Cancer by Sfakianakis Alexandros: 04/21/16

Health utility, a summary measure of quality of life, has not been previously used to compare outcomes among childhood cancer survivors and individuals without a cancer history. We estimated health utility (0, death; 1, perfect health) using the Short Form-6D (SF-6D) in survivors (n = 7105) and siblings of survivors (n = 372) (using the Childhood Cancer Survivor Study cohort) and the general population (n = 12 803) (using the Medical Expenditures Panel Survey). Survivors had statistically significantly lower SF-6D scores than the general population (mean = 0.769, 95% confidence interval [CI] = 0.766 to 0.771, vs mean = 0.809, 95% CI = 0.806 to 0.813, respectively, P < .001, two-sided). Young adult survivors (age 18-29 years) reported scores comparable with general population estimates for people age 40 to 49 years. Among survivors, SF-6D scores were largely determined by number and severity of chronic conditions. No clinically meaningful differences were identified between siblings and the general population (mean = 0.793, 95% CI = 0.782 to 0.805, vs mean = 0.809, 95% CI = 0.806 to 0.813, respectively). This analysis illustrates the importance of chronic conditions on long-term survivor quality of life and provides encouraging results on sibling well-being. Preference-based utilities are informative tools for outcomes research in cancer survivors.

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Molecular characterization of salivary duct carcinoma

Purpose Salivary duct carcinoma (SDC) is an aggressive salivary malignancy which is resistant to chemotherapy and has high mortality rates. We investigated the molecular landscape of SDC, focusing on genetic alterations and gene expression profiles. Experimental Design We performed whole-exome sequencing, RNA sequencing and immunohistochemical analyses in 16 SDC tumors, and examined selected alterations via targeted sequencing of 410 genes in a second cohort of 15 SDCs. Results SDCs harbored a higher mutational burden than many other salivary carcinomas (1.7 mutations/megabase). The most frequent genetic alterations were mutations in TP53 (55%), HRAS (23%), PIK3CA (23%), and amplification of ERBB2 (35%). Most (74%) tumors had alterations in either MAP kinase (BRAF/HRAS/NF1) genes or ERBB2. Potentially targetable alterations based on supportive clinical evidence were present in 61% of tumors. Androgen receptor (AR) was overexpressed in 75%; several potential resistance mechanisms to androgen deprivation therapy (ADT) were identified, including the AR-V7 splice variant (present in 50%, often at low ratios compared to full length AR) and FOXA1 mutations (10%). Consensus clustering and pathway analyses in transcriptome data revealed striking similarities between SDC and molecular apocrine breast cancer. Conclusions This study illuminates the landscape of genetic alterations and gene expression programs in SDC, identifying numerous molecular targets and potential determinants of response to AR antagonism. This has relevance for emerging clinical studies of ADT and other targeted therapies in SDC. The similarities between SDC and apocrine breast cancer indicate that clinical data in breast cancer may generate useful hypotheses for SDC.

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Bim Binding to Mcl-1 Causes Resistance to ABT-199

Purpose: To investigate the molecular mechanism underlying intrinsic resistance to ABT-199. Experimental Design: Western blots and real-time RT-PCR were used to determine levels of Mcl-1 after ABT-199 treatment alone or in combination with cytarabine or daunorubicin. Immunoprecipitation of Bim and Mcl-1 were used to determine the effect of ABT-199 treatment on their interactions with Bcl-2 family members. Lentiviral shRNA knockdown of Bim and CRISPR knockdown of Mcl-1 were used to confirm their role in resistance to ABT-199. JC-1 assays and flow cytometry were used to determine drug-induced apoptosis. Results: Immunoprecipitation of Bim from ABT-199 treated cell lines and a primary patient sample demonstrated decreased association with Bcl-2, but increased association with Mcl-1 without corresponding change in mitochondrial outer membrane potential. ABT-199 treatment resulted in increased levels of Mcl-1 protein, unchanged or decreased Mcl-1 transcript levels, and increased Mcl-1 protein half-life, suggesting that the association with Bim plays a role in stabilizing Mcl-1 protein. Combining conventional chemotherapeutic agent cytarabine or daunorubicin with ABT-199 resulted in increased DNA damage along with decreased Mcl-1 protein levels, compared to ABT-199 alone, and synergistic induction of cell death in both AML cell lines and primary patient samples obtained from AML patients at diagnosis. Conclusions: Our results demonstrate that sequestration of Bim by Mcl-1 is a mechanism of intrinsic ABT-199 resistance and supports the clinical development of ABT-199 in combination with cytarabine or daunorubicin for the treatment of AML.

