BACKGROUND: Successful treatment of breast cancer is frequently limited by the resistance of tumors to chemotherapy. Recent studies suggested a role for protein kinase C (PKC) in the resistance to chemotherapy. Here we u...BACKGROUND: Successful treatment of breast cancer is frequently limited by the resistance of tumors to chemotherapy. Recent studies suggested a role for protein kinase C (PKC) in the resistance to chemotherapy. Here we used retrospective analysis of breast cancer biopsies of neoadjuvantly treated patients to investigate the correlation of PKC expression with aggressiveness and resistance to chemotherapy. PATIENTS AND METHODS: Our cohort (n = 25) included patients with advanced and aggressive breast cancers, who underwent neoadjuvant therapy with the CAF regimen (cyclophosphamide, doxorubicin, fluorouracil). Core biopsies (pre-chemotherapy) and surgical biopsies of primary tumors and lymph node metastases (post-chemotherapy) were scored for PKCeta (PKCh) and PKCepsilon (PKCe) expression in the cytoplasm, cell membrane, nuclear membrane, and the nucleus. RESULTS: Our results showed increased expression of PKCh (not PKCe) in the cytoplasm and cell membranes of post-chemotherapy biopsies (p = 0.03). PKCh presence in cell membranes, indicating activation, was in correlation with poor survival (p = 0.007). CONCLUSION: PKCh staining in cell and nuclear membranes is an indicator for poor survival and a predictor for the effectiveness of neoadjuvant treatment. Other avenues of treatment should be considered for these patients. PKCh presents a target for therapy where inhibition of its activity and/or translocation to membranes could interfere with the resistance to chemotherapy.
BACKGROUND: The aim of this study was to determine the efficacy and safety of loading-dose intravenous (i.v.) ibandronate in women with breast cancer and bone metastases. PATIENTS AND METHODS: In this prospective, phase...BACKGROUND: The aim of this study was to determine the efficacy and safety of loading-dose intravenous (i.v.) ibandronate in women with breast cancer and bone metastases. PATIENTS AND METHODS: In this prospective, phase II, open-label study, 13 women with breast cancer, bone metastases, and moderate/severe bone pain received ibandronate 6 mg/day (i.v. loading-dose 15 min infusion over 3 consecutive days) with follow-up until day 14. Endpoints included pain response (primary), duration until pain response, analgesic use, Karnofsky index, safety (including hematologic, biochemical, and urine examinations), and adverse events. RESULTS: Pain intensity decreased on days 7 and 14 versus day 1 (mean visual analogue scale score: 3.2 ± 2.2 and 3.0 ± 2.1 versus 6.1 ± 0.9, respectively; p < 0.01 for both). Mean time to pain response was 8.2 ± 3.3 days. Mean rate of analgesic use decreased (69.2%, 16.7% and 15.4% on days 1, 7 and 14, respectively). Mean Karnofsky index score increased (80.8 ± 13.1 and 80.8 ± 13.2, on days 7 and 14 versus 77.7 ± 11.7 on day 1; p < 0.05 on both days). CONCLUSION: Bone pain and analgesic use decreased in women with breast cancer and bone metastases following loading dose i.v. ibandronate which was well-tolerated with no renal safety concerns.
BACKGROUND: Alveolar soft-part sarcoma (ASPS) is a rare sarcoma often occurring in young patients that is characterized by the unbalanced translocation der(17)t(X;17) (p11;q25). Although it usually shows an indolent clin...BACKGROUND: Alveolar soft-part sarcoma (ASPS) is a rare sarcoma often occurring in young patients that is characterized by the unbalanced translocation der(17)t(X;17) (p11;q25). Although it usually shows an indolent clinical course, the prognosis is usually poor in advanced disease. Since standard chemotherapy regimens used in soft-tissue sarcomas lack efficacy in ASPS, new therapeutic options are needed. We investigated the efficacy of trabectedin, which has demonstrated activity in a variety of cancer types including some of the most prevalent translocation-related sarcomas. PATIENTS AND METHODS: 7 patients with metastatic or advanced ASPS treated with trabectedin in the Sarcoma Center Berlin-Brandenburg and the University Hospital of Greifswald were analyzed for median progression-free survival (mPFS), overall survival (OS), and therapy-related toxicity. RESULTS: In 6 patients with documented disease progression, disease stabilization was reached with trabectedin; only 1 patient experienced progressive disease. The mPFS and OS were 7 months and 21 months, respectively, since the start of trabectedin treatment. Overall, no severe Common Toxicity Criteria (CTC) grade 3 or 4 toxicity was observed. CONCLUSIONS: The poor prognosis of patients with ASPS has so far been due to the unavailability of effective systemic treatments. Trabectedin can be considered the only currently registered drug with clinical activity in this disease.
