A phase II study of a human anti-PDGFRα monoclonal antibody (olaratumab, IMC-3G3) in previously treated patients with metastatic gastrointestinal stromal tumors.

Background: This study evaluated tumor response to olaratumab (an anti-PDGFRα monoclonal antibody) in previously treated patients with metastatic gastrointestinal stromal tumor (GIST) with or without PDGFRα mutations (cohorts 1 and 2, respectively). Patients and methods: Patients received olaratumab 20 mg/kg intravenously every 14 days until disease progression, death, or intolerable toxicity occurred. Outcome measures were 12-week tumor response, progression-free survival (PFS), overall survival (OS), and safety. Results: Of 30 patients enrolled, 21 patients received ≥1 dose of olaratumab. In the evaluable population (cohort 1, n = 6; cohort 2, n = 14), no complete response (CR) or partial response (PR) was observed. Stable disease (SD) was observed in 3 patients (50.0%) in cohort 1 and 2 patients (14.3%) in cohort 2. Progressive disease (PD) was observed in 3 patients (50.0%) in cohort 1 and 12 patients (85.7%) in cohort 2. The 12-week clinical benefit rate (CR + PR + SD) (90% CI) was 50.0% (15.3-84.7%) in cohort 1 and 14.3% (2.6-38.5%) in cohort 2. SD lasted beyond 12 weeks in 5 patients (cohort 1, n = 3; cohort 2, n = 2). Median PFS (90% CI) was 32.1 (5.0-35.9) weeks in cohort 1 and 6.1 (5.7-6.3) weeks in cohort 2. Median OS was not reached in cohort 1 and was 24.9 (14.4-49.1) weeks in cohort 2. All patients in cohort 1 and 9 (64.3%) in cohort 2 experienced an olaratumab-related adverse event (AE), most commonly fatigue (38.1%), nausea (19.0%), and peripheral edema (14.3%). Two grade ≥3 olaratumab-related events were reported (cohort 1, syncope; cohort 2, hypertension). Conclusions: Olaratumab had an acceptable AE profile in patients with GIST. While there was no apparent effect on PFS in patients without PDGFRα mutations, patients with PDGFRα-mutant GIST (all with D842V mutations) treated with olaratumab had longer disease control compared with historical data for this genotype. ClinicalTrials.gov Identifier: NCT01316263.

Open-label, randomized study of individualized, pharmacokinetically (PK)-guided dosing of paclitaxel combined with carboplatin or cisplatin in patients with advanced non-small-cell lung cancer (NSCLC).

BACKGROUND: Variable chemotherapy exposure may cause toxicity or lack of efficacy. This study was initiated to validate pharmacokinetically (PK)-guided paclitaxel dosing in patients with advanced non-small-cell lung cancer (NSCLC) to avoid supra- or subtherapeutic exposure. PATIENTS AND METHODS: Patients with newly diagnosed, advanced NSCLC were randomly assigned to receive up to 6 cycles of 3-weekly carboplatin AUC 6 or cisplatin 80 mg/m(2) either with standard paclitaxel at 200 mg/m(2) (arm A) or PK-guided dosing of paclitaxel (arm B). In arm B, initial paclitaxel dose was adjusted to body surface area, age, sex, and subsequent doses were guided by neutropenia and previous-cycle paclitaxel exposure [time above a plasma concentration of 0.05 µM (Tc>0.05)] determined from a single blood sample on day 2. The primary end point was grade 4 neutropenia; secondary end points included neuropathy, radiological response, progression-free survival (PFS) and overall survival (OS). RESULTS: Among 365 patients randomly assigned, grade 4 neutropenia was similar in both arms (19% versus 16%; P = 0.10). Neuropathy grade ≥2 (38% versus 23%, P < 0.001) and grade ≥3 (9% versus 2%, P < 0.001) was significantly lower in arm B, independent of the platinum drug used. The median final paclitaxel dose was significantly lower in arm B (199 versus 150 mg/m(2), P < 0.001). Response rate was similar in arms A and B (31% versus 27%, P = 0.405), as was adjusted median PFS [5.5 versus 4.9 months, hazard ratio (HR) 1.16, 95% confidence interval (CI) 0.91-1.49, P = 0.228] and OS (10.1 versus 9.5 months, HR 1.05, 95% CI 0.81-1.37, P = 0.682). CONCLUSION: PK-guided dosing of paclitaxel does not improve severe neutropenia, but reduces paclitaxel-associated neuropathy and thereby improves the benefit-risk profile in patients with advanced NSCLC. CLINICAL TRIAL INFORMATION: NCT01326767 (https://clinicaltrials.gov/ct2/show/NCT01326767).