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Targeted dual-modality imaging in renal cell carcinoma

Purpose: Antibodies labeled with both a near-infrared fluorescent dye and a radionuclide can be used for tumor-targeted intraoperative dual-modality imaging. Girentuximab is a chimeric monoclonal antibody against carbonic anhydrase IX (CAIX), an antigen expressed in 95% of clear cell renal cell carcinoma (ccRCC). This study aimed to assess the feasibility of targeted dual-modality imaging with 111In-girentuximab-IRDye800CW using ex vivo perfusion of human tumorous kidneys. Experimental design: Seven radical nephrectomy specimens of ccRCC patients were perfused during 11-15h with dual-labeled girentuximab and subsequently rinsed during 2.5-4h with Ringer's Lactate solution. Then, dual-modality imaging was performed on a 5-10-mm thick lamella of the kidney. Fluorescence imaging was performed with a clinical fluorescence camera set-up as applied during image-guided surgery. The distribution of Indium-111 in the slice of tumor tissue was visualized by autoradiography. In two perfusions an additional dual-labeled control antibody was added to demonstrate specific accumulation of dual-labeled girentuximab in CAIX-expressing tumor tissue. Results Both radionuclide and fluorescence imaging clearly visualized uptake in tumor tissue and tumor-to-normal tissue borders, as confirmed (immuno)histochemically and by gamma counting. Maximum uptake of girentuximab in tumor tissue was 0.33 % of the injected dose per gram (mean 0.12 %ID/g, range 0.01 - 0.33 %ID/g), while maximum uptake in the normal kidney tissue was 0.04 %ID/g (mean 0.02 %ID/g, range 0.00 - 0.04 %ID/g). Conclusion: Dual-labeled girentuximab accumulated specifically in ccRCC tissue, indicating the feasibility of dual-modality imaging to detect ccRCC. A clinical study to evaluate intraoperative dual-modality imaging in ccRCC patients has been initiated.

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Marked improvement in leptomeningeal carcinomatosis and spinal cord metastases following alectinib treatment of crizotinib-resistant ALK-positive lung adenocarcinoma

Abstract

We report a case of 50-year-old Japanese female with anaplastic lymphoma kinase (ALK)-positive, crizotinib-resistant lung adenocarcinoma, whose leptomeningeal carcinomatosis and spinal cord metastases were dramatically improved by the second-generation ALK inhibitor alectinib. Magnetic resonance imaging (MRI) revealed multiple brain metastases at diagnosis of lung cancer. Carboplatin/paclitaxel/bevacizumab chemotherapy was administered, but enlargement of brain tumors was observed after 3 months. Gamma knife radiosurgery was performed and then the patient received second-line chemotherapy with crizotinib. After 4 months brain MRI revealed the development of leptomeningeal carcinomatosis. Despite the patient undergoing whole brain radiotherapy, spinal cord metastases appeared. Third-line chemotherapy with alectinib was initiated for the management of metastases in central nervous system (CNS) including those in the leptomeninges and spine cord. After 3 months, marked tumor responses were observed in both the leptomeningeal carcinomatosis and spinal cord metastases. This report suggests that alectinib is a promising drug for ALK-positive lung adenocarcinoma with CNS metastases.

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Depression and healthcare service utilization in patients with cancer

Abstract

Objective

It is estimated that as many as 38% of cancer patients suffer from depression, which may have distal impacts on cancer care, including clinical outcomes, health care utilization, and cost of care. The purpose of this study was to determine the impact of depression on overall healthcare utilization among patients with cancer.

Methods

A retrospective analysis of administrative data was conducted on 5055 patients with an ICD-9 diagnosis of cancer from a single large healthcare system. Of these, 561 (11.1%) had ICD-9 diagnoses consistent with a depressive disorder. Negative binomial regression modeling was used to test the association between depression status and total annual healthcare visits for the year 2011. Logistic regression was used to examine the association between depression and secondary outcomes of emergency department visit, overnight hospitalization, and 30-day hospital readmission.

Results

After adjusting for age, gender, race/ethnicity, insurance type, medical comorbidities, length of time with cancer, and metastatic status, depressed patients had significantly more annual non-mental health provider healthcare visits (aRR = 1.76, 95% CI = 1.61–1.93), and were significantly more likely to have an ED visit (OR = 2.45; 95% CI = 1.97–3.04), overnight hospitalization (OR = 1.81; 95% CI = 1.49–2.20), and 30-day hospital readmission (OR = 2.03; 95% CI = 1.48–2.79) than non-depressed patients with cancer.

Conclusions

Among patients with cancer, the presence of depression was associated with greater healthcare utilization. Effective screening for, and management of, depression may help reduce overall healthcare utilization and cost while improving care quality. Copyright © 2016 John Wiley & Sons, Ltd.

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Tyrosine Kinase Inhibitors and Vascular Toxicity: Impetus for a Classification System?

Abstract

The introduction of molecularly targeted therapies with tyrosine kinase inhibitors has revolutionized cancer therapy and has contributed to a steady decline in cancer-related mortality since the late 1990s. However, not only cardiac but also vascular toxicity has been reported for these agents, some as expected on-target effects (e.g., VEGF receptor inhibitors) and others as unanticipated events (e.g., BCR-Abl inhibitors). A sound understanding of these cardiovascular toxic effects is critical to advance mechanistic insight into vascular disease and clinical care. From a conceptual standpoint, there might be value in defining type I (permanent) and type II (transient) vascular toxicity. This review will focus on the tyrosine kinase inhibitors in current clinical use and their associated vascular side effects.

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50% Response rates: half-empty or half-full?

Abstract

When the Black Women's Health Study, a prospective cohort of over 59,000 women who have been followed since 1995, invited all of its participants to provide a DNA sample for future research, only 51 % of those participants agreed to do so. Responders were significantly older and more health conscious than non-responders. The Black Women's Health Study is a unique resource, but this low level of response and its resulting self-selection bias are now the norm in contemporary epidemiologic, and especially cohort, studies. Epidemiology desperately needs new approaches that work better and cost less. The literature on predictors of response focuses too narrowly on participant characteristics and does not identify any clear steps studies can take to increase participation. To improve research quality, cost-efficiency, and long-term sustainability of studies, epidemiology can and should approach, analyze, and leverage response-rate data more creatively and extensively than most studies have done to date.

