Pazopanib (GW786034) and cyclophosphamide in patients with platinum-resistant, recurrent, pre-treated ovarian cancer - Results of the PACOVAR-trial.

PURPOSE: The prognosis is poor for patients with recurrent, platinum-resistant epithelial ovarian cancer (EOC). Evidence suggests that antiangiogenic treatment modalities could play a major role in EOC. A combined therapy consisting of the investigational oral antiangiogenic agent pazopanib and metronomic oral cyclophosphamide may offer a well-tolerable treatment option to patients with recurrent, previously treated EOC. PATIENTS AND METHODS: This study was designed as a multicenter phase I trial evaluating the optimal dose as well as activity and tolerability of pazopanib with metronomic cyclophosphamide in the treatment of patients with recurrent, platinum-resistant, previously treated ovarian, peritoneal, or fallopian tube cancer. Here, 50mg cyclophosphamide were combined with 400 to 800mg pazopanib daily. RESULTS: Sixteen patients were treated; mean age was 66years. At dose levels (DL) I and II, one instance of dose-limiting toxicity (DLT) was seen in one of 6 patients. At DL III, two of four patients showed a DLT, leading to a maximum tolerated dose (MTD) of 600mg pazopanib daily. Median number of administered cycles was 6 (2-13), with three patients being treated for at least 13months. Median progression-free survival (PFS) and overall survival (OS) were 8.35months and 24.95months, respectively. 155 adverse events (AE) occurred, most frequently elevation of liver enzymes, leukopenia, diarrhea and fatigue. Altogether, five serious adverse events (SAE) developed in four patients. CONCLUSION: Pazopanib 600mg daily p.o. and metronomic cyclophosphamide 50mg daily p.o. is a feasible regimen for patients with recurrent platinum-resistant EOC and showed promising activity in this previously treated patient population. TRIAL REGISTRATION: Clin.trial.gov registry no.: NCT01238770.

[Nuclear medicine procedure guideline for sentinel lymph node localization]. / DGN-Handlungsempfehlung (S1-Leitlinie) ­ Version 3.

The authors present a procedure guideline for scintigraphic detection of sentinel lymph nodes in malignant melanoma, in breast cancer, in penile and vulva tumors, in head and neck cancer, and in prostate carcinoma. Important goals of sentinel lymph node scintigraphy comprise reduction of the extent of surgery, lower postoperative morbidity and optimization of histopathological examination focussing on relevant lymph nodes. Sentinel lymph node scintigraphy itself does not diagnose tumorous lymph node involvement and is not indicated when lymph node or distant metastases have been definitely diagnosed before sentinel lymph node scintigraphy. Procedures are compiled with the aim to reliably localise sentinel lymph nodes with a high detection rate typically in early tumour stages. New aspects in this guideline are new radiopharmaceuticals such as tilmanocept and Tc-99m-PSMA and SPECT/CT allowing an easier anatomical orientation. Initial dynamic lymphoscintigraphy in breast cancer is of little significance nowadays. Radiation exposure is low so that pregnancy is not a contraindication for sentinel lymph node scintigraphy. A one-day protocol should preferentially be used. Even with high volumes of scintigraphic sentinel lymph node procedures surgeons, theatre staff and pathologists receive a radiation exposure < 1 mSv/year so that they do not require occupational radiation surveillance. Aspects of quality control were included (scintigraphy, quality control of gamma probe, 6 h SLN course for surgeons, certified breast centers, medical surveillance center).

Oblimersen combined with docetaxel, adriamycin and cyclophosphamide as neo-adjuvant systemic treatment in primary breast cancer: final results of a multicentric phase I study.