[Gastrointestinal stromal tumours bigger than 20 cm: experience with imatinib chemotherapy in neoadjuvant intention]. / Gastrointestinale Stromatumore größer als 20 cm: Erfahrungen mit Imatinib in neoadjuvanter Intention.

The size of the primary tumour is considered the most important risk factor for the development of metastasis or local recurrence in case of gastrointestinal stromal tumour (GIST). Until now no prospective data are available in the literature about the role of neadjuvant therapy with Imatinib. Between 2009 and 2012 seven patients with a giant GIST > 20 cm underwent a neadjuvant treatment with Imatinib, a radical operation, followed by an adjuvant therapy. These patients were controlled with regard to peri- and postoperative morbidity and disease-free survival. Two patients were considered not resectable and one patient showed liver metastasis at the time of diagnosis. RECIST responses to the neoadjuvant Imatinib were: 2/7 patients with stable disease, 3/7 partial response, 2/7 partial response with down-staging (resectable disease). Because of the following tumour localisations (6 gastric and 1 rectal), six gastrectomies (one en-bloc with left pancreas) and one Holm operation were performed. The patient with simultaneous liver metastasis developed a tumour progression during the follow-up but the others are still tumour free after 2 years. We detected a significant tumour volume regression due to the neadjuvant chemotherapy in cases of GIST > 20 cm (30 %). Our series showed good results for a neadjuvant therapy in cases of giant GIST with the achievement of 100 % R0 resection without a high morbidity rate (in the literature a tumor size > 10 cm and poor localisation is associated to a high risk of R1 - 2 and high morbidity). Peri- and postoperative morbidity are acceptable and the tumour free survival at 2 years is 85 %.

Pemetrexed in patients with refractory soft tissue sarcoma: a non-comparative multicenter phase II study of the German Sarcoma Group AIO-STS 005.

BACKGROUND: This study evaluated efficacy and safety of pemetrexed in patients with refractory soft tissue sarcoma. METHODS: Patients received pemetrexed intravenously at a dose of 500 mg/m² every 21 days until progression or unacceptable toxicity. The primary endpoint was objective tumor response. RESULTS: Fourty-eight of 53 screened patients were included and received a total of 200 cycles (median 2; range 1-30). Median age was 53 years (range, 20-81). The observed toxicity profile was favorable. NCI-CTC hematologic grade 3/4 toxicity consisted of neutropenia in 13 %, anemia in 15 %, and febrile neutropenia in 4 % of patients of patients, respectively. Non-hematologic CTC grade 3/4 toxicity consisted of elevated ASAT/ALAT in 10 %, hyperglycemia in 6 %, infection with or without neutropenia in 6 %, nausea in 2 % and stomatitis in 2 % of patients. No other grade 3 toxicities and no treatment-related toxic deaths were observed. Overall response as defined by RECIST was 5 %, 16 patients experienced stable disease (40 %). The estimated 3- and 6-months progression-free rates were 33.3 % and 14.6 %, respectively. CONCLUSIONS: In patients with refractory STS, pemetrexed is well tolerated and moderately effective. The confirmed objective response rate in STS is low, however, disease stabilizations are seen in a high proportion of patients (ClinicalTrials.gov NCT00427466).

Effect of concurrent chemotherapy and hyperthermia on outcome of preoperative radiotherapy of high-risk soft tissue sarcomas.