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Alveologenesis: key cellular players and fibroblast growth factor 10 signaling

Abstract

Background

Alveologenesis is the last stage in lung development and is essential for building the gas-exchanging units called alveoli. Despite intensive lung research, the intricate crosstalk between mesenchymal and epithelial cell lineages during alveologenesis is poorly understood. This crosstalk contributes to the formation of the secondary septae, which are key structures of healthy alveoli.

Conclusions

A better understanding of the cellular and molecular processes underlying the formation of the secondary septae is critical for the development of new therapies to protect or regenerate the alveoli. This review summarizes briefly the alveologenesis process in mouse and human. Further, it discusses the current knowledge on the epithelial and mesenchymal progenitor cells during early lung development giving rise to the key cellular players (e.g., alveolar epithelial cell type I, alveolar epithelial cell type II, alveolar myofibroblast, lipofibroblast) involved in alveologenesis. This review focusses mainly on the role of fibroblast growth factor 10 (FGF10), one of the most important signaling molecules during lung development, in epithelial and mesenchymal cell lineage formation.

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Inhaled protein/peptide-based therapies for respiratory disease

Abstract

Asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF) are all chronic pulmonary diseases, albeit with different etiologies, that are characterized by airflow limitation, chronic inflammation, and abnormal mucus production/rheology. Small synthetic molecule-based therapies are commonly prescribed for all three diseases. However, there has been increased interest in "biologicals" to treat these diseases. Biologicals typically constitute protein- or peptide-based therapies and are often more potent than small molecule-based drugs. In this review, we shall describe the pros and cons of several different biological-based therapies for respiratory disease, including dornase alfa, a recombinant DNAase that reduces mucus viscosity and short palate lung and nasal epithelial clone 1 (SPLUNC1)-derived peptides that treat Na⁺ hyperabsorption and rebalance CF airway surface liquid homeostasis.

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Case 12-2016: An 8-Year-Old Boy with an Enlarging Mass in the Right Breast

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Presentation of Case. Dr. Charumathi Baskaran (Pediatrics): An 8-year-old boy was seen in an outpatient clinic of this hospital because of an enlarging mass in the right breast. One week before this presentation, the patient was seen by a pediatrician at another medical facility for a routine…

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A meta-analysis identifies ERCC1 gene polymorphism as a predictor of better patient response to treatment with radiochemotherapy

Abstract

Purpose

This meta-analysis aimed to evaluate whether an association exists between the ERCC1 rs11615 (C>T) polymorphism and patient response to platinum-based chemotherapy and radiation-based chemotherapy.

Methods

Publications were selected from PubMed and MEDLINE. A meta-analysis was conducted to determine the association between genetic polymorphisms and response to platinum-based chemotherapy and radiation-based chemotherapy by checking the odds ratios (ORs) and 95 % confidence intervals (CIs).

Results

In our overall analysis, the ERCC1 rs11615 (C>T) polymorphism was not associated with response to platinum-based chemotherapy in five comparison models. In the subgroup analyses by ethnicity, the ERCC1 rs11615 (C>T) polymorphism was shown to be significantly associated with objective response in Caucasian patients treated with platinum-based chemotherapy in the recessive model (TT vs. CT/CC: OR 0.696, 95 % CI 0.508–0.954, heterogeneity = 0.330), but the association was not observed in the Asian population. The C allele was significantly associated with better response to radiochemotherapy in the recessive model comparison (TT vs. CC/CT: OR 0.724, 95 % CI 0.585–0.869, heterogeneity = 0.008). Subgroup analysis by cancer type revealed that the C allele of ERCC1 rs11615 predicted a better response in esophageal cancers in two comparison models (T vs. C: OR 0.756, 95 % CI 0.648–0.880, heterogeneity = 0.653; TT vs. TC/CC: OR 0.457, 95 % CI 0.306–0.684, heterogeneity = 0.723). Stratified analysis by ethnicity showed a better response in Caucasians in allelic comparison model (T vs. C: OR 0.895, 95 % CI 0.819–0.977, heterogeneity = 0.095).

Conclusion

Together, our results suggest that the ERCC1 rs11615 (C>T) polymorphism was associated with therapeutic response in Caucasian patients and C allele of ERCC1 rs11615 could represent a genetic molecular marker to predict better patient response to radiochemotherapy in recessive model. However, larger prospective randomized trials will be required.

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The combination of HLA - B15:01 and DRB115:01 is associated with gemcitabine plus erlotinib-induced interstitial lung disease in patients with advanced pancreatic cancer

Abstract

Purpose

In a phase III study of gemcitabine plus erlotinib for advanced pancreatic cancer conducted in Canada, the incidence of interstitial lung disease (ILD) was 3.5 %. However, the incidence of ILD was reported as high as 8.5 % in a Japanese phase II study. These results suggest the influence of ethnic factors in the association of the use of gemcitabine plus erlotinib with the incidence of ILD. Here, we conducted a prospective study to analyze the relationship between human leukocyte antigen (HLA) alleles and ILD in Japanese patients with advanced pancreatic cancer receiving gemcitabine plus erlotinib.

