Current Recommendations for Minimally Invasive Surgical Staging in Ovarian Cancer

Opinion statement

Minimally invasive surgery (MIS) currently is performed to stage and treat ovarian cancer at different stages of disease; however, the higher level of evidence from existing studies is IIB. Despite the absence of randomized controlled trials, MIS represents a safe and adequate procedure for treating and staging early ovarian cancer, and its use has increased significantly in clinical practice. Major concerns are related to minimizing tumor disruption or dissemination, removing the adnexal mass intact, adequate retroperitoneal staging, and fertility-sparing surgery for young patients. The main goal for patients with advanced ovarian cancer is to determine the best therapeutic strategy by evaluating the risks and benefits of primary debulking surgery versus neoadjuvant chemotherapy followed by interval debulking surgery. The use of staging laparoscopy in patients with advanced epithelial ovarian cancer appears to be the most researched and accepted approach. Regarding other types and stages of ovarian cancer, although the evidence is very promising, clinical trials performed by expert gynecologic oncology surgeons in referral centers are still needed to prove the efficacy of such an approach in these patients. In particular, MIS has provided an opportunity to remove localized recurrences, with both retroperitoneal and intraperitoneal diffusion.

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Does Radiation Have a Role in Advanced Stage Hodgkin’s or Non-Hodgkin Lymphoma?

Opinion statement

Radiation therapy (RT) is one of the most effective agents available in the treatment of lymphomas. However, it is a local treatment, and today, with systemic treatments assuming a primary role for induction of response, RT is primarily used for consolidation. For advanced stage lymphomas, the indications for the use of RT have been questioned and debated, and proper randomized evidence is sparse. RT has significant long-term side effects, and the very extended RT fields of the past yielded unacceptable toxicity in many patients. Modern advanced imaging and conformal RT techniques now enable treatment of larger and anatomically more challenging target volumes with much less radiation to normal tissues and consequently much lower risks of long-term complications. The modern concept of involved site radiation therapy (ISRT) has now been accepted as standard in lymphomas. In advanced Hodgkin lymphoma (HL), RT to residual disease and/or initial bulk benefits some patients, depending on the chemotherapy regimen used. The more intensive the chemotherapy regimen, the fewer patients benefit from RT. In advanced aggressive non-Hodgkin lymphoma (NHL), most of the evidence comes from the most common type, the diffuse large B cell lymphoma (DLBCL). In patients treated with modern immunochemotherapy, RT to initial bulky disease or extralymphatic involvement is beneficial. For both HL and aggressive NHL, RT to residual masses after systemic treatment is of benefit. The role of PET in the evaluation and indication for RT to residual masses has not been tested in randomized trials. In advanced indolent NHL, very low dose RT offers excellent palliation with very few side effects. Modern RT in advanced lymphomas warrants further evaluation in randomized trials.

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Post-diagnosis social networks, and lifestyle and treatment factors in the After Breast Cancer Pooling Project

Abstract

Objective

Larger social networks have been associated with better breast cancer survival. To investigate potential mediators, we evaluated associations of social network size and diversity with lifestyle and treatment factors associated with prognosis.

Methods

We included 9331 women from the After Breast Cancer Pooling Project who provided data on social networks within approximately two years following diagnosis. A social network index was derived from information about the presence of a spouse or intimate partner, religious ties, community participation, friendship ties, and numbers of living relatives. Diversity was assessed as variety of ties, independent of size. We used logistic regression to evaluate associations with outcomes and evaluated whether effect estimates differed using meta-analytic techniques.

Results

Associations were similar across cohorts though analyses of smoking and alcohol included US cohorts only because of low prevalence of these behaviors in the Shanghai cohort. Socially isolated women were more likely to be obese (OR = 1.21, 95% CI:1.03–1.42), have low physical activity (<10 MET-hours/week, OR = 1.55, 95% CI:1.36–1.78), be current smokers (OR = 2.77, 95% CI:2.09-3.68), and have high alcohol intake (≥15 g/d, OR = 1.23, 95% CI:1.00–1.51), compared with socially integrated women. Among node positive cases from three cohorts, socially isolated women were more likely not to receive chemotherapy (OR = 2.10, 95% CI:1.30–3.39); associations differed in a fourth cohort. Other associations (nonsignificant) were consistent with less intensive treatment in socially isolated women. Low social network diversity was independently associated with more adverse lifestyle, but not clinical, factors.

Conclusions

Small, less diverse social networks measured post-diagnosis were associated with more adverse lifestyle factors and less intensive cancer treatment. Copyright © 2016 John Wiley & Sons, Ltd.

