removals are important risk factors of ONJ. Neither treatment with high-dose chemotherapy with autologous stem cell transplantation nor treatment with corticosteroids, thalidomide or bortezomib is a risk factor in this study.

Genetic dissection of apoptosis and cell cycle control in response of colorectal cancer treated with preoperative radiochemotherapy

BackgroundIn previous analyses we identified therapy-induced upregulation of the CDK inhibitor p21CIP/WAF-1 and consequently decreased tumor cell proliferation or loss of Bax as adverse factors for survival in rectal cancer treated with radiochemotherapy. Here, we address the individual role of p53 and its transcriptional targets, p21CIP/WAF-1 and Bax, on apoptosis induced by individual components of multimodal anticancer therapy, i.e. 5-fluorouracil (5-FU), ionising γ-radiation (IR) and heat shock/hyperthermia.MethodsWe analysed tumor samples 66 patients with rectal carcinoma treated by a neoadjuvant approach with radiochemotherapy ± heat shock/hyperthermia for the expression and mutation of p53 and the expression of p21CIP/WAF-1 and Bax. These data were correlated with the tumor response. The functional relevance of p53, p21CIP/WAF-1 and Bax was investigated in isogeneic HCT116 cell mutants treated with 5-FU, IR and heat shock.ResultsRectal carcinoma patients who received an optimal heat shock treatment showed a response that correlated well with Bax expression (p = 0.018). Local tumor response in the whole cohort was linked to expression of p21CIP/WAF-1 (p < 0.05), but not p53 expression or mutation. This dichotomy of p53 pathway components regulating response to therapy was confirmed in vitro. In isogeneic HCT116 cell mutants, loss of Bax but not p53 or p21CIP/WAF-1 resulted in resistance against heat shock. In contrast, loss of p21CIP/WAF-1 or, to a lesser extent, p53 sensitized predominantly for 5-FU and IR.ConclusionThese data establish a different impact of p53 pathway components on treatment responses. While chemotherapy and IR depend primarily on cell cycle control and p21, heat shock depends primarily on Bax. In contrast, p53 status poorly correlates with response. These analyses therefore provide a rational approach for dissecting the mode of action of single treatment modalities that may be employed to circumvent clinically relevant resistance mechanisms in rectal cancer.

Successful Treatment of Patients With Multiple Myeloma and Impaired Renal Function With Lenalidomide: Results of 4 German Centers

UNLABELLEDnRetrospective multicenter analysis of 26 patients with multiple myeloma to assess the efficacy and toxicity of relapse treatment with lenalidomide/dexamethasone in renal-function impairment. Analysis showed myeloma overall response rate of 84%, with 42% of patients with improvement of renal function. Lenalidomide/dexamethasone is highly effective, with acceptable toxicity in the renally impaired patient group.nnnPURPOSEnRenal impairment is one of the main complications of multiple myeloma associated with unfavorable prognosis. Lenalidomide in combination with dexamethasone is an effective treatment of relapsed and/or refractory multiple myeloma and may be used in patients with myeloma and with renal insufficiency with appropriate dose adaption according to creatinine clearance (CLCr). However, there are limited data on the use of this regimen in patients with myeloma and with impaired renal function.nnnPATIENTS AND METHODSnWe report on 26 patients, in 4 German centers, with impaired renal function and relapsed and/or refractory multiple myeloma who were treated with lenalidomide/dexamethasone-based regimens; we retrospectively analyzed their data.nnnRESULTSnAll 26 patients had a CLCr < 60 mL/min. Six patients were permanently or temporarily dialysis dependent. Overall response rate (ie, at least a partial response) was 84%. The rate of renal response (at least minor renal response) was 42%, with 6 patients achieving a complete renal response. A median time of 28 days was documented until first response. Six patients had grade 3/4 thromboembolic events; all but one of these patients received prophylaxis with acetylsalicylic acid.nnnCONCLUSIONnLenalidomide-based treatment is highly effective and is an attractive treatment option in patients with multiple myeloma with impaired renal function. In this analysis, renal function was improved in a substantial proportion of patients.

Effect of dance on cancer-related fatigue and quality of life.