BACKGROUND AND PURPOSE: As treatment results for high-risk soft tissue sarcoma are still disappointing, treatment intensification is warranted. We performed a retrospective analysis of multimodal preoperative treatment to evaluate the additional effect of concurrent chemotherapy and/or locoregional hyperthermia in comparison to radiotherapy alone. PATIENTS AND METHODS: Between 1999 and 2011, 28 patients were treated with neoadjuvant radiotherapy to a median 45 Gy for high-risk soft tissue sarcoma. All tumors were deep-seated and grade 2 or 3, 86% (n = 24) larger than 5 cm. Multimodal treatment (n = 12) consisted of ifosfamide (n = 7), locoregional hyperthermia (n = 3), or both modalities (n = 2) concurrent to radiotherapy. RESULTS: Prognostic factors (grade, size, histology, location) were balanced in the groups with and without concurrent multimodal treatment. There was a significant improvement of disease-specific survival (100% vs. 70% at 3 years, p = 0.03) with multimodal treatment. Distant metastases-free survival was influenced, but was not statistically significant. Local control and disease-free survival did not differ in the two groups. CONCLUSION: Our data suggest that multimodal treatment with ifosfamide and/or locoregional hyperthermia in combination with neoadjuvant radiotherapy might improve outcome in high-risk soft tissue sarcomas.

Clear-cell sarcoma of the soft tissue--a rare diagnosis with a fatal outcome.

Clear-cell sarcomas account for less than 1% of all soft tissue tumours. They most often occur in middle-aged adults as a deeply located lesion with predilection to the tendons and aponeuroses. The aim of the present study was to show possible influencing factors on the outcome after surgical treatment in a detailed case series. We reviewed the medical records of 11 patients with the diagnosis of a clear-cell sarcoma of the soft tissue. These cases were analysed with regard to age, gender, localisation, tumour size, recurrence free survival and overall survival. A minimum follow up of 12 months was achieved. The mean age at the point of diagnosis was 47.9 years. Metastases occurred after a mean of 19.2 months. In the cases with a tumour diameter >5 cm, metastases occurred earlier. When treated in a specialist centre, metastases occurred later. Patients died a mean of 18.4 months after developing metastatic disease. Patients with tumour size >5 cm at the point of primary diagnosis died earlier than patients with a tumour size <5 cm. It is important to detect clear-cell sarcomas as soon as possible and the final surgical treatment should be performed in a centre familiar with the treatment of soft tissue tumours not only to prolong overall survival, but also to treat the patient in a multiprofessional team.

Thrombopoietic cells and the bone marrow vascular niche.

Megakaryocytes and platelets have been known to secrete angiogenic growth factors for a long time. However, there is little in vivo data on the regulation of angiogenesis by thrombopoietic cells. Both megakaryocytes and platelets are known to carry and release a multitude of both pro- and antiangiogenic mediators. Thus, it remained unknown how the "angiogenic phenotype" of thrombopoietic cells would be determined. Our group established that platelets contribute to angiogenesis as carriers of SDF-1, which is released by platelets in response to stimulation with hematopoietic cytokines. Indeed, even the action of VEGF-A seems to be mediated in part by the release of SDF-1 from stimulated platelets, thereby attracting proangiogenic hematopoietic cells. Moreover, the analysis of murine plasma and serum showed that similar to VEGF-A, SDF-1 is almost exclusively derived from platelets, and only trace amounts are detectable in platelet poor plasma. Because tumor patients' platelets have been shown to contain lower amounts of thrombospondin (Tsp), we generated Tsp-1 and Tsp-2 double knockout mice by crossing the single knockout lines. Interestingly, megakaryocytes and platelets derived from these mice confer a proangiogenic phenotype both in the bone marrow and in reperfusion of ischemic hindlimbs, thereby verifying the hypothesis of pro- and antiangiogenic platelet constituents "in balance."

Liposarcoma of the Spermatic Cord: Impact of Final Surgical Intervention--An Institutional Experience.