BACKGROUND: Anthracyclines are agents with a wellknown cardiotoxicity. The study sought to evaluate the hemodynamic response to an anthracycline using realtime continuous-wave (CW)-Doppler ultrasound cardiac output monit...BACKGROUND: Anthracyclines are agents with a wellknown cardiotoxicity. The study sought to evaluate the hemodynamic response to an anthracycline using realtime continuous-wave (CW)-Doppler ultrasound cardiac output monitoring (USCOM) and echocardiography in combination with serum biomarkers. METHODS: 50 patients (26 male, 24 female, median age 59 years) suffering from various types of cancer received an anthracycline-based regimen. Patients' responses were measured at different time points (T0 prior to infusion, T1 6 h post infusion, T2 after 1 day, T3 after 7 days, and T4 after 3 months) with CW-Doppler ultrasound (T0-T4) and echocardiography (T1, T4) for hemodynamic parameters such as stroke volume (SV; SVUSCOM ml) and ejection fraction (EF; EFechocardiography%) and with NT-pro-BNP and hs-Troponin T (T0-T4). RESULTS: During the 3-month observation period, the relative decrease in the EF determined by echocardiography was -2.1% (▵T0-T4, T0 71 ± 7.8%, T4 69.5 ± 7%, p = 0.04), whereas the decrease in SV observed using CW-Doppler was -6.5% (▵T0-T4, T0 54 ± 19.2 ml, T4 50.5 ± 20.6 ml, p = 0.14). The kinetics for serum biomarkers were inversely correlated. CONCLUSIONS: Combining real-time CW-Doppler USCOM and serum biomarkers is feasible for monitoring the immediate and chronic hemodynamic changes during an anthracycline-based regimen; the results obtained were comparable to those from echocardiography.
BACKGROUND: Adult granulosa cell tumors (GCTs) are frequently hormonally active. Thus, hormonal agents have been evaluated for the treatment of advanced-stage or recurrent disease. CASE REPORT: A 39-year-old patient pres...BACKGROUND: Adult granulosa cell tumors (GCTs) are frequently hormonally active. Thus, hormonal agents have been evaluated for the treatment of advanced-stage or recurrent disease. CASE REPORT: A 39-year-old patient presented with recurrent GCT. The patient received multiple treatment modalities, including surgery and 2 different chemotherapy regimens (cisplatin- and taxanebased). Abdominal computed tomography following these treatments showed local recurrence with multiple implants. The patient's inhibin B level increased to 187 pg/ml at this time. The patient was treated with leuprolide 11.25 mg every 3 months and tamoxifen 20 mg twice daily. The patient's inhibin B level began to decrease after 1 month and returned to normal after 4 months. The patient has been maintained on this treatment for 2 years and has tolerated the drugs well. CONCLUSION: The combination of leuprolide and tamoxifen had limited side effects in the presented patient and might be a viable treatment option for women with advanced-stage or recurrent adult ovarian GCTs.
BACKGROUND: Histiocytic sarcoma (HS) is a rare but highly aggressive disease. The cancer-specific survival of patients with HS is short and only limited response to conventional chemotherapy or radiation therapy is seen....BACKGROUND: Histiocytic sarcoma (HS) is a rare but highly aggressive disease. The cancer-specific survival of patients with HS is short and only limited response to conventional chemotherapy or radiation therapy is seen. Some data from single case reports have suggested efficacy for high-dose chemotherapy and autologous/allogeneic stem cell transplantation. CASE REPORT: We report on 4 cases of HS, and demonstrate that different druggable receptors are expressed on HS. Using immunohistochemistry, we detected the expression of platelet-derived growth factor receptor, vascular endothelial growth factor receptor and epidermal growth factor receptor, which are all well-known targets for novel targeted agents. Based on the marker profile, different novel targeted therapies including imatinib, sorafenib and bevacizumab were applied to the patients. We observed a varying clinical course for each patient. CONCLUSION: In our case series, we demonstrated that different receptors, which represent potential targets for novel drugs, are expressed on HS tumor cells. For a definitive assessment of the efficacy of these agents a prospective case study of a larger number of patients should be performed.