Methods

Patients were treated with gemcitabine (1000 mg/m²; administered by intravenous infusion on days 1, 8, and 15 every 4 weeks) and erlotinib (given orally at 100 mg/day). We compared the frequencies of HLA alleles in patients who did and did not develop ILD.

Results

A total of 57 patients were treated, and 4 patients (7.0 %) developed ILD. The combination of HLA-B*15:01 and DRB1*15:01 was observed in 2 of 4 patients (50 %) with ILD and in only 1 of 53 patients without ILD (2 %) resulting in odds ratio of 52.0 (95 % CI 3.2–842.5; p = 0.011).

Conclusion

These results suggest that the combination of HLA-B*15:01 and DRB1*15:01 is associated with ILD in Japanese patients with advanced pancreatic cancer receiving gemcitabine plus erlotinib.

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Phase I study of safety and tolerability of sunitinib in combination with sirolimus in patients with refractory solid malignancies and determination of VEGF (VEGF-A) and soluble VEGF-R2 (sVEGFR2) in plasma

Abstract

Purpose

Sirolimus, an oral mTOR inhibitor, may complement the anti-angiogenic and anti-tumor activity of sunitinib, an oral small molecule inhibitor of multiple receptor tyrosine kinases, by vertical disruption of vascular epithelial growth factor receptor (VEGFR) signaling, by reducing the compensatory production of VEGF in sunitinib-treated patients and also by directly inhibiting tumor cell proliferation. We conducted this phase 1 study to investigate the maximum tolerated dose (MTD) for this combination of sunitinib and sirolimus in humans.

Patients and methods

Sunitinib was given at 50 mg daily × 28 every 6 weeks. The first cohort received sunitinib alone for cycle 1 (50 mg daily for 2 weeks followed by 2 weeks off) and received sunitinib at standard dose 50 mg daily for 4 weeks followed by 2 weeks off in combination with sirolimus 4 mg weekly; this dose and schedule were further investigated in second cohort. The third cohort received decreased dose of sunitinib at 37.5 mg daily for 4 weeks followed by 2 weeks off in combination with sirolimus at 4 mg weekly. Sirolimus dose was escalated to 8 mg weekly in fourth cohort.

Results

Eighteen patients with ECOG PS of 0 or 1 were enrolled, median age 57 years (range 24–76), M:F ratio: 11:7. Median number of prior treatments is 2 (range 0–5); six patients had no prior systemic therapy. Half of patients from the first two cohorts required dose reduction or early discontinuation of treatment; therefore, sunitinib dose was decreased to 37.5 mg daily in third and fourth cohort. In third and fourth cohort, one-third of patients required dose modification during cycle 1 or cycle 2. Multiple patients had significant toxicities including fatigue and hand–foot syndrome. One patient developed interstitial pneumonitis, and one patient died suddenly on day 8 due to progressive disease. There were six patients who tolerated four or more cycles. Among these six patients, two patients with renal cell carcinoma (RCC) achieved partial response; one subsequently underwent surgical resection of residual renal mass and lymph node dissection and achieved complete response afterward. One with metastatic melanoma also achieved complete response after metastatectomy. There was no apparent pharmacokinetic interaction between sunitinib and sirolimus. 4 mg weekly sirolimus did not reduce the sunitinib-induced circulating VEGF production but stimulated more VEGF production through some unknown compensatory mechanism.

Conclusion

Toxicity precluded dose escalation of weekly sirolimus in combination with a standard sunitinib dose/schedule. These results suggest caution when combining targeted agents lacking specificity for tumor signaling or vasculature.

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Tanshinone I induces apoptosis and pro-survival autophagy in gastric cancers

Abstract

Purpose

To investigate the occurrence of apoptosis and autophagy on human gastric cancer cells after treatment by Tanshinone I, as well as the relationship between them.

Methods

BGC823 and SGC7901 cells were treated with Tanshinone I; the cell proliferation was measured using CCK-8 and clone formation assay; and the expression of apoptosis- and autophagy-associated proteins was detected by Western blot. Autophagic vacuoles in cells were observed with LC3 dyeing using confocal fluorescent microscopy, and apoptotic cells were detected via flow cytometry. Bcl-2 was overexpressed in gastric cells treated with Tanshinone I or not, and autophagy relative protein was investigated; the interaction between Beclin-1 and Bcl-2 was detected by immunoprecipitation. Cell apoptosis was detected when autophagy was inhibited by ATG7-siRNA. Tumor growth was assessed by subcutaneous inoculation of cells into BALB/c nude mice.

Results

Tanshinone I inhibited the proliferation of BGC823 and SGC7901 cells, and induced cell apoptosis by inhibiting anti-apoptosis protein Bcl-2. Tanshinone I also increased the conversion of LC3I to LC3II and triggered autophagosome formation, without changing the expression of Beclin-1. However, the Beclin-1 VPS34 complexes were increased after Tanshinone I treatment via inhibiting Bcl-2 expression. Moreover, disturbing autophagy by knockdown of ATG7 expression contributed to Tanshinone I-induced apoptosis. In vivo assay showed that combination with autophagy inhibitor chloroquine in nude mice bearing BGC823 xenograft significantly augmented the antitumor effect of Tanshinone I.

