Explore the vast range of titles available.

Examine the effects of baseline hypertension (HTN) and statin or proton pump inhibitor (PPI) use on sunitinib treatment outcomes in STAR-TOR, a real-world registry. Presence or absence of HTN and use or nonuse of statins or PPIs were determined at registry entry. End points included overall survival (OS) and progression-free survival (PFS). Data were from 557 patients. Presence or absence of HTN did not affect OS or PFS. PFS (median [95% CI]) was longer in statin users (9.4 [6.5–13.6] months) versus nonusers (6.9 [5.7–8.2] months) (p = 0.0442). OS was shorter in PPI users (20.2 [14.9–28.3] months) versus nonusers (25.7 [22.7–33.0] months) (p = 0.0212). Comorbidities and comedications may affect real-world sunitinib treatment outcomes. Clinical Trial Registration: NCT00700258 ( ) A plain language version of this article is available and is published alongside the paper online.

Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an \"Immunotherapy Summit\" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators; others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet if overcome, have the potential to improve outcomes of patients with cancer.

The phosphatidylinositol-3-kinase (PI3K) pathway is one of the most commonly activated signaling pathways in pancreatic cancer and is a target of interest for new therapeutic approaches. NVP-BGT226 is a novel dual class PI3K/mammalian target of rapamycin (mTOR) inhibitor that has entered Phase I/II clinical trials. We analyzed the effect of NVP-BGT226 (10–100 nM) on the pancreatic cell lines Panc-1, BxPc-3, AsPC-1 and MiaPaCa-2 in regard to cell viability, induction of apoptosis, cell cycle, and expression of the antiapoptotic genes Survivin , MCL-1 , BCL-2 and BCL-xL . Cell viability decreased within 24–72 h after exposure to about 50% compared to untreated control cells in a concentration- but not time-dependent manner. Cell cycle analysis revealed that NVP-BGT226 induced predominantly G0/G1 cell cycle arrest. Additionally, real-time RT-PCR and Western blot analysis showed a remarkable decrease of Survivin expression. Originally designed as a dual inhibitor, there was only a significant inhibition of p-mTOR. In summary, the dual PI3K/mTOR inhibitor NVP-BGT226 induces G0/G1 arrest and acts, at least, partially via downregulation of Survivin.

Background Increased glycolytic activity is a hallmark of cancer, allowing staging and restaging with 18 F-fluorodeoxyglucose-positron-emission-tomography (PET). Since interim-PET is an important prognostic tool in Hodgkin lymphoma (HL), the aim of this study was to investigate the expression of proteins involved in the regulation of glucose metabolism in the different HL subtypes and their impact on clinical outcome. Methods Lymph node biopsies from 54 HL cases and reactive lymphoid tissue were stained for glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA) and lactate exporter proteins MCT1 and MCT4. In a second series, samples from additional 153 HL cases with available clinical data were stained for GLUT1 and LDHA. Results Membrane bound GLUT1 expression was frequently observed in the tumor cells of HL (49% of all cases) but showed a broad variety between the different Hodgkin lymphoma subtypes: Nodular sclerosing HL subtype displayed a membrane bound GLUT1 expression in the Hodgkin-and Reed-Sternberg cells in 56% of the cases. However, membrane bound GLUT1 expression was more rarely observed in tumor cells of lymphocyte rich classical HL subtype (30%) or nodular lymphocyte predominant HL subtype (15%). Interestingly, in both of these lymphocyte rich HL subtypes as well as in progressively transformed germinal centers, reactive B cells displayed strong expression of GLUT1. LDHA, acting downstream of glycolysis, was also expressed in 44% of all cases. We evaluated the prognostic value of different GLUT1 and LDHA expression patterns; however, no significant differences in progression free or overall survival were found between patients exhibiting different GLUT1 or LDHA expression patterns. There was no correlation between GLUT1 expression in HRS cells and PET standard uptake values. Conclusions In a large number of cases, HRS cells in classical HL express high levels of GLUT1 and LDHA indicating glycolytic activity in the tumor cells. Although interim-PET is an important prognostic tool, a predictive value of GLUT1 or LDHA staining of the primary diagnostic biopsy could not be demonstrated. However, we observed GLUT1 expression in progressively transformed germinal centers and hyperplastic follicles, explaining false positive results in PET. Therefore, PET findings suggestive of HL relapse should always be confirmed by histology.