BACKGROUND: Hemangioblastomas represent rare benign tumors of the central nervous system. In the case of metastatic spread and limited surgical options, systemic treatment may be considered. However there is no standard...BACKGROUND: Hemangioblastomas represent rare benign tumors of the central nervous system. In the case of metastatic spread and limited surgical options, systemic treatment may be considered. However there is no standard of care beyond surgery. CASE REPORT: We report the cases of 2 patients with progressive multilocular hemangioblastomas, who showed clinical benefit and radiological stabilization of tumor growth after treatment with bevacizumab, an antibody against the vascular endothelial growth factor. CONCLUSION: Our case reports suggest activity of bevacizumab in hemangioblastomas after failure of standard therapeutic options.
BACKGROUND: Patients with solid tumors have an increased risk of venous thromboembolism, potentially related to a venous port system. In case of catheter-related thrombosis despite full anticoagulation, further treatment...BACKGROUND: Patients with solid tumors have an increased risk of venous thromboembolism, potentially related to a venous port system. In case of catheter-related thrombosis despite full anticoagulation, further treatment administration is difficult. CASE REPORT: A 41-year-old female patient with a K-Ras wild-type adenocarcinoma of the rectum was diagnosed with systemic disease in June 2008 after several local recurrences treated with surgery and additive chemotherapy. To administer chemotherapy with FOLFIRI (folinic acid, 5-fluorouracil, irinotecan) and bevacizumab, a venous port system into the vena subclavia was implanted. In April 2009, the computed tomography (CT) scan revealed a portassociated thrombosis with cava superior syndrome, despite treatment with phenprocoumon and an international normalized ratio (INR) of 3.75 at the time of the event. The port system was explanted. According to the possible relationship to bevacizumab, treatment was discontinued, followed by rapid disease progression. Access to peripheral veins became virtually impossible. Therefore, a radiocephalic fistula was established. For 9 months, the patient has been receiving several therapeutic agents with 20 punctures of the fistula, revealing no locoregional events (e.g. arterial, venous or cutaneous). CONCLUSION: The application of current therapeutic agents by an arteriovenous fistula seems to be a feasible option for patients with restricted peripheral or central vein status and/or medical history of thrombotic events disabling the use of a port system.
BACKGROUND: The aim of this study was to evaluate whether positron emission tomography-computed tomography (PET-CT) could be used as part of the staging work-up in patients with limited-stage disease (LD) small cell lung...BACKGROUND: The aim of this study was to evaluate whether positron emission tomography-computed tomography (PET-CT) could be used as part of the staging work-up in patients with limited-stage disease (LD) small cell lung cancer (SCLC). PATIENTS AND METHODS: Between January 2002 and December 2007, a total of 73 patients with presumed LD on CT, who underwent a PET-CT scan, were included in this study. RESULTS: Conventional work-up revealed distant metastases in 12 patients. Out of 61 patients diagnosed as LD SCLC, PET-CT found unexpected distant metastases in 15 (24.6%) patients (LD/extensive-stage disease (ED)) of whom 13 (21.3%) were upstaged as a consequence. In 10 (76.9%) of the 13 upstaged patients, treatment was changed. The median survival of LD/LD SCLC patients who underwent concurrent chemoradiotherapy and chemotherapy only was 21.9 and 17.5 months, respectively. The median survival of LD/ED and ED/ED SCLC patients who received chemotherapy only was 17.4 and 14.1 months, respectively. The median survival of LD/LD SCLC patients who received concurrent chemoradiotherapy was superior to that of LD/ ED and ED/ED patients who received chemotherapy only (p = 0.037 and 0.004, respectively). CONCLUSION: The addition of PET-CT seems to allow more accurate staging and may thus protect a percentage of SCLC patients from potentially futile and toxic radiotherapy.
BACKGROUND: We investigated the efficacy and tolerability of cisplatin and 5-fluorouracil (5-FU) plus bevacizumab as neoadjuvant therapy for patients with locally advanced resectable esophageal cancer. PATIENTS AND METHO...BACKGROUND: We investigated the efficacy and tolerability of cisplatin and 5-fluorouracil (5-FU) plus bevacizumab as neoadjuvant therapy for patients with locally advanced resectable esophageal cancer. PATIENTS AND METHODS: In this prospective phase II study, 22 patients with adenocarcinoma and 6 with squamous cell carcinoma received 2 4-day cycles of bevacizumab 7.5 mg/kg followed by cisplatin 80 mg/m(2) infusion on day 1 followed by 5-FU 1,000 mg/m(2) as a 96-h continuous infusion on days 1-4, separated by a 3-week interval. RESULTS: The response rate was 39%, the R0 resection rate was 43%, and the median overall survival (OS) was 17 months. The regimen was well tolerated, with the most common severe toxicities being venous thromboembolism (10%), nausea, and gastrointestinal bleeding (7% each). In 37 patients previously treated with cisplatin and 5-FU alone at our institution and thus serving as historical controls, the response rate was 30%, the R0 resection rate was 44%, and the median OS was 23 months. There was no statistically significant difference between the 2 groups of patients. CONCLUSION: Adding bevacizumab to cisplatin and 5-FU neoadjuvant chemotherapy was active and well tolerated but did not seem to improve the resection rate or OS compared with prior regimens, including the historical controls at our institution.