Conclusions

Tanshinone I induced apoptosis and pro-survival autophagy via inhibiting Bcl-2 expression on gastric cancer, and the combination of chloroquine and Tanshinone I could inhibit tumor growth more efficiently than monotherapy, which might be considered as an effective strategy for the treatment for gastric cancer.

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Survivorship care plans and adherence to lifestyle recommendations among breast cancer survivors

Abstract

Purpose

The effectiveness of survivorship care plans has not been widely tested. We evaluated whether a one-time brief lifestyle consultation as part of a broader survivorship care plan was effective at changing diet and lifestyle patterns.

Methods

A diverse sample of women with stage 0-III breast cancer were randomized to control or intervention groups within 6 weeks of completing adjuvant treatment. Both groups received the National Cancer Institute publication, "Facing Forward: Life after Cancer Treatment." The intervention group also met with a nurse (1 h) and a nutritionist (1 h) to receive personalized lifestyle recommendations based upon national guidelines. Diet, lifestyle, and perceived health were assessed at baseline, 3 and 6 months. Linear regression analyses evaluated the effects of the intervention adjusted for covariates.

Results

A total of 126 women completed the study (60 control/66 intervention, 61 Hispanic/65 non-Hispanic). At 3 months, the intervention group reported greater knowledge of a healthy diet (P = 0.047), importance of physical activity (P = 0.03), and appropriate use of dietary supplements (P = 0.006) and reported lower frequency of alcohol drinking (P = 0.03) than controls. At 6 months, only greater knowledge of a healthy diet (P = 0.01) persisted. The intervention was more effective among non-Hispanics than Hispanics on improving attitude towards healthy eating (P = 0.03) and frequency of physical activity (P = 0.006).

Conclusions

The intervention changed lifestyle behaviors and knowledge in the short-term, but the benefits did not persist.

Implications for Cancer Survivors

Culturally competent long-term behavioral interventions should be tested beyond the survivorship care plan to facilitate long-term behavior change among breast cancer survivors.

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Selective activation of TNFR1 and NF-κB inhibition by a novel biyouyanagin analogue promotes apoptosis in acute leukemia cells

Abstract

Background

Acquired resistance towards apoptosis is a hallmark of cancer. Elimination of cells bearing activated oncogenes or stimulation of tumor suppressor mediators may provide a selection pressure to overcome resistance. KC-53 is a novel biyouyanagin analogue known to elicit strong anti-inflammatory and anti-viral activity. The current study was designed to evaluate the anticancer efficacy and molecular mechanisms of KC-53 against human cancer cells.

Methods

Using the MTT assay we examined initially how KC-53 affects the proliferation rates of thirteen representative human cancer cell lines in comparison to normal peripheral blood mononuclear cells (PBMCs) and immortalized cell lines. To decipher the key molecular events underlying its mode of action we selected the human promyelocytic leukemia HL-60 and the acute lymphocytic leukemia CCRF/CEM cell lines that were found to be the most sensitive to the antiproliferative effects of KC-53.

Results

KC-53 promoted rapidly and irreversibly apoptosis in both leukemia cell lines at relatively low concentrations. Apoptosis was characterized by an increase in membrane-associated TNFR1, activation of Caspase-8 and proteolytic inactivation of the death domain kinase RIP1 indicating that KC-53 induced mainly the extrinsic/death receptor apoptotic pathway. Regardless, induction of the intrinsic/mitochondrial pathway was also achieved by Caspase-8 processing of Bid, activation of Caspase-9 and increased translocation of AIF to the nucleus. FADD protein knockdown restored HL-60 and CCRF/CEM cell viability and completely blocked KC-53-induced apoptosis. Furthermore, KC-53 administration dramatically inhibited TNFα-induced serine phosphorylation on TRAF2 and on IκBα hindering therefore p65/NF-κΒ translocation to nucleus. Reduced transcriptional expression of pro-inflammatory and pro-survival p65 target genes, confirmed that the agent functionally inhibited the transcriptional activity of p65.

Conclusions

Our findings demonstrate, for the first time, the selective anticancer properties of KC-53 towards leukemic cell lines and provide a detailed understanding of the molecular events underlying its dual anti-proliferative and pro-apoptotic properties. These results provide new insights into the development of innovative and targeted therapies for the treatment of some forms of leukemia.

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Gemcitabine and docetaxel in relapsed and unresectable high-grade osteosarcoma and spindle cell sarcoma of bone

Abstract

Background

Few new compounds are available for relapsed osteosarcoma. We retrospectively evaluated the activity of gemcitabine (G) plus docetaxel (D) in patients with relapsed high-grade osteosarcoma and high-grade spindle cell sarcoma of bone (HGS).

Methods

Patients receiving G 900 mg/m² d 1, 8; D 75 mg/m² d 8, every 21 days were eligible. Primary end-point: progression-free survival (PFS) at 4 months; secondary end-point: overall survival (OS) and response rate.

Results

Fifty-one patients were included, with a median age of 17 years (8–71), 26 (51 %) were pediatric patients. GD line of treatment: 2nd in 14 patients, ≥3rd in 37. 25 (49 %) patients had metastases limited to lungs, 26 (51 %) multiple sites. Histology: 40 (78 %) osteosarcoma, 11 (22 %) HGS. Eight (16 %) patients achieved surgical complete response (sCR2) after GD.