Targeted agents sunitinib and temsirolimus are effective in advanced renal cell carcinoma. Treatment algorithms for single-agent use have been proposed in order to optimize timing and type of therapy. The aim of this study was to investigate the tolerability and adverse event profile of patients who received sunitinib and temsirolimus in sequence. We performed a retrospective analysis of patients with advanced renal cell carcinoma who received temsirolimus after disease progression under sunitinib therapy. Dosages of both drugs were in accordance with the recommendations given by the respective manufacturers. Temsirolimus was provided before its official approval within a compassionate use program. Adverse event assessment followed the National Cancer Institute Common Toxicity Criteria. Thirteen patients receiving temsirolimus after progression under sunitinib were identified. Overall treatment time with targeted drugs (sunitinib/temsirolimus) was 34.8 (17–78) weeks, treatment with sunitinib was 28.6 (12–72), and with temsirolimus 6.2 (2–16) weeks, respectively, whereas mean therapy interruption time between both approaches was 4.4 (2–12) weeks. Under sunitinib, we observed 52 transient adverse events, 49 (94.2%) were of grade I/II, whereas 3 (5.8%) were of grade III. Under temsirolimus 36 adverse events, only grade I/II in nature were remarked. Sequential use of temsirolimus after progression under sunitinib seems to be feasible and results in a predictable, medically manageable side effect profile. Further evaluation is necessary to define the oncological validity of this sequencing approach.

Die nicht-klarzelligen Nierenzellkarzinome (nccRCC) haben einen Anteil von ca. 20–25 % an den RCC. Unter nccRCC werden ca. 20 unterschiedliche histologisch und/oder molekular definierte Entitäten subsumiert. Viele Entitäten haben nur einen Anteil von ≤ 1 %. Bedingt durch die Rarität der Subpopulationen gibt es bisher keine größeren randomisierten Studien und es besteht eine gewisse Unsicherheit hinsichtlich der optimalen Behandlungsempfehlungen. Es werden die bisherigen Therapieempfehlungen beim lokalisierten und fortgeschrittenem nccRCC dargestellt. Die Daten der diversen Systemtherapien werden dargestellt. Bei nccRCC gibt es mangels Daten und insbesondere randomisierter Studien keine unterschiedlichen entitätsbezogene Therapierichtlinien. Die Tumoren sollten analog zu den klarzelligen Nierenzellkarzinomen behandelt werden. Es können Monotherapien mit einem TKI (Tyrosinkinaseinhibitor, beim chromophoben RCC auch mit einem mTOR-Inhibitor [mTOR, „mechanistic target of rapamycin“]) oder mit einer Kombinationstherapie ICI/ICI (Immun-Checkpoint-Inhibitior) oder TKI/ICI in Abhängigkeit von den Risikofaktoren und individueller Entscheidung eingesetzt werden. Randomisierte Studien sind dringend erforderlich.

Purpose: This study was undertaken to investigate the clinical value in staging patients with plasmacytoma (PC) using positron emission tomography (PET). Methods: Fifteen patients with known PC underwent PET using F-18 fluorodeoxyglucose (FDG-PET). FDG-PET was done for staging in 11 patients and for restaging in 4 patients. Eleven patients had PC of bone, and 4 patients had extramedullary PC. The results of all available imaging modalities, such as x-ray, magnetic resonance imaging (MRI), computed tomography (CT), bone scans, and of the clinical course, were used for verification of detected lesions. Results: Intensively increased tracer uptake was observed in 9 of 11 patients with bone lesions. One osteolytic lesion showed only slightly increased FDG-uptake and another PC of a rib (30 mm diameter) presented without FDG-uptake. The four extramedullary PC showed an intensively increased tracer uptake. In addition, 20 (10 confirmed) further plasmacytoma lesions, which were negative on the standard staging methods, were detected in 4 patients (27%). Since the diagnosis was changed from PC to multiple myeloma, a potentially curative local therapy was changed to a palliative systemic therapy.Conclusion: Although FDG-PET was false negative in 1 patient (7%) and indeterminate in another patient, additional lesions were detected in 5 (33%) of the patients, resulting in a change in the therapy regimen in 4 (27%) of the 15 patients.