PurposeCancer-related fatigue is a multidimensional symptom with an underestimated prevalence and severity in cancer patients. The aim of the study was to evaluate the effect of dance as a holistic sportive activity in cancer patients under active anticancer treatment with fatigue as endpoint.Patients and methodsForty patients under active anticancer treatment (adjuvant (25), palliative (11) or neoadjuvant (4)) with moderate or severe fatigue (≥4 on the visual analogue scale) were investigated in two groups for severity of fatigue (visual analogue scale, Functional Assessment of Chronic Illness Therapy: Fatigue questionnaire), quality of life (European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire) and physical performance (6-minute walk test) before and after the study period—group A (nu2009=u200920): intervention (10 dance classes in 5xa0weeks in addition to counselling) and group B (nu2009=u200920): control (no dance, standard of care, counselling).ResultsWe found significant improvements for cancer-related fatigue in the intervention group (baseline meanu2009±u2009SD 5.95u2009±u20091.701, end-of-study mean 3.8u2009±u20091.542, pu2009=u20090.001, reduction of 36 %) compared to the control group (baseline mean 4.95u2009±u20090.999, end-of-study mean unchanged at 5.0u2009±u20091.556, pu2009=u20090.887); as well as for emotional and social functioning scales and physical performance (pu2009<u20090.05).ConclusionDance might be an appropriate, effective approach for treatment of cancer-related fatigue.

Combination of bortezomib-based chemotherapy and extracorporeal free light chain removal for treating cast nephropathy in multiple myeloma

Besides amyloidosis and light chain deposition disease, the most common histological type of renal lesion is cast nephropathy in 30% of patients with multiple myeloma [2]. In contrast to amyloidosis, cast nephropathy is believed to be potentially reversible when circulating light chains are rapidly reduced. We report on three patients with multiple myeloma and cast nephropathy treated with a bortezomib-based chemotherapy in addition to a newly developed high-cutoff polyflux® haemofilter. Reduction in serum free light chain levels was achieved within 10–12 days, with all three patients improving their renal function.

Thrombocytopenia as first manifestation of splenic angiosarcoma

Dear Editor, Angiosarcoma is a rare mesenchymal neoplasia with an incidence of only 0.14–0.25 cases per million [1]. Most common sites of occurrence are skin and superficial soft tissues, followed by breast, liver, spleen, and bone. Early stage metastases to lung, liver, and lymph nodes are common and overall prognosis is poor [2, 3]. Only approx. 5% of angiosarcomas originate from the spleen, and the existing casuistic reports suggest a dismal clinical prognosis. Here, we describe a rare case of splenic angiosarcoma leading to thrombocytopenia as first manifestation of the disease. A 64-year-old woman presented as hematologic outpatient inMarch 2008 with isolated thrombocytopenia (58/nl) and chronic, slowly progressive fatigue. Thrombocytopenia was first noted in 2006. Pre-existing medical conditions and physical examination were unremarkable. The remaining full blood count was without pathological findings (hemoglobin 12.2 g/dl, normal erythrocyte indices, leukocytes 6.9/nl with normal differential count). Differential diagnosis for moderate thrombocytopenia included various causes for immune destruction of platelets, impaired thrombocyte production, and hypersplenism. However, laboratory screening tests for lymphoma, autoimmune diseases, and virus infections resulted negative. A bone marrow aspirate gave an unspecific picture with unremarkable cellular properties, normal count of megakaryocytes but diffuse infiltration of mature plasma cells up to 15%. A bone marrow biopsy showed hyperplastic left shifted granulopoiesis, left shifted megakaryopoiesis, and erythropoiesis in a hypercellular tissue, partially accompanied with B-cell-rich non-monoclonal lymphocytic aggregates. An abdominal ultrasound showed massive splenomegaly with multiple highly echogenic circular lesions. Multislice computed tomography (MSCT) confirmed splenomegaly (measuring 21 cm craniocaudal) and revealed multiple hypodense lesions with central hyperdense structures (Fig. 1a). In addition, multiple lytic bone lesions in the vertebral column were present. MSCT-guided biopsy of these lytic bone lesions showed infiltrates of a mesenchymal neoplasia containing atypic mitotic bodies, a proliferation fraction of 40% (MIB-1) and negativity for pancytokeratin and S 100. Immunohistochemistry stained positive for vimentin, CD31, CD34, and factor VIII, but negative for desmin, actin, and HHV8, leading to the diagnosis of angiosarcoma (Fig. 2). Meanwhile, the patient suffered from symptomatic splenomegaly (abdominal pain, symptoms of GI tract displacement), and since splenic angiosarcoma may be complicated by splenic rupture [4, 5], an elective splenectomy was performed. Histological examination confirmed the diagnosis of primary splenic angiosarcoma. In addition, the patient was offered palliative chemotherapy and infusions of bisphosphonates; the latter were started immediately. Chemotherapy with paclitaxel (90 mg/m weekly) began with a delay of several weeks (patient’s choice) at a S. Raffel :B. Hildebrandt : I. Sturm (*) Department of Hematology and Oncology, Charite Campus Virchow Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany e-mail: isrid.sturm@charite.de