BACKGROUND: With sorafenib displaying the highest affinities for Flt3, VEGFR (vascular endothelial growth factor receptor) and Raf and dasatinib for Abl and Src kinases, the profiles of kinases targeted by these inhibito...BACKGROUND: With sorafenib displaying the highest affinities for Flt3, VEGFR (vascular endothelial growth factor receptor) and Raf and dasatinib for Abl and Src kinases, the profiles of kinases targeted by these inhibitors differ strongly. MATERIALS AND METHODS: Dose-dependent effects of the inhibitors on freshly isolated chronic lymphocytic leukemia (CLL) cells were assessed as increased phosphatidylserine exposure. Inhibition by sorafenib and dasatinib of survival and anti-apoptotic signaling in CLL cells was examined by Western blot analysis. RESULTS: Sorafenib uniformly induced apoptosis in CLL lymphocytes with a concentration inhibiting by 50% (IC50) of 8 mM, whereas the response to dasatinib was heterogeneous with the onset of inhibition at submicromolar concentrations but with IC50 values below 25 mM in only a few samples. At the respective pharmacologically achievable plasma concentrations, the inhibitors showed more efficient apoptosis induction by sorafenib than by dasatinib and less than additive mutual enhancement in combination. Co-culture with the bone marrow stroma cell line HS-5 increased the viability of untreated CLL cells but did not protect from sorafenib-induced apoptosis. CONCLUSIONS: Sorafenib or dasatinib displayed sigmoidal or saturation-type dose-response relationships for apoptosis induction, which were uniform or highly divergent, respectively, among individual CLL samples and therefore might complement each other in their clinical potential for CLL.
BACKGROUND: E-cadherin, a transmembrane adhesion molecule, is implicated in the development of many solid tumors as well as in the acquisition of metastatic potential of epithelial tumors. Its clinical use has yet to be...BACKGROUND: E-cadherin, a transmembrane adhesion molecule, is implicated in the development of many solid tumors as well as in the acquisition of metastatic potential of epithelial tumors. Its clinical use has yet to be established. PATIENTS AND METHODS: The prognostic value of E-cadherin expression in 134 invasive ductal breast carcinoma patients over a 10-year follow-up period was investigated. Additionally, the correlation between E-cadherin expression and other traditional prognostic factors was investigated. RESULTS: A statistically significant influence on overall survival was found for estrogen receptor, tumor size, histological and nuclear grade, HER2, lymph node involvement, vascular invasion, proliferative index, and E-cadherin. E-cadherin expression had a significant impact on overall survival and development of metastases in the group of patients not receiving chemotherapy, while it had no such effect in the group of patients who received chemotherapy. CONCLUSION: We conclude that determination of E-cadherin expression can be used as an adjunct in selecting patients who may benefit from adjuvant chemotherapy in the presence of otherwise favorable prognostic factors.
PURPOSE: Local hypofractionated stereotactic radiation treatment (hfSRT) of early stage non-small cell lung cancer (NSCLC) represents a highly effective treatment alternative in medically inoperable patients. METHOD: Bet...PURPOSE: Local hypofractionated stereotactic radiation treatment (hfSRT) of early stage non-small cell lung cancer (NSCLC) represents a highly effective treatment alternative in medically inoperable patients. METHOD: Between June 2007 and December 2010, 65 patients with NSCLC were treated with image-guided hypofractionated radiotherapy. The Union Internationale Contre le Cancer (UICC) stage distribution was: IA, n = 19; IB, n = 15; IIB, n = 5; IIIA, n = 10; IIIB, n = 6; and IV, n = 10. The fractionation schedule used was 3 × 12.5 Gy (n = 36) prescribed to the encompassing 67% isodose line for peripheral primary tumours, and 8 × 6 Gy (n = 26) or 8 × 5 Gy (n = 3) prescribed to the encompassing 80% isodose line for centrally located tumours. RESULTS: Mean follow-up was 13.8 months (range 1-41 months). Until now 6 patients developed a local recurrence, 2 of them in combination with mediastinal lymph node failure. The 1-year actuarial local control rate was 93% and overall survival 79%. Pneumonitis was seen in 14 patients (21.5%) (Common Terminology Criteria for Adverse Events (CTCAE) grade I: n = 12, and II: n = 2) after a median time period of 9.5 months. No patient developed pneumonitis of CTCAE grade III or higher. CONCLUSION: Image-guided hfSRT is effective and feasible in patients with non-operable NSCLC, even in higher stages, whenever local control is crucial and there are contraindications against systemic therapy.
