Gemcitabine in soft tissue or bone sarcoma resistant to standard chemotherapy: a phase II study

Purpose: To assess the efficacy of gemcitabine in patients with a variety of sarcomas that have failed to respond or escaped Adriamycin- and ifosfamide-based chemotherapy. Patients and methods: A group of 18 symptomatic heavily pretreated patients with sarcomas of bone or soft tissue received one induction course of gemcitabine at a dose of 1000 mg/m² per week for 7 consecutive weeks, followed by 1 week rest. Response to the induction course was assessed by interview and by repeated ancillary tests. If no progression was observed, maintenance by gemcitabine 1000 mg/m² per week for 3 weeks every 28 days was given until failure was clinically or radiologically evident. Results: A total of 51 cycles of gemcitabine were given including 18 cycles of induction. A mean of 3.6 postinduction cycles were given to nine patients. The treatment was well tolerated by the patients. One partial response (leiomyosarcoma) and one minimal response (angiosarcoma) were observed, yielding a true objective response rate of 5.5%. An additional six patients achieved stabilization of disease (chondrosarcoma and osteosarcoma), yielding an overall progression-free rate of 44%. The median time to progression was more than 27 weeks. Clinical benefit response was observed only in those who also achieved a progression-free state. Conclusion: Gemcitabine was found to be effective in achieving stabilization and even a minimal response of soft tissue or bone sarcoma refractory to standard chemotherapy. Received: 10 June 1999 / Accepted: 7 September 1999     

ErbB4 increases the proliferation potential of human lung cancer cells and its blockage can be used as a target for anti-cancer therapy

Clinical and experimental data suggest that ErbB-4, a member of the epidermal growth factor receptor family, may have a role in cancer progression and response to treatment. We found recently, using a retrospective clinical analysis, that expression of ErbB-4 receptor is correlated with metastatic potential and patient survival in non-small-cell lung cancer (NSCLC). The purpose of this work was to correlate the expression of the ErbB-4 and lung cancer cells growth in vitro and in vivo and to determine the therapeutic potential of a monoclonal antibody to ErbB-4 against lung cancer. For this aim, we ectopically expressed ErbB-4 in a human NSCLC cell line that did not express the ErbB-4 protein. Overexpression of ErbB-4 produced a constitutively activated ErbB-4 receptor. The transfected ErbB-4 positive clones showed an increased cell proliferation in vitro and in vivo in comparison with parental ErbB-4 negative cells and with the cells transfected by neomycin-resistant gene. A monoclonal antibody to ErbB-4 showed both an inhibitory effect on growth rate and an increasing apoptotic rate in the cells expressing ErbB-4. The results of the current study provide evidence that ErbB-4 plays a significant role in human lung cancer and may serve as a molecular target for anticancer therapy.     

Radiotherapy for spinal cord compression in patients with soft-tissue sarcoma

PURPOSE: Spinal metastases of soft-tissue sarcoma (STS) occur rarely and pose a therapeutic problem. Although wide resection is warranted for best local control, it is rarely feasible. A radiotherapy (RT) dose of 70 Gy is usually needed to treat limb STS, but only 45 Gy can be given to the spine. In the present series, we report our experience using RT to treat spinal cord compression (SpCC) associated with STS. METHODS AND MATERIALS: The medical files of 19 adult patients with STS and SpCC were reviewed. RT was considered in all the cases, together with steroids and analgesics. The prescribed dose was 30 Gy in 10 fractions within 12 days. The effect of treatment was evaluated on a clinical basis. RESULTS: Twenty-three events of SpCC were found. The prevailing symptom was pain. The Karnofsky performance status was 40-70% at presentation. RT was given in all but 1 patient and surgical decompression in 3. Small, but important, improvements in signs and Karnofsky performance status were noted in 14 of 23 cases of SpCC, expressed mainly by pain alleviation and restoration of independence. The median survival after the diagnosis of SpCC was 5 months. CONCLUSION: Radiotherapy is an important tool in palliating SpCC in patients with STS.     

Should We Give Prophylactic “Renal‐Dose” Dopamine After Coronary Artery Bypass Surgery?