Four-month PFS rate was 46 %, and significantly better for patients with ECOG 0 (ECOG 0: 54 % vs ECOG 1: 43 % vs ECOG 2: 0 %; p = 0.003), for patients undergoing metastasectomy after GD (sCR2 75 % vs no-sCR2 40 %, p = 0.02) and for osteosarcoma (osteosarcoma 56 % vs HGS 18 %; p = 0.05), with no differences according to age, line of treatment, and pattern of metastases.

Forty-six cases had RECIST measurable disease: 6 (13 %) patients had a partial response (PR), 20 (43 %) had stable disease (SD) and 20 (43 %) had progressive disease (PD).

The 1-year OS was 30 %: 67 % for PR, 54 % for SD and 20 % for PD (p = 0.005).

Conclusions

GD is an active treatment for relapsed high-grade osteosarcoma, especially for ECOG 0 patients, and should be included in the therapeutic armamentarium of metastatic osteosarcoma.

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The Lung Screen Uptake Trial (LSUT): protocol for a randomised controlled demonstration lung cancer screening pilot testing a targeted invitation strategy for high risk and hard-to-reach patients

Abstract

Background

Participation in low-dose CT (LDCT) lung cancer screening offered in the trial context has been poor, especially among smokers from socioeconomically deprived backgrounds; a group for whom the risk-benefit ratio is improved due to their high risk of lung cancer. Attracting high risk participants is essential to the success and equity of any future screening programme. This study will investigate whether the observed low and biased uptake of screening can be improved using a targeted invitation strategy.

Methods/design

A randomised controlled trial design will be used to test whether targeted invitation materials are effective at improving engagement with an offer of lung cancer screening for high risk candidates. Two thousand patients aged 60–75 and recorded as a smoker within the last five years by their GP, will be identified from primary care records and individually randomised to receive either intervention invitation materials (which take a targeted, stepped and low burden approach to information provision prior to the appointment) or control invitation materials. The primary outcome is uptake of a nurse-led 'lung health check' hospital appointment, during which patients will be offered a spirometry test, an exhaled carbon monoxide (CO) reading, and an LDCT if eligible. Initial data on demographics (i.e. age, sex, ethnicity, deprivation score) and smoking status will be collected in primary care and analysed to explore differences between attenders and non-attenders with respect to invitation group. Those who attend the lung health check will have further data on smoking collected during their appointment (including pack-year history, nicotine dependence and confidence to quit). Secondary outcomes will include willingness to be screened, uptake of LDCT and measures of informed decision-making to ensure the latter is not compromised by either invitation strategy.

Discussion

If effective at improving informed uptake of screening and reducing bias in participation, this invitation strategy could be adopted by local screening pilots or a national programme.

Trial registration

This study was registered with the ISRCTN (International Standard Registered Clinical/soCial sTudy Number : ISRCTN21774741) on the 23^rd September 2015 and the NIH ClinicalTrials.gov database (NCT0255810) on the 22^nd September 2015.

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CAR T Cell Therapy in Acute Lymphoblastic Leukemia and Potential for Chronic Lymphocytic Leukemia

Opinion statement

Adoptive transfer of autologous T cells engineered to express a chimeric antigen receptor (CAR) represents a powerful targeted immunotherapy that has shown great promise in some of the most refractory leukemias. CAR-modified T cells directed against CD19 have led the way, setting a high standard with remission rates as high as 90 % in clinical trials for relapsed/refractory acute lymphoblastic leukemia (ALL). Yet, the first demonstration of efficacy was in another disease, chronic lymphocytic leukemia (CLL), in which CD19-targeted CAR T cells eradicated bulky, highly refractory disease. Despite early encouraging results, clinical trials in CLL have yielded lower response rates, revealing disease-specific differences in response in this form of immunotherapy. Ongoing research focused on identifying and overcoming these limitations, promises to improve response rates. Beyond the induction of remission, the transformative impact of engineered T cell therapy lies in its potential for long-term disease control. With longer follow-up and durable T cell persistence now reported, we are closer to answering the question of whether sustained remissions are possible with CAR T cell monotherapy. As might be expected with a highly effective therapy using a single mechanism of action, escape pathways have emerged. Combinatorial approaches are needed to anticipate and prevent this mode of relapse. Lastly, toxicity management is vital to ensure the safety of this exciting cancer immunotherapy.

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SABR vs. Limited Resection for Non-small Cell Lung Cancer: Are We Closer to an Answer?

Opinion statement

Lobectomy is currently the guideline-recognized gold standard for the treatment of early-stage non-small cell lung cancer (ES-NSCLC) in patients who are surgical candidates. In patients who are not medically fit for surgery, stereotactic ablative radiotherapy (SABR) is the treatment of choice with good reported rates of local control and overall survival. For patients at high risk for lobectomy, sublobar resection (SLR) may achieve similar outcomes as lobectomy, especially for peripheral tumors ≤2 cm. While there are merits to both SLR and SABR for these high-risk patients, evidence is conflicting on which may be preferred in the context of clinical and cost-effectiveness outcomes. For SABR, a histologic diagnosis is preferred prior to treatment. However, some individuals may be at high risk for biopsy, and a likelihood-of-malignancy probability threshold of >85 % has been proposed as reasonable to proceed with SABR in a positron emission tomography (PET)-positive lesion without histology. Increased risks of SABR are noted in ultra-central tumors and in patients recently treated with anti-VEGF therapy. Co-existing interstitial lung disease can cause increased treatment-related toxicity in both SABR and surgery. Toxicity is generally well tolerated for SABR and SLR, though treatment-related mortality may be higher in surgery. Ongoing comparative effectiveness research, especially through randomized control trials, is crucial in further delineating the roles of SLR and SABR in the treatment of ES-NSCLC.