BACKGROUND: Combining the Bcl-2 down-regulator oblimersen with cytotoxic treatment leads to synergistic antitumor effects in preclinical trials. This multicentric phase I study was carried out to evaluate maximum tolerated dose (MTD), safety and preliminary efficacy of oblimersen in combination with docetaxel, adriamycin and cyclophosphamide as neo-adjuvant systemic treatment (NST) in primary breast cancer (PBC). METHODS: Previously untreated patients with PBC T2-4a-c N0-3 M0 received one cycle of docetaxel 75 mg/m(2), adriamycin 50 mg/m(2) and cyclophosphamide 500 mg/m(2) administered on day 5 combined with escalating doses of oblimersen as a 24-h continuous infusion on days 1-7 followed by five cycles of combination of docetaxel, adriamycin and cyclophosphamide (TAC) without oblimersen every 3 weeks. Prophylactic antibiotic therapy and granulocyte colony-stimulating factor administration were used in all six cycles. Blood serum samples were taken throughout the treatment period for pharmacokinetic analysis. RESULTS: Twenty-eight patients were enrolled (median age, 50 years; ductal-invasive histology, 68%; tumorsize 2-5 cm, 61%; grade 3, 43%; hormone receptor negative, 36%; Her2 positive 18%) and received oblimersen in a dose of 3 mg/kg/day (cohort I, nine patients), 5 mg/kg/day (cohort II, nine patients) and 7 mg/kg/day (cohort III, 10 patients) respectively. No dose-limiting toxicity occurred. Following oblimersen combined with TAC, the most severe toxicity was neutropenia [National Cancer Institute-Common Toxicity Criteria (NCI-CTC) grades 1-2/3/4] which developed in 0/0/56% of patients (cohort I), 11/0/56% of patients (cohort II) and 20/20/50% of patients (cohort III). No febrile neutropenia occurred. Most common adverse events (all NCI-CTC grade < or = 2) were fatigue, nausea, alopecia, headache and flue-like symptoms observed in 78% (cohort I), 89% (cohort II) and 90% (cohort III) of patients. With increasing dose of oblimersen, a higher incidence of grade IV leukopenia and neutropenia was noted. At the MTD of 7 mg/kg/day of oblimersen, serious adverse events occurred in 40% of the patients. CONCLUSION: Oblimersen up to a dose of 7 mg/kg/day administered as a 24-h infusion on days 1-7 can be safely administered in combination with standard TAC on day 5 as NST in patients with PBC. The safety and preliminary efficacy warrants further evaluation of oblimersen in combination with every cycle of the TAC regimen in a randomized trial.

Tumour-adapted Reduction Mammoplasty - a New (Old) Breast Conserving Strategy: Review.

Today over 70 % of patients treated for primary breast carcinoma in certified breast centres are managed with breast conserving surgery. The classical semicircular incision directly above the tumour, though in many cases easily carried out and associated with good cosmetic results, does have limitations. Unsatisfactory aesthetic results often occur when tumour location is unfavourable or when there is unfavourable tumour size relative to breast size. Distortion of the nipple, changes to breast shape and retraction of skin overlying surgical defects can occur. Tumour-adapted reduction mammoplasty/mastopexy or the "modified B technique" offer excellent chances of combining the oncological demands of breast surgery with satisfactory symmetrical cosmetic results. This article reviews a traditional, old operative technique that has been re-embraced in various new forms.

Bendamustine hydrochloride - a renaissance of alkylating strategies in anticancer medicine.

Alkylating drugs represent one of the oldest classes of anticancer medicine used in a broad variety of clinical indications. Bendamustine hydrochloride (Ribomustine, Treanda) is a newer alkylating agent which has already been under intensive clinical investigation and has gained emerging interest due to its unique pharmacological properties, particularly in resistant or refractory diseases. This article provides basic information on the molecular mechanisms of action of bendamustine and its pharmacological characteristics and an overview on published clinical trials where bendamustine is analyzed as a single agent as well as in combination therapies for the treatment of solid tumors and hematologic malignancies.

Doppler sonography of the fetal middle cerebral artery in the management of massive fetomaternal hemorrhage.

Massive fetomaternal hemorrhage (FMH) is a rare complication in pregnancy that may cause hydrops or can even be life-threatening for the fetus. We report on the case of a 19-year-old gravida I, para 0, who presented to our clinic at 32 weeks of gestation due to decreased fetal movements. The initial fetal heart rate tracing at admission showed a sinusoidal pattern without decelerations. The ultrasound examination performed immediately described a normally developed fetus with normal amounts of amniotic fluid and without abnormities of the placental structure. Doppler sonography of the fetal middle cerebral artery gave rise to the strong suspicion of fetal anemia, so that a cordocentesis was prepared for potential intrauterine blood transfusion. Meanwhile, the rate of fetal hemoglobin (HbF) cells in the maternal blood was found to be markedly increased with 66 per thousand. Correspondingly, cardiotocographic findings worsened with repeated decelerations, thus an immediate cesarean section was performed based on the suspected diagnosis of an acute FMH. A fetus weighing 1,860 g was delivered, who had severe anemia with hemoglobin level of 4.0 g/dl. After a direct blood transfusion, HbF levels normalized rapidly, the fetus stabilized, and a normal recovery has thus far been reported. The presented case demonstrates the successful and straightforward diagnosis, as well as the management of a case of severe FMH and illustrates the special value of Doppler sonography in this context.

Perfusion-weighted magnetic resonance imaging in patients with carotid artery disease before and after carotid endarterectomy.