OBJECTIVE: A prospective double-blind randomized study undertaken to assess the effect of postoperative prophylactic "renal-dose" dopamine on post-coronary artery bypass grafting surgery's clinical outcome. METHODS: Eighty-five consecutive patients undergoing CABG operation were randomized to receive either 3-5 microg/kg/min dopamine (group D, n = 41) or saline as placebo (group P, n = 45) for 48 postoperative hours. Clinical outcome parameters were collected for four postoperative days. RESULTS: Preoperative and operative parameters were similar in both groups. Four patients from group P and none from group D reached an end-point of the study (oliguria, renal dysfunction) and received dopamine. Two patients from group P and none from group D needed an additional inotropic support. Mean arterial pressure values were similar during the first 24 hours after operation, but left atrial pressure values tended to be higher in group P (10 +/- 4 vs 7 +/- 3 mmH2O, p = 0.18). The mean pH was higher in group D at 8 hours after operation (7.38 +/- 0.2 vs 7.36 +/- 0.3, p = NS), due to higher bicarbonate levels (23 +/- 2 mmol/l vs 21 +/- 2, p = 0.49). The incidence of lung congestion in chest X-rays and CT scans was significantly higher in group P (50% vs 29%, p = 0.073 at 48 hours postoperatively). Room air blood O2 saturation and maximal expiratory volume tended to be higher in group D (at 72 hours after operation- 92 +/- 4 vs 90%+/- 5, p = 0.29 and 646 +/- 276 vs 485 ml +/- 206, p = 0.16, respectively). There was no statistical difference in urine output but the amount of furosemide given to patients in group P was significantly higher (during the first 8 hours 2.5 +/- 0.5 vs. 0.3 mg +/- 1.6, p = 0.07). Plasma creatinine levels were significantly lower in group D (at 24 hours 0.93 +/- 0.02 vs 1.05 mg/dL +/- 0.02, p = 0.02). Mobilization after surgery was faster in group D. CONCLUSIONS: Prophylactic dopamine administration after coronary artery bypass grafting surgery improves patient hemodynamic and renal status, reduces the need for additional medical support (inotropes and furosemide) and thus, provides stable postoperative course.     

Activation of dsRNA dependent protein kinase PKR in Karpas299 does not lead to cell death

Activated double-stranded RNA (dsRNA)-dependent protein kinase PKR is a potent growth inhibitory protein that is primarily activated in virally infected cells, inducing them to die. We have recently shown that PKR can be selectively activated in cancer cells, by in situ generation of dsRNA following introduction of antisense RNA complementary to an RNA expressed specifically in the cancer cell. The feasibility of this approach was demonstrated using a glioblastoma line that overexpresses a truncated form of the EGFR. PKR and its signaling pathway are not restricted to a given cell line; therefore, in principle, this dsRNA killing approach can be applied to any cancer that expresses unique RNA sequences. Nonetheless, applying this approach to Karpas299 cells, from a T-cell non-Hodgkin's lymphoma that harbors the NPM/ALK translocation, did not result in cell death, implying that PKR signaling pathway is repressed in this cell line. Indeed, the phosphorylation of eIF2alpha by PKR was impaired in Karpas299 cells. Furthermore, levels of the cellular inhibitor p67 were elevated in these cells. Long antisense, as well as RNAi for p67, delivered into Karpas299 cells by adenoviruses, reduced p67 levels. The reduction in p67 levels led to increased phosphorylation of eIF2alpha, and an additive effect was achieved by coinfection with NPM/ALK-AS encoding adenoviruses. Infection with these adenoviruses, however, did not promote growth inhibition. These findings imply that anti-apoptotic mechanisms counteract PKR signaling in this T-cell non-Hodgkin's lymphoma.     

Learning-induced reduction in post-burst after-hyperpolarization (AHP) is mediated by activation of PKC

We studied the role of protein kinase C (PKC) and protein kinase A (PKA) in mediating learning-related long lasting reduction of the post-burst after-hyperpolarization (AHP) in cortical pyramidal neurons. We have shown previously that pyramidal neurons in the rat piriform (olfactory) cortex from trained (TR) rats have reduced post-burst AHP for 3 days after odour-discrimination learning, and that this reduction is due to decreased conductance of calcium-dependent potassium current. In the present study, we examined whether this long-lasting reduction in AHP is mediated by second messenger systems. The broad-spectrum kinase inhibitor, H7, increased the AHP in neurons from TR rats, but not in neurons from pseudo-trained (pseudo-TR) and naive rats. Consequently, the difference in AHP amplitude between neurons from TR and control animals was diminished. This effect was also obtained by application of the specific PKC inhibitor, GF-109203x. The PKC activator, 1-Oleoyl-2-acetyl-sn-glycerol (OAG), significantly reduced the AHP in neurons from naive and pseudo-TR rats, but not in neurons from TR rats, so that the difference between the groups was abolished. The PKA-specific inhibitor, H-89, increased the AHP in neurons from all groups to a similar extent, and the difference in AHP amplitude between neurons from TR rats and neurons from controls was maintained. We suggest that while the post-burst AHP in piriform cortex pyramidal neurons is modulated by both PKC and PKA, a PKC-dependent process maintains the learning-related reduction of the AHP in these cells.     