Initial results from the ongoing GALLIUM trial have shown that patients with follicular lymphoma have a longer progression-free survival after first-line immunochemotherapy with obinutuzumab than with rituximab. The aim of this secondary analysis was to evaluate the prognostic value of PET–CT responses after first-line immunochemotherapy in the GALLIUM study. GALLIUM is an open-label, parallel-group randomised, phase 3 trial, which recruited previously untreated patients with CD20-positive follicular lymphoma (grades 1–3a; disease stage III/IV, or stage II with largest tumour diameter ≥7 cm) who were aged 18 years or older and met the criteria for needing treatment. Eligible patients were randomly assigned in a 1:1 ratio to receive intravenous administration of obinutuzumab (1000 mg on days 1, 8, and 15 of cycle 1, then day 1 of subsequent cycles) or rituximab (375 mg/m2 on day 1 of each cycle), in six 21-day cycles with cyclophosphamide, doxorubicin, vincristine, and prednisone (known as CHOP; oral administration) followed by two 21-day cycles of antibody alone, or eight 21-day cycles cyclophosphamide, vincristine, and prednisone (known as CVP; oral administration), or six 28-day cycles with bendamustine, followed by maintenance antibody every 2 months for up to 2 years. The primary endpoint of the trial, investigator-assessed progression-free survival, has been reported previously. This secondary analysis reports PET and CT-based responses at end-of-induction therapy and explains their relation with progression-free and overall survival outcomes in patients with available scans. As per protocol, during the trial, PET scans (mandatory in the first 170 patients enrolled at sites with available PET facilities, and optional thereafter), acquired at baseline and end of induction (PET population), were assessed prospectively by investigators and an independent review committee (IRC) applying International Harmonisation Project (IHP) 2007 response criteria, and retrospectively by the IRC only applying current Lugano 2014 response criteria. IRC members (but not study investigators) were masked to treatment and clinical outcome when assessing response. The landmark analyses excluded patients who died or progressed (contrast enhanced CT-based assessment of progressive disease, or started next anti-lymphoma treatment) before or at end of induction. GALLIUM is registered at ClinicalTrials.gov, number NCT01332968. 1202 patients were enrolled in GALLIUM between July 6, 2011, and Feb 4, 2014, of whom 595 were included in the PET population; 533 (IHP 2007; prospective analysis), and 508 (Lugano 2014; retrospective analysis) were analysed for progression-free survival (landmark analysis). At end of induction, 390 of 595 patients (65·5% [95% CI 61·6–69·4]) achieved PET complete response according to IHP 2007 criteria, and 450 (75·6% [95% CI 72·0–79·0]) obtained PET complete metabolic response according to Lugano 2014 criteria. With a median of 43·3 months of observation (IQR 36·2–51·8), 2·5-year progression-free survival from end of induction was 87·8% (95% CI 83·9–90·8) in PET complete responders and 72·0% (63·1–79·0) in non-complete responders according to IRC-assessed IHP 2007 criteria (hazard ratio [HR] 0·4, 95% CI 0·3–0·6, p<0·0001). According to Lugano 2014 criteria, 2·5-year progression-free survival in complete metabolic responders was 87·4% (95% CI 83·7–90·2) and in non-complete metabolic responders was 54·9% (40·5–67·3; HR 0·2, 95% CI 0·1–0·3, p<0·0001). Our results suggest that PET is a better imaging modality than contrast-enhanced CT for response assessment after first-line immunochemotherapy in patients with follicular lymphoma. PET assessment according to Lugano 2014 response criteria provides a platform for investigation of response-adapted therapeutic approaches. Additional supportive data are welcomed. F Hoffmann-La Roche.

Renal cell carcinomas (RCCs) represent one of the ten leading cancer entities with an increasing incidence especially in the western world. Unfortunately, about 25% of the patients develop metastatic RCC (mRCC) associated with a most unfavorable prognosis. In the recent years, various new agents targeting VEGF or VEGF receptor (VEGFR) or the mTOR pathway have been approved for the treatment of mRCC with significant prolongation of progression-free survival and, in part, of overall survival (OS). Targeting the mTOR kinase is an interesting option for mRCC. Temsirolimus, one of the available mTOR inhibitors, has been approved as a single agent in poor-risk mRCC patients based on the pivotal Phase III trial showing a significant superiority in OS versus IFN-α or temsirolimus + IFN-α, which has been verified by a pivotal Phase III trial. The benefit has been shown for clear cell carcinoma and papillary RCC as well. For poor prognosis patients, temsirolimus improves median survival by 3.6 months. In second-line treatment compared with sorafenib following first-line treatment with sunitinib temsirolimus showed a relative progression-free survival benefit for patients with nonclear cell RCC with temsirolimus. The median OS for the temsirolimus group was 12.27 and 16.64 months for the sorafenib group. In 2007, the US FDA granted approval for temsirolimus for the treatment of advanced RCC.

The therapy of advanced (clear-cell) renal cell carcinoma (RCC) has recently experienced tremendous changes. Several new treatments have been developed, with PD-1 immune-checkpoint inhibition being the backbone of therapy. Diverse immunotherapy combinations change current first-line standards. These changes also require new approaches in subsequent lines of therapy. In an expert panel, we discussed the new treatment options and how they change clinical practice. While first-line immunotherapies introduce a new level of response rates, data on second-line therapies remains poor. This scenario poses a challenge for clinicians as guideline recommendations are based on historical patient cohorts and agents may lack the appropriate label for their in guidelines recommended use. Here, we summarize relevant clinical data and consider appropriate treatment strategies.