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How young people describe the impact of living with and beyond a cancer diagnosis: feasibility of using social media as a research method

Abstract

Objective

Young people with cancer exhibit unique needs. During a time of normal physical and psychological change, multiple disease and treatment-related symptoms cause short and long-term physical and psychosocial effects. Little is known about how young people cope with the impact of cancer and its treatment on daily routines and their strategies to manage the challenges of cancer and treatments. We aimed to determine how young people describe these challenges through a social media site.

Methods

Using the principles of virtual ethnography and watching videos on a social media site we gathered data from young people describing their cancer experience. Qualitative content analysis was employed to analyse and interpret the narrative from longitudinal 'video diaries' by 18 young people equating to 156 films and 27 h and 49 min of recording. Themes were described then organized and clustered into typologies grouping commonalities across themes.

Results

Four typologies emerged reflective of the cancer trajectory: treatment and relenting side effects, rehabilitation and getting on with life, relapse, facing more treatment and coming to terms with dying.

Conclusions

This study confirms the need for young people to strive towards normality and creating a new normal, even where uncertainty prevailed. Strategies young people used to gain mastery over their illness and the types of stories they choose to tell provide the focus of the main narrative. Social Media sites can be examined as a source of data, to supplement or instead of more traditional routes of data collection known to be practically challenging with this population. Copyright © 2016 John Wiley & Sons, Ltd.

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Turning Cancer Cells into Cancer Killers [News in Brief]

Researchers have changed leukemia cells into natural killer cells by adding a specific antibody to bone marrow cells from patients with acute myeloblastic leukemia. The induced natural killer cells killed leukemia cells in culture. The antibody does not trigger the same conversion in bone marrow from healthy patients.

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Olaparib Targets Some Advanced Prostate Cancers [News in Brief]

In the phase II TOPARP-A clinical trial, patients with metastatic castrate-resistant prostate cancer who were treated with the PARP inhibitor olaparib lived nearly three times longer without their cancer worsening if their tumors had mutations in at least one of 12 DNA repair genes. However, physicians say that a larger trial is needed to confirm olaparib's effectiveness against the disease before they start routinely sequencing tumors and prescribing the drug.

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Brain May Prime Metastatic Cell Growth [News in Brief]

Metastasizing tumor cells lose expression of the tumor suppressor PTEN at a much higher rate when they enter the brain compared to other organs, suggesting that the brain's unique microenvironment may prime metastatic cells for aggressive growth, a recent study reports. The findings may have implications for developing targeted therapies for brain metastases.

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PF-06463922 Overcomes Primary Resistance in Neuroblastoma [Research Articles]

Neuroblastomas harboring activating point mutations in anaplastic lymphoma kinase (ALK) are differentially sensitive to the ALK inhibitor crizotinib, with certain mutations conferring intrinsic crizotinib resistance. To overcome this clinical obstacle, our goal was to identify inhibitors with improved potency that can target intractable ALK variants such as F1174L. We find that PF-06463922 has high potency across ALK variants and inhibits ALK more effectively than crizotinib in vitro. Most importantly, PF-06463922 induces complete tumor regression in both crizotinib-resistant and crizotinib-sensitive xenograft mouse models of neuroblastoma, as well as in patient-derived xenografts harboring the crizotinib-resistant F1174L or F1245C mutations. These studies demonstrate that PF-06463922 has the potential to overcome crizotinib resistance and exerts unprecedented activity as a single targeted agent against F1174L and F1245C ALK-mutated xenograft tumors, while also inducing responses in an R1275Q xenograft model. Taken together, these results provide the rationale to move PF-06463922 into clinical trials for treatment of patients with ALK-mutated neuroblastoma.

Significance: The next-generation ALK/ROS1 inhibitor PF-06463922 exerts unparalleled activity in ALK-driven neuroblastoma models with primary crizotinib resistance. Our biochemical and in vivo data provide the preclinical rationale for fast-tracking the development of this agent in children with relapsed/refractory ALK-mutant neuroblastoma. Cancer Discov; 6(1); 96–107. ©2015 AACR.

See related commentary by Versteeg and George, p. 20.

This article is highlighted in the In This Issue feature, p. 1

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The Nuclear Lamina Protein Lamin B1 Is a Selective Autophagy Substrate [Autophagy]

Selective autophagy degrades lamin B1 in response to oncogenic and genotoxic insults.

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Targeting the Ribosome to Treat MYC-Driven Lymphoma [Research Briefs]

Ribosome biogenesis and protein synthesis are dysregulated in many cancers, with those driven by the proto-oncogene c-MYC characterized by elevated Pol I–mediated ribosomal rDNA transcription and mTORC1/eIF4E-driven mRNA translation. Here, we demonstrate that coordinated targeting of rDNA transcription and PI3K–AKT–mTORC1-dependent ribosome biogenesis and protein synthesis provides a remarkable improvement in survival in MYC-driven B lymphoma. Combining an inhibitor of rDNA transcription (CX-5461) with the mTORC1 inhibitor everolimus more than doubled survival of Eμ-Myc lymphoma–bearing mice. The ability of each agent to trigger tumor cell death via independent pathways was central to their synergistic efficacy. CX-5461 induced nucleolar stress and p53 pathway activation, whereas everolimus induced expression of the proapoptotic protein BMF that was independent of p53 and reduced expression of RPL11 and RPL5. Thus, targeting the network controlling the synthesis and function of ribosomes at multiple points provides a potential new strategy to treat MYC-driven malignancies.