Tumor specific activation of PKR as a non-toxic modality of cancer treatment

Over the past decade progress has been made in the development of therapies against cancer. Small molecules, mainly tyrosine kinase inhibitors (tyrphostins) like Gleevec, Iressa targeting CML and EGFR overexpressing tumors have entered the clinic, where a large number of other tyrphostins are at various stages of clinical development. In parallel a few antibodies like Herceptin targeting breast cancer overexpressing Her-2 and Rituxan targeting B cell malignancies are utilized in the clinic. In all these cases success is moderate and restricted to a narrow population of patients, except for Gleevec which is effective for a long duration for chronic CML. The cancer community agrees that this is actually a unique exception that proves the rule. Over the past few years a few modalities of cancer gene therapies have emerged. In this short review we shall summarize our efforts to develop methods to activate PKR selectively in cancer cells.     

Phase II study of carboplatin and etoposide as salvage treatment for patients with metastatic breast cancer

A phase II study of carboplatin and etoposide as salvage polychemotherapy in metastatic, infiltrating breast carcinoma was carried out with 25 multiply pretreated patients. Six of 25 patients (24%) had a partial response that lasted an average of 3.5 months; of the six responders, four had undergone either four or five previous chemotherapeutic treatments. Eight of 25 patients (32%) had stable disease, and 11 (44%) manifested disease progression. The median survival from time of entry to the salvage protocol was 8 months. There were treatment responses in lung, chest wall, liver, and skeleton. The most common side effects were leukopenia (68% of 25 patients), thrombocytopenia (56%), anemia (40%), fever (28%), and weakness (16%). Carboplatin combined with etoposide may be an effective and tolerable salvage regimen in advanced breast cancer.     

Radiation Therapy of Metastatic Spinal Cord Compression. Multidisciplinary team diagnosis and treatment

Purpose: To evaluate the effectiveness of a multidisciplinary approach to spinal cord compression (SCC) in accordance with prospective protocol, providing a uniform approach to diagnosis, decision making concerning optimal treatment modality in any particular case of SCC, treatment performance and evaluation of treatment results. The SCC patients treated by radiation therapy are described.Materials and Methods: Patients with SCC were examined and treated by a multidisciplinary team consisting of a neurologist, radiologist, oncologist, orthopedic surgeon, and neurosurgeon. Seventy-nine patients for whom radiation was recommended received a 30Gy radiation dose to a compression-causing mass and course of high dose dexamethasone. Three fractions of 5Gy and 5 fractions 3Gy each were delivered by Co60 or 8MV photon beam in 12 days. Treatment outcome was essentially evaluated by ambulation capabilities which were considered to be the main problem of SCC. Changes in other neurologic motor, sensory and autonomic disturbances were also evaluated.Results: Seventy-two percent of the patients were already non-ambulatory at diagnosis. The first symptom was motor deficiency in only 33% of them while in all other cases it was pain. Ambulation capability was the main prognosticator of treatment outcome; 90% of patients who were ambulatory before treatment remained so while 33% of the non-ambulatory patients regained their ability to walk. The grade of motor disturbance was also an important variable: among the non-ambulatory patients, 50% of the paretic but only 14% of the plegic ones became ambulatory. Overall, 51% of the study patients were ambulatory after undergoing radiation. The ambulatory state after treatment was the main predictor for survival.Conclusion: Close cooperation of a multidisciplinary team in diagnosis and treatment according to the above protocol enabled the achievement of good results of radiation treatment in SCC. Early diagnosis and early treatment should further enhance therapeutic outcome.     

Palliative Major Amputation and Quality of Life in Cancer Patients

Limb sparing surgery has replaced the amputation surgery in the treatment of limb sarcomas. Recurrent or persistent disease constitutes a major problem. Local symptoms such as agonizing pain, fractures, tumor fungation, inability to walk and inability to maintain daily activities, further impair the patient's quality of life. In this clinical set-up palliative amputation should be considered. Eighteen patients with soft-tissue or bone sarcomas and 3 patients with metastatic carcinoma underwent palliative major amputation. Hemipelvectomy was performed in 3 patients, hip disarticulation in 10, knee disarticulation or below-knee amputation in 3 patients, shoulder disarticulation in one patient and forequarter amputation in 4 patients. Local control of the disease and pain and improvement of the performance status were observed in 19 evaluable patients. The mobility was restored in 15 patients with lower limb surgery. The median survival following the procedure was 9 months. There was only one case of immediate post-operative death. Severe phantom pain was not reported by any of the patients. Quality of life was reported to be improved by two-thirds of the patients. To conclude, we have found palliative major amputation surgery worth performing in low-performance status cancer patients with locally advanced disease.