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Radioembolization as a Treatment Strategy for Metastatic Colorectal Cancer to the Liver: What Can We Learn from the SIRFLOX Trial?

Opinion statement

In the setting of liver metastases from colorectal cancer (CRC), radioembolization with yttrium-90 has been used to treat chemotherapy refractory disease with a growing interest to establish its efficacy in prospective trials combined with first- and second-line chemotherapy. SIRFLOX is an ongoing, multi-center, phase 3 randomized trial comparing first-line chemotherapy alone or in combination with yttrium-90 radioembolization in patients with CRC who have isolated liver metastases or liver-dominant metastases. Preliminary results from SIRFLOX demonstrate that radioembolization combined with first-line chemotherapy is safe and feasible. There was no significant difference in median overall progression-free survival (PFS) between the combined radioembolization-chemotherapy and chemotherapy-only arms (10.7 versus 10.2 months). Although the trial did not meet its primary endpoint of improved median PFS, there was a significant increase in the median hepatic PFS (20.5 versus 12.6 months; p = 0.02) favoring the combination arm. Thus, combining radioembolization with chemotherapy in the first-line setting may be most effective for liver-limited metastatic CRC. Since radioembolization targets liver disease, it is plausible that the trial failed to achieve an improvement in PFS given that 40 % of the SIRFLOX population had extra-hepatic disease. It is also possible that the overall median PFS may be a poor surrogate endpoint, and other endpoints like overall survival still needs to be delineated in this setting. In addition, it is crucial to document improvement or delay in time to deterioration in quality of life symptom endpoints in this population. SIRFLOX is the first of three prospective studies that assess the efficacy of adding radioembolization to first-line chemotherapy, and the combined data from these trials will provide the necessary power for an overall survival analysis. The final results of SIRFLOX will be eagerly awaited to determine if the increased hepatic PFS in preliminary data will translate to increased overall survival benefit.

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Mitochondrial SIRTs in Cancer

The past few decades have witnessed a furious attention of scientific community toward identifying novel molecular factors and targets that could be exploited for drug development for cancer management. One such factor is the sirtuin (SIRT) family of nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases. The role of SIRTs in cancer is extremely complex, with dichotomous functions depending on cell contexts. Mammalian SIRTs (SIRT1–7) differ in their cellular localization and biologic functions. Among these, SIRT -3, -4, and -5 are located in the mitochondria and are being carefully investigated. These mitochondrial SIRTs (mtSIRT) regulate multiple cellular and physiologic processes, including cell cycle, gene expression, cell viability, stress response, metabolism, and energy homeostasis. Recent research suggests that mtSIRTs influence tumors by regulating the metabolic state of the cell. Although the research on the role of mtSIRTs in cancer is still in its infancy, studies have suggested tumor suppressor as well as tumor promoter roles for them. This review is focused on discussing up-to-date information about the roles and functional relevance of mtSIRTs (SIRT -3, -4, -5) in cancers. We have also provided a critical discussion and our perspective on their dual roles, as tumor promoter versus tumor suppressor, in cancer. Cancer Res; 76(9); 1–7. ©2016 AACR.

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EMT Can Be Modulated by Fine Tuning MALAT1 and HuR

Epithelial-to-mesenchymal transition (EMT) is a core process underlying cell movement during embryonic development and morphogenesis. Cancer cells hijack this developmental program to execute a multi-step cascade, leading to tumorigenesis and metastasis. CD133 (PROM1), a marker of cancer stem cells, has been shown to facilitate EMT in various cancers, but the regulatory networks controlling CD133 gene expression and function in cancer remain incompletely delineated. In this study, we show that a ribonucleoprotein complex including the long noncoding RNA MALAT1 and the RNA-binding protein HuR (ELAVL1) binds the CD133 promoter region to regulate its expression. In luminal nonmetastatic MCF-7 breast cancer cells, HuR silencing was sufficient to upregulate N-cadherin (CDH2) and CD133 along with a migratory and mesenchymal-like phenotype. Furthermore, we found that in the basal-like metastatic cell line MDA-MB-231 and primary triple-negative breast cancer tumor cells, the repressor complex was absent from the CD133-regulatory region, but was present in the MCF-7 and primary ER+ tumor cells. The absence of the complex from basal-like cells was attributed to diminished expression of MALAT1, which, when overexpressed, dampened CD133 levels. In conclusion, our findings suggest that the failure of a repressive complex to form or stabilize in breast cancer promotes CD133 upregulation and an EMT-like program, providing new mechanistic insights underlying the control of prometastatic processes. Cancer Res; 76(9); 1–11. ©2016 AACR.