BACKGROUND: Paratesticular liposarcomas are almost always mistakenly diagnosed as inguinal hernias subsequently followed by inadequate operation. METHODS: 14 consecutive patients with paratesticular liposarcoma were retrospectively reviewed. Preoperative management was evaluated. Disease-free and overall survival were determined. RESULTS: In 11 patients primary and in 3 patients recurrent liposarcoma of the spermatic cord were diagnosed. Regarding primary treatment in primary surgical intervention resection was radical (R0) in 7 of 14 (50%) patients, marginal (R1) in 6 (43%) patients, and incomplete with macroscopic residual tumour (R2) in 1 (7%) patient. Primary treatment secondary surgical intervention was performed in 4 patients: resection was radical (R0) in 3 (75%) patients and marginal (R1) in 1 (25%) patient. Regarding secondary treatment in recurrent disease resection was marginal (R1) in 3 patients (100%). Final histologic margins were negative in 10 patients with primary disease (71%) and positive in 4 patients with subsequent recurrent disease. After radical resection disease-free survival rates at 3 years were 100%. Overall survival at 4.5 years (54 (18-180) months) was 64%. CONCLUSION: An incomplete first surgical step increases the number of positive margins leading to local recurrences and adverse prognoses. Aggressive surgery should be attempted to attain 3-dimensional negative margins.

[Pulmonary infection in neutropenia]. / Pulmonale Infektion bei Neutropenie - Fall 1/2015.

UNLABELLED: MEDICAL HISTORY AND CLINICAL COURSE: A 42-year-old patient with hairy cell leukemia had been treated for 3 years by a hematologist in private practice. Initially the patient received 1 course of cladribine upon which the disease went into complete remission. 6 weeks ago a relapse was diagnosed and combination therapy with cladibrin and rituximab was initiated. Now the patient presented to the emergency room with shortness of breath and pain when breathing. INVESTIGATIONS, TREATMENT AND COURSE: In the chest x-ray, patchy infiltrates and pleural effusions were found on both sides. The subsequently performed computed tomography showed bilateral compactions with an Halo suspicious for fungal infiltrates. Upon admission to the hospital, an empirical antibiotic therapy with clarithromycin and piperacillin/tazobactam was initiated, which was later escalated to meropenem and linezolid. Additionally, an antifungal therapy with voriconazole was started and later switched to liposomal amphotericin B. At his admission, a positive aspergillus antigen could be detected in the microbiological laboratory. Under antimycotic treatment the aspergillus antigen was repeatedly negative. The patient presented with pronounced cytopenias and after a switch of therapy to vemurafenib and filgrastim, the hematopoiesis could only be stimulated insufficiently. The patient was transferred to the intensive care unit three days after admission with severe respiratory failure. He died on day 8 after admission. AUTOPSY AND DIAGNOSIS: Diagnosis was consistent with relapse of hairy cell leukemia with positive BRAF mutation and a bone marrow infiltration > 80 %. Autopsy revealed a significant hepato-splenomegaly, a lack of erythro-, granulo- and thrombopoiesis. Clots interspersed with fungal hyphae were found in both lungs and an infarction of the spleen with evidence of fungal hyphae was detected. The cultural findings post mortem on yeast or mold were negative. CONCLUSION: Patients with refractory hairy cell leukemia and prolonged neutropenia are at increased risk for systemic fungal infections. Therefore, prohylactic antimycotic therapy should be considered early in this group of patients. The therapeutic approach of vemurafenib in treatment-refractory hairy cell leukemia is promising and offers an additional treatment option. In the present case, the patient could unfortunately not be stabilized due to the septic complications.

Correlations between hematopoietic progenitor cell counts as measured by Sysmex and CD34+ cell harvest yields following mobilization with different regimens.

PURPOSE: The Sysmex SE-9000 cell counter provides an estimate of immature cells referred to as hematopoietic progenitor cells (HPC). HPC counts should correlate with CD34+ counts in mobilized peripheral blood and apheresis to allow optimization of apheresis timing. METHODS: We correlated the HPC counts as measured in the immature information channel with CD34+ cell levels as determined by FACS (HPCA-2 antibody, Becton Dickinson) from mobilized peripheral blood in 40 samples (27 patients and three healthy donors) and in aphereses ( n=113, 41 patients and 20 healthy donors). RESULTS: In mobilized blood, HPC counts were correlated with CD34+ cells ( r=0.78, P<0.0001, n=40). The HPC counts were about 1.5-fold higher than CD34+ cell counts with a median (range) of 84 (1-747)/microl and 57 (1-370)/microl, respectively. In CD34+ selected cell preparations ( n=8), HPC counts were about fourfold lower than CD34+ cell counts with a median (range) of 179 (67-693)/microl and 760 (191-4309)/microl, respectively. In apheresis preparations, linear regression analyses were performed for the group of stem cell donors ( n=44), the group of lymphoma patients ( n=23), the multiple myeloma group ( n=21), and the group of solid tumors ( n=25). Interestingly, no correlation between HPC counts and CD34+ cell counts was found in the G-CSF-mobilized healthy donor group ( r=0.23, P=0.13). Pairing of HPC counts and CD34+ counts was effective in the group of patients receiving chemotherapy + G-CSF for stem cell mobilization: lymphoma group ( r=0.67, P=0.0005), multiple myeloma group ( r=0.56, P=0.008), and the group of solid tumors ( r=0.52, P=0.007). CONCLUSIONS: Lymphoma and multiple myeloma patients who were moderately pretreated and mobilized with chemotherapy and G-CSF showed the best results in correlation analyses even at low HPC counts. Therefore, HPC measurement can be used for timing of apheresis in these patients.