Thromboembolien, Aborte und ein krankes Neugeborenes

ZusammenfassungHomozystein ist ein bekannter Risikofaktor für Thromboembolien und Gefäßerkrankungen. In der Gynäkologie und Geburtshilfe sind komplizierte Schwangerschaftsverläufe und Aborte bei Hyperhomozysteinämie beschrieben worden. Unsere Patientin war in der Schwangerschaft wegen einer Hyperhomozysteinämie mit hochdosierter Folsäure behandelt worden, dadurch wurde eine perniziöse Anämie maskiert. Der voll gestillte Säugling der Patientin musste im Alter von 5xa0Monaten wegen eines ausgeprägten Vitamin-B12-Mangels mit neurologischer Manifestation stationär behandelt werden. Während parenteraler Vitamin-B12-Substitution normalisierte sich der Homozysteinspiegel der Mutter, das Kind wies Fortschritte in der neurologischen Entwicklung auf.AbstractHomocysteine is a risk factor for the development of thromboembolic disorders and vascular diseases. Furthermore, complications during pregnancy have been ascribed to hyperhomocysteinemia. We report on a pregnant woman being substituted by high doses folic acid for hyperhomocysteinemia. Thereby, the underlying pernicious anemia was masked. After birth, the neonate was exclusively breastfed. At the age of 5xa0months, the infant had to be admitted to hospital due to severe vitamin B12-deficiency. Using parenteral vitamin B12 substitution, homocystein levels of the mother normalized and the infant throve and prospered again.Homocysteine is a risk factor for the development of thromboembolic disorders and vascular diseases. Furthermore, complications during pregnancy have been ascribed to hyperhomocysteinemia. We report on a pregnant woman being substituted by high doses folic acid for hyperhomocysteinemia. Thereby, the underlying pernicious anemia was masked. After birth, the neonate was exclusively breastfed. At the age of 5 months, the infant had to be admitted to hospital due to severe vitamin B(12)-deficiency. Using parenteral vitamin B(12) substitution, homocystein levels of the mother normalized and the infant throve and prospered again.

Sickle cell disease, pulmonary hypertension, and sarcoidosis.

Dear Editor, Sickle cell disease is known for its pulmonary complications. One is an acute life-threatening pulmonary event, known as acute chest syndrome, with high mortality in adult sickle cell patients. Recently, increasing attention is paid to a condition of chronic pulmonary hypertension described in up to 30% of adult sickle cell patients and associated with reduced longterm survival [1]. The pathophysiology of this condition is poorly understood, and the contributing factors might be reduced nitric oxide bioavailability due to chronic hemolysis, thromboembolic events, chronic lung disease due to repeated vaso-occlussive crisis, iron overload, or left heart failure due to chronic anemia [2]. Here we describe the rare case of acute right heart decompensation in a sickle cell patient due to mediastinal and pulmonary sarcoidosis. A 42-year-old black patient (164 cm/77 kg) was admitted for inpatient treatment due to progressive dyspnea without fever, which started 3 weeks before. Homozygous sickle cell anemia was diagnosed 25 years before. Initially, a splenectomy and a cholecystectomy were performed. Since 1997, the patient was on hydroxyurea for repeated severe vasoocclusive crisis. In 2003 and 2007, the passager necessity for mechanical ventilation was recorded, the first triggered by pausing the hydroxyurea therapy, and the second assigned to a Staphylococcus aureus pneumonia. A hip necrosis was treated with total hip replacement in 2006. Outpatient medication included an ACE inhibitor for high blood pressure, folic acid, hydroxyurea (20 mg/kg/day), calcium/Vitamin D supplements, and desferasirox for treatment of iron overload. Physical examination revealed a patient in severely compromised general condition, tachypnoeic, with jugular vein distension and peripheral edema. Results of the physical examination were otherwise unremarkable. Laboratory tests revealed Coombs-negative hemolytic anemia (Hb 6.8 g/dl, LDH 637 U/l, bilirubin 2.7 mg/dl) with reticulocytosis, mild leukocytosis (13.1/nl), and hyperkalemia (5.4 mmol/l). Respiratory acidosis with the sign of global respiratory insufficiency (pH 7.251, sO2 88%, pCO2 54.5) was noted. In the initial X-ray of the chest, a right perihilar mass and a granulomatous infiltration of the lungs along with a global increase in heart size were seen (Fig. 1). Ann Hematol (2008) 87:591–592 DOI 10.1007/s00277-008-0437-4