Bone metastases are the most common cause of pain in patients with advanced cancer, and are associated with progressive skeletal destruction, spinal problems, and hypercalcaemia. Radiotherapy, analgesia, and surgery are...Bone metastases are the most common cause of pain in patients with advanced cancer, and are associated with progressive skeletal destruction, spinal problems, and hypercalcaemia. Radiotherapy, analgesia, and surgery are the accepted treatment options for chronic malignant bone pain, with a stepped approach being generally recommended. In the past decade, the bisphosphonates, which reduce bone turnover, increase bone mass, and decrease the risk of fracture, have become established as an effective treatment in patients with cancer metastasising to bone. The nitrogencontaining bisphosphonate, ibandronate, has been shown to reduce the risk of skeletal events after oral or intravenous administration in controlled clinical trials in various malignancies, and to confer significant palliation of bone pain and improvements in health-related quality of life in patients with metastatic breast cancer, in particular. Tolerability of this agent has been good, with very low frequencies of acute-phase reactions and osteonecrosis of the jaw, and no evidence of acute nephrotoxicity.
BACKGROUND: Metastatic epithelioid hemangioendothelioma of the kidney is a rare malignant vascular tumor with a wide spectrum of behaviors. CASE REPORT: We present the case of a 53-year-old male patient with tumor metast...BACKGROUND: Metastatic epithelioid hemangioendothelioma of the kidney is a rare malignant vascular tumor with a wide spectrum of behaviors. CASE REPORT: We present the case of a 53-year-old male patient with tumor metastases which developed after radical nephrectomy. We describe the immunohistochemistry profile of the tumor and the successful long-term results of treatment with sunitinib, a multi-targeted tyrosine kinase inhibitor. Also, we discuss the rationale for using this type of medication based on immunohistochemistry results. CONCLUSION: To the best of our knowledge, this is the first reported case of metastatic renal epithelioid hemangioendothelioma treated successfully with sunitinib.
BACKGROUND: Lymphomatoid granulomatosis is a rare angiodestructive B-cell lymphoproliferative disorder associated with Epstein-Barr virus infection. It predominantly affects the lungs, skin, liver, kidneys, spleen, and c...BACKGROUND: Lymphomatoid granulomatosis is a rare angiodestructive B-cell lymphoproliferative disorder associated with Epstein-Barr virus infection. It predominantly affects the lungs, skin, liver, kidneys, spleen, and central nervous system. Testicular involvement has never previously been described. The authors present the first documented case of testicular involvement in lymphomatoid granulomatosis. CASE REPORT: A 55-year-old gentleman with confirmed lymphomatoid granulomatosis on lung biopsy was noted to have a swelling in his scrotum. Ultrasound scanning demonstrated multiple ill-defined areas of reduced echogenicity throughout both testes with evidence of increased vascularity. Biopsy of the testis confirmed the presence of lymphomatoid granulomatosis. The patient was commenced on alpha-interferon therapy. However, marked clinical improvement occurred only following addition of high-dose oral corticosteroid approximately 1 week later. This resulted in resolution of the testicular swelling and his other symptoms. CONCLUSION: Prognosis with lymphomatoid granulomatosis depends mainly on grade. Our patient responded well to therapy but will continue to be closely followed up in the outpatient setting.
BACKGROUND: Primary myelofibrosis belongs to the group of myeloproliferative syndromes. Extramedullary hematopoiesis in the liver can lead to portal hypertension. PATIENT AND METHODS: We report a case of a patient with l...BACKGROUND: Primary myelofibrosis belongs to the group of myeloproliferative syndromes. Extramedullary hematopoiesis in the liver can lead to portal hypertension. PATIENT AND METHODS: We report a case of a patient with life-threatening, endoscopically not treatable bleeding from esophageal varices due to extramedullary hematopoiesis of the liver that was successfully treated with placement of a transjugular intrahepatic porto-systemic stent-shunt (TIPS). RESULTS: Therapy of variceal bleeding by TIPS insertion was successful. During a 29-month follow-up, no hepatic failure, hepatic encephalopathy, or further variceal bleeding episode occurred. CONCLUSION: TIPS placement is a well-established procedure for the treatment of complications due to portal hypertension mainly due to liver cirrhosis. This report illustrates that TIPS placement can also be a promising treatment option in patients with primary myelofibrosis and portal hypertension due to extramedullary hematopoiesis.