Changes in the distribution of non-neuronal elements in rat median eminence and in anterior pituitary hormone secretion after activation of tuberoinfundibular dopamine neurones by brain stimulation or nicotine.

In order to investigate the posssibility of acute functional changes in non-neuronal elements (mainly tanycytes) of the median eminence, the proportion of portal capillary surface covered by such elements was measured by quantitative electron microscopy in ovariectomized, oestrogen-progesterone-pretreated rats. In some of these animals, the functional state of the tuberoinfundibular dopamine (DA) neurones was assessed by histochemical microfluorimetry. Serum concentrations of luteinizing hormone (LH), growth hormone (GH) and prolactin were determined by radioimmunoassay. Two different types of treatment, i.e. systemic administration of nicotine (1 mg/kg, s.c.) or electrical stimulation in the medial amygdaloid nucleus, markedly reduced the percentage of capillary surface covered by non-neuronal profiles within 20 and 15 min, respectively. At the same time, the tuberoinfundibular DA system responded by an increase in cellular fluorescence intensity, reflecting neuronal activation. Medial preoptic stimulation had basically the same effect but with more variability in the change in capillary coverage by tanycytes. The action of nicotine was prevented by pretreatment with the DA receptor blocking agent, pimozide (5 mg/kg), which indicates (1) that a dopaminergic mechanism was involved in the nicotine effect and (2) that the tanycyte response was elicited by DA released from nerve terminals acting at some receptor site. Nicotine also lowered serum levels of GH and prolactin. Pimozide antagonized only the effect on prolactin. While the reaction of DA neurones and capillary coverage by tanycytes were correlated with each other in individual rats, no statistically significant correlation was observed between tanycyte response and hormone levels, so that no conclusions can as yet be drawn as to the neuroendocrine significance of the tanycyte reaction. These results indicate that rapid changes in the proportion or portal capillary surface covered by non-neuronal profiles can be elicited by stimulation of extrahypothalamic brain areas or by activation of cholinergic mechanisms. The tanycyte response appears to be mediated at least in part by the tuberoinfundibular DA neurones.

Voice onset time production and perception in apraxic subjects.

This study explored the relationship between the perception and production of voice onset time (VOT) in apraxic subjects. Spectrograms of the words, "bees" and "peas" spoken by apraxic subjects were acoustically analyzed to obtain a measure of VOT. The subjects also identified the initial cognate ("b" or "p") from synthetically generated speech spanning a voiced to voiceless time continuum. The results suggest that apraxic subjects have production as well as perceptual errors in the voicing feature but no significant relationship was found between the two measures.

Effects of phonetic distance on recognition of synthetic sentences.

Phonetic replacements for the syllable initial consonants and clusters of words in sentences were made according to the scale of phonetic distance devised by Black (Perceptual Differences Between Consonants. Columbus: The Ohio State University, 1974). The impact of such replacements upon the intelligibility of synthetically produced sentences was shown to be substantial. The regression of intelligibility over distance was strong, providing support for the construct validity of Black's scaling.

Contamination of autologous peripheral blood progenitor cell grafts predicts overall survival after high-dose chemotherapy in multiple myeloma.