OBJECTIVE: The purpose of this study was to investigate the potential of perfusion-weighted magnetic resonance imaging for preoperative and postoperative evaluation of cerebral hemodynamics in patients undergoing carotid endarterectomy for carotid artery stenosis. METHODS: We examined 26 patients with angiographically proven stenoses (60%-99%) of the internal carotid artery preoperatively. Perfusion imaging studies were performed by bolus-tracking of a dosage of 0.2 mmol/kg body weight of gadolinium diethylenetriaminepentaacetic acid on a 1.5-T scanner using a T2*-weighted fast low-angle shot sequence. The observed signal intensities were converted pixel by pixel into concentration-time curves. In each patient, the hemispheres were compared and the difference between the normalized first moments (NFMs) and the percentage changes of the regional cerebral blood volume (CBV) were calculated. Three months postoperatively, perfusion-weighted magnetic resonance imaging was performed in 13 patients. RESULTS: In patients with <80% stenosis (n = 10), there was no significant alteration of NFM and regional CBV compared with the contralateral hemisphere (-0.16 +/- 0.7 s, +5.9 +/- 24.6%). In patients with stenoses >or=80% (n = 16), we found an increase in NFM ipsilateral to the stenosis of 1.2 +/- 0.92 s (P < .001) and an increase of CBV of 16.8 +/- 15.2% (P < .005). Three months postoperatively, perfusion parameters were normal in all 13 patients examined. CONCLUSIONS: Perfusion-weighted magnetic resonance imaging is well suited to evaluate the preoperative and postoperative hemodynamic changes in patients with carotid artery stenosis. This noninvasive, semiquantitative magnetic resonance technique could prove to be a valuable adjunct in identification of patients who might benefit from carotid endarterectomy.

Improvement of carotid blood flow after carotid endarterectomy--evaluation using intraoperative ultrasound flow measurement.

OBJECTIVES: to examine the relationship between the degree of extracranial internal carotid artery (ICA) stenosis and changes in the ipsilateral ICA blood flow after carotid endarterectomy (CEA). MATERIALS AND METHODS: in a prospective study we studied 51 patients with unilateral 60-99% ICA stenosis (median degree 84%, asymptomatic stenosis n = 13, symptomatic stenosis n = 38). The degree of ICA diameter stenosis was determined by ex-vivo plastination of the surgically removed atherosclerotic specimen and video-assessed planimetry. Intraoperative transit time ultrasound flow measurements of the carotid arteries were performed before and after CEA. Blood flow changes were assessed by mathematical approximations. Statistics were done by use of the Wilcoxon signed Rank test. RESULTS: common carotid artery (CCA) and ICA median blood flow increased after CEA from 370 and 130 ml/min to 450 and 282 ml/min, respectively (p <.001). The relative increase of ICA blood flow was 5% and 18% for 60-69% and 70-79% ICA stenosis (n.s.) but 70% and 247% for 80-89% and 90-99% stenosis (p <.001 each). Mathematical evaluation (fourth-polynomal function) determined a significant increase of carotid blood flow after CEA in ICA stenosis of > or =82.3%. CONCLUSIONS: in the absence of severe contralateral ICA occlusive disease a significant increase of ipsilateral ICA blood flow by CEA can be expected in patients with an ICA stenosis of > or =82.3% (linear degree of stenosis, ECST criteria).

Grading of internal carotid artery stenosis: validation of Doppler/duplex ultrasound criteria and angiography against endarterectomy specimen.

OBJECTIVES: duplex ultrasound has replaced angiography prior to carotid endarterectomy (CEA) in many institutions. However, the indications for CEA are based on angiographically controlled studies and widely accepted ultrasound criteria do not exist. Consequently, the reliability of Doppler and/or duplex ultrasound to predict a high-grade ICA stenosis has to be proven. DESIGN: prospective validation study. MATERIALS: one hundred and fifty carotid bifurcations assessed by ultrasound and selective angiography and 68 acrylat outcasts of carotid specimen after eversion CEA. METHODS: ICA stenosis was measured angiographically according to the ECST criteria. Combined Doppler acoustic standard criteria (CDASC), peak systolic frequency (PSF), peak systolic velocity (PSV) and end-diastolic velocity (EDV) served as criteria for the ultrasound assessment. These criteria and the results of angiography were compared to the degree of ICA stenosis determined by specimen measurements. RESULTS: the median degree of ICA stenosis as assessed by angiography (82%, range 56-97%) and CDASC (83%, range 50-99%) corresponded well to the specimen measurements (80%, range 50-95%). The sensitivity of angiography and CDASC to predict a 70-90% ICA stenosis (ECST criteria) compared to the specimen measurements was 88% and 95%, respectively. The positive predictive value (PPV) reached 92% and 96%, respectively. CDASC were equivalent to angiography and were superior to the best single frequency or velocity parameters. If CDASC do not indicate a >/=70% ICA stenosis in spite of a PSV >/=180 cm/s and/or an EDV >/=50 cm/s, angiography may detect patients with a >70% ICA stenosis. CONCLUSIONS: CDASC are valid in the quantification of high-grade ICA stenosis. They are more reliable than single velocity and/or frequency measurements. However, if velocity criteria and CDASC do not agree, angiography should be performed.