Successful long-term monotherapy with rituximab in a patient with chronic lymphocytic leukemia of the B-cell-lineage: a case report

IntroductionTreatment of chronic lymphocytic leukemia of the B-cell-lineage is strongly based upon clinical staging because of the heterogeneous clinical course of this disease.Case presentationWe describe a 62-year-old patient with newly diagnosed chronic lymphocytic leukemia of the B-cell-lineage who did not respond to several chemotherapy regimens including chlorambucil, fludarabine and cyclophosphamide, developing a marked neutropenia and thrombocytopenia with life-threatening infections. Further chemotherapy appeared not feasible because of bone marrow toxicity. The patient was treated with 600 mg/m2 rituximab weekly followed by eight courses of biweekly therapy and then by long-term maintenance therapy, achieving almost complete remission of the symptoms and disease control.ConclusionAfter resistance to standard chemotherapy with chlorambucil and fludarabine, a patient with chronic lymphocytic leukemia of the B-cell-lineage was successfully treated with rituximab.

Thromboembolien, Aborte und ein krankes Neugeborenes@@@Thromboembolic events, abortions and a sick infant – Unusual presentation of a vitamin deficiency: Ungewöhnliche Präsentation eines Vitaminmangels

ZusammenfassungHomozystein ist ein bekannter Risikofaktor für Thromboembolien und Gefäßerkrankungen. In der Gynäkologie und Geburtshilfe sind komplizierte Schwangerschaftsverläufe und Aborte bei Hyperhomozysteinämie beschrieben worden. Unsere Patientin war in der Schwangerschaft wegen einer Hyperhomozysteinämie mit hochdosierter Folsäure behandelt worden, dadurch wurde eine perniziöse Anämie maskiert. Der voll gestillte Säugling der Patientin musste im Alter von 5xa0Monaten wegen eines ausgeprägten Vitamin-B12-Mangels mit neurologischer Manifestation stationär behandelt werden. Während parenteraler Vitamin-B12-Substitution normalisierte sich der Homozysteinspiegel der Mutter, das Kind wies Fortschritte in der neurologischen Entwicklung auf.AbstractHomocysteine is a risk factor for the development of thromboembolic disorders and vascular diseases. Furthermore, complications during pregnancy have been ascribed to hyperhomocysteinemia. We report on a pregnant woman being substituted by high doses folic acid for hyperhomocysteinemia. Thereby, the underlying pernicious anemia was masked. After birth, the neonate was exclusively breastfed. At the age of 5xa0months, the infant had to be admitted to hospital due to severe vitamin B12-deficiency. Using parenteral vitamin B12 substitution, homocystein levels of the mother normalized and the infant throve and prospered again.Homocysteine is a risk factor for the development of thromboembolic disorders and vascular diseases. Furthermore, complications during pregnancy have been ascribed to hyperhomocysteinemia. We report on a pregnant woman being substituted by high doses folic acid for hyperhomocysteinemia. Thereby, the underlying pernicious anemia was masked. After birth, the neonate was exclusively breastfed. At the age of 5 months, the infant had to be admitted to hospital due to severe vitamin B(12)-deficiency. Using parenteral vitamin B(12) substitution, homocystein levels of the mother normalized and the infant throve and prospered again.