BACKGROUND: Despite of the introduction of novel treatment modalities for multiple myeloma, high-dose chemotherapy with hematopoietic stem-cell rescue is still considered the standard of care for eligible patients <65 years of age. As we have previously reported, stem-cell grafts regularly contain quantities of plasma cells measurable by flow cytometry. However, the pathogenetic significance of this finding remains unknown. METHODS: Multiple myeloma patients (n = 60) were mobilized with chemotherapy and filgrastim. Peripheral blood stem cell grafts were obtained by standard leukapheresis, and the number of CD38++/CD138+ cells/kg was determined by flow cytometry. Plasma cell contamination above a threshold of 4.5 x 10(5) plasma cells/kg was considered "high", whereas lower quantities of plasma cells or absent plasma cells in the graft were considered "low". RESULTS: Progression-free survival: the median statistical progression-free survival was 33.5 months (range 11-99 months) in the high-contamination group (n = 16) versus 47 months (range 8-148 months) in the low-contamination group (n = 44). This difference turned out not to be statistically significant (P = 0.15). However, the difference was highly significant regarding overall survival with 53 months (range 11-119 months) in the high-contamination group and with 114 months (range 8-158 months) in the low-contamination group (P = 0.012). CONCLUSIONS: Patients with >4.5 x 10(5) plasma cells/kg contaminating the peripheral blood stem cell graft received after high-dose chemotherapy have a significantly reduced overall survival. Whether high contamination of grafts with plasma cells might reflect residual in vivo tumor mass prior to stem cell transplantation and a generally more aggressive behavior of malignant myeloma cells in these patients, or whether reinfused plasma cells contribute to an unfavorable course of disease remains to be determined.

Beta-galactosidase staining on bone marrow. The osteoclast pitfall.

The enzyme beta-galactosidase, encoded by the bacterial gene lac-Z, is commonly used as a histochemical reporter to track transplanted cells in vivo or to analyze temporospatial gene expression patterns by coupling expression of specific target genes to beta-galactosidase activity. Previously, endogenous beta-galactosidase activity has been recognized as a confounding factor in the study of different soft tissues, but there is no description of the typical background on bone marrow sections when using the chromogenic substrate 5-Bromo-4-chloro-3-indolyl beta-D-Galactoside (X-Gal). In this report, we show that osteoclasts in bone marrow sections specifically and robustly stain blue with X-Gal. This leads to a typical background when bone marrow is examined that is present from the first day post partum throughout the adult life of experimental mice and can be confused with transgenic, bacterial beta-galactosidase expressing hematopoietic or stromal cells. Experimental variations in the X-Gal staining procedure, such as pH and time of exposure to substrate, were not sufficient to avoid this background. Therefore, these data demonstrate the need for strenuous controls when evaluating beta-galactosidase positive bone marrow cells. Verifiable bacterial beta-galactosidase positive bone marrow cells should be further identified using immunohistological or other approaches. Specifically, beta-galactosidase positive hematopoietic or stromal cells should be proven specifically not to be osteoclasts by co-staining or staining adjacent sections for specific markers of hematopoietic and stromal cells.

[Loss of bone mass in patients with anorexia on tube feeding and its prevention with biphosphonates]. / Knochensubstanzverlust bei Anorexie-Patientinnen unter Sondenernährung und dessen Prävention mit Bisphosphonaten.

Women with long-lasting anorexia nervosa often display osteopenia. Furthermore, we have observed additional marked loss of bone mass under tube feeding in underweight anorexia patients. Such loss of bone substances can lead to spontaneous fractures. Therefore, we investigated in this study whether this undesirable effect of tube-feeding might be prevented by administration of bisphosphonates (Didronel), a substance that inhibits the activity of osteoclasts. Bone density was assessed by a high-precision, low dose, quantitative computed tomography of the distal radius and the distal tibia. A group of 6 anorexia patients (tube feeding with an initial underweight of 74.9 +/- 10.3% of ideal weight, mean +/- SD) treated with bisphosphonates showed only slight loss of trabecular bone (0.8 +/- 0.2%, mean +/- SEM) after 2 months of observation, whereas in 2 control groups a marked diminution of trabecular bone was observed (4.4 +/- 0.7% and 7.6 +/- 1.1% respectively, p less than 0.001 for each comparison). Cortical bone was unchanged throughout. Treatment with bisphosphonates provides effective prevention of bone loss observed in tube-feeding.