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HOXB7 Action in Solid Tumors

Strong lines of evidence have established a critical role for the homeodomain protein HOXB7 in cancer. Specifically, molecular and cellular studies have demonstrated that HOXB7 is a master regulatory gene, capable of orchestrating a variety of target molecules, resulting in the activation of several oncogenic pathways. HOXB7 overexpression correlates with clinical progression and poor outcome of cancer patients. Specific inhibition of HOXB7 is particularly relevant in cancers still lacking effective therapies, such as tamoxifen-resistant breast cancer and melanoma. Mechanistic studies are providing additional targets of therapy, and biomarker studies are further establishing its importance in early diagnosis and prognosis. Cancer Res; 1–6. ©2016 AACR.

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Pericellular HA: A Portable Prometastatic Microenvironment

Hyaluronan (HA) is a structurally simple polysaccharide, but its ability to act as a template for organizing pericellular matrices and its regulated synthesis and degradation are key to initiating repair responses. Importantly, these HA functions are usurped by tumor cells to facilitate progression and metastasis. Recent advances have identified the functional complexities associated with the synthesis and degradation of HA-rich matrices. Three enzymes synthesize large HA polymers while multiple hyaluronidases or tissue free radicals degrade these into smaller bioactive fragments. A family of extracellular and cell-associated HA-binding proteins/receptors translates the bioinformation encrypted in this complex polymer mixture to activate signaling networks required for cell survival, proliferation, and migration in an actively remodeling microenvironment. Changes in HA metabolism within both the peritumor stroma and parenchyma are linked to tumor initiation, progression, and poor clinical outcome. We review evidence that metastatic tumor cells must acquire the capability to autonomously synthesize, assemble, and process their own "portable" HA-rich microenvironments to survive in the circulation, metastasize to ectopic sites, and escape therapeutic intervention. Strategies to disrupt the HA machinery of primary tumor and circulating tumor cells may enhance the effectiveness of current conventional and targeted therapies. Cancer Res; 76(9); 1–6. ©2016 AACR.

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Metastatic breast cancer: HER2 immunity epitope spreading

The addition of trastuzumab to chemotherapy extends survival among patients with HER2+ breast cancer. Prior work showed that trastuzumab and chemotherapy augments HER2 extracellular domain (ECD)-specific antibodies. The present study investigated whether combination therapy induced immune responses beyond HER2-ECD and, importantly, whether those immune responses were associated with survival. Pre-treatment and post-treatment sera were obtained from 48 women with metastatic HER2+ breast cancer on NCCTG (now Alliance for Clinical Trials in Oncology) studies N0337 and N983252. IgG to HER2 intracellular domain (ICD), HER2-ECD, p53, IGFBP2, CEA and tetanus toxoid were examined. Sera from 25 age-matched controls and 26 surgically-resected HER2+ patients were also examined. Prior to therapy, some patients with metastatic disease had elevated antibodies to IGFBP2, p53, HER2-ICD, HER2-ECD, and CEA, but not to tetanus toxin, relative to controls and surgically-resected patients. Treatment augmented antibody responses to HER2-ICD in 69% of metastatic patients, which was highly associated with improved PFS (HR 0.5, p=0.0042) and OS (HR=0.7, p=0.038). Augmented antibody responses to HER2-ICD also correlated (p=0.03) with increased antibody responses to CEA, IGFBP2, and p53, indicating that treatment induces epitope spreading. Paradoxically, patients who already had high preexisting immunity to HER2-ICD did not respond to therapy with increased antibodies to HER2-ICD and demonstrated poorer progression free (PFS, HR=1.6, p<0.0001) and overall survival (OS, HR=1.4, p=0.0006). Overall, the findings further demonstrate the importance of the adaptive immune system in the efficacy of trastuzumab-containing regimens. -

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Cross-cancer analysis reveals novel pleiotropic associations

Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-staged approach to conduct genome-wide association studies for lung, ovary, breast, prostate and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression.

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MIF-miR301b-NR3C2 axis in PDAC Aggressiveness

Pancreatic cancers with aberrant expression of macrophage migration inhibitory factor (MIF) are particularly aggressive. To identify key signaling pathways that drive disease aggressiveness in tumors with high MIF expression, we analyzed the expression of coding and non-coding genes in high and low MIF-expressing tumors in multiple cohorts of pancreatic ductal adenocarcinoma (PDAC) patients. The key genes and pathways identified were linked to patient survival and were mechanistically, functionally and clinically characterized using cell lines, a genetically engineered mouse model and PDAC patient cohorts. Here we report evidence of a novel MIF-driven signaling pathway that inhibits the orphan nuclear receptor NR3C2, a previously undescribed tumor suppressor that impacts aggressiveness and survival in PDAC. Mechanistically, MIF upregulated miR-301b which targeted NR3C2 and suppressed its expression. PDAC tumors expressing high levels of MIF displayed elevated levels of miR-301b and reduced levels of NR3C2. Additionally, reduced levels of NR3C2 expression correlated with poorer survival in multiple independent cohorts of PDAC patients. Functional analysis showed that NR3C2 inhibited epithelial-to-mesenchymal transition and enhanced sensitivity to the gemcitabine, a chemotherapeutic drug used in PDAC standard of care. Furthermore, genetic deletion of MIF disrupted a MIF-mir-301b-NR3C2 signaling axis, reducing metastasis and prolonging survival in a genetically engineered mouse model of PDAC. Taken together, our results offer a preclinical proof-of-principle for candidate therapies to target a newly described MIF-miR-301b-NR3C2 signaling axis for PDAC management.

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