Significance: Treatment options for the high proportion of cancers driven by MYC are limited. We demonstrate that combining pharmacologic targeting of ribosome biogenesis and mTORC1-dependent translation provides a remarkable therapeutic benefit to Eμ-Myc lymphoma–bearing mice. These results establish a rationale for targeting ribosome biogenesis and function to treat MYC-driven cancer. Cancer Discov; 6(1); 59–70. ©2015 AACR.

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TRK Inhibitor Shows Early Promise [News in Brief]

Results from a phase I study show that the TRK inhibitor LOXO-101 is well tolerated and effective, with patients whose tumors bear NTRK fusions responding well and durably to this targeted therapy.

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MECP2 Is a Frequently Amplified Oncogene That Mimics RAS [Research Briefs]

An unbiased genome-scale screen for unmutated genes that drive cancer growth when overexpressed identified methyl cytosine-guanine dinucleotide (CpG) binding protein 2 (MECP2) as a novel oncogene. MECP2 resides in a region of the X-chromosome that is significantly amplified across 18% of cancers, and many cancer cell lines have amplified, overexpressed MECP2 and are dependent on MECP2 expression for growth. MECP2 copy-number gain and RAS family member alterations are mutually exclusive in several cancer types. The MECP2 splicing isoforms activate the major growth factor pathways targeted by activated RAS, the MAPK and PI3K pathways. MECP2 rescued the growth of a KRAS^G12C-addicted cell line after KRAS downregulation, and activated KRAS rescues the growth of an MECP2-addicted cell line after MECP2 downregulation. MECP2 binding to the epigenetic modification 5-hydroxymethylcytosine is required for efficient transformation. These observations suggest that MECP2 is a commonly amplified oncogene with an unusual epigenetic mode of action.

Significance:MECP2 is a commonly amplified oncogene in human malignancies with a unique epigenetic mechanism of action. Cancer Discov; 6(1); 45–58. ©2015 AACR.

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Large Studies Expand Genomic View of CLL [News in Brief]

The largest genomic studies on chronic lymphocytic leukemia to date confirm the genetic heterogeneity of the disease, reveal dozens of putative new driver mutations, and trace the evolution of tumors during treatment and relapse.

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Cross-Priming and Immunomodulatory mAbs [Research Briefs]

Weak and ineffective antitumor cytotoxic T lymphocyte (CTL) responses can be rescued by immunomodulatory mAbs targeting PD-1 or CD137. Using Batf3^–/– mice, which are defective for cross-presentation of cell-associated antigens, we show that BATF3-dependent dendritic cells (DC) are essential for the response to therapy with anti-CD137 or anti–PD-1 mAbs. Batf3^–/– mice failed to prime an endogenous CTL-mediated immune response toward tumor-associated antigens, including neoantigens. As a result, the immunomodulatory mAbs could not amplify any therapeutically functional immune response in these mice. Moreover, administration of systemic sFLT3L and local poly-ICLC enhanced DC-mediated cross-priming and synergized with anti–CD137- and anti–PD-1–mediated immunostimulation in tumor therapy against B16-ovalbumin–derived melanomas, whereas this function was lost in Batf3^–/– mice. These experiments show that cross-priming of tumor antigens by FLT3L- and BATF3-dependent DCs is crucial to the efficacy of immunostimulatory mAbs and represents a very attractive point of intervention to enhance their clinical antitumor effects.

Significance: Immunotherapy with immunostimulatory mAbs is currently achieving durable clinical responses in different types of cancer. We show that cross-priming of tumor antigens by BATF3-dependent DCs is a key limiting factor that can be exploited to enhance the antitumor efficacy of anti–PD-1 and anti-CD137 immunostimulatory mAbs. Cancer Discov; 6(1); 71–9. ©2015 AACR.

See related commentary by Robert-Tissot and Speiser, p. 17.

This article is highlighted in the In This Issue feature, p. 1

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Lymphatic Vessels, Inflammation, and Immunity in Skin Cancer [Review]

Skin is a highly ordered immune organ that coordinates rapid responses to external insult while maintaining self-tolerance. In healthy tissue, lymphatic vessels drain fluid and coordinate local immune responses; however, environmental factors induce lymphatic vessel dysfunction, leading to lymph stasis and perturbed regional immunity. These same environmental factors drive the formation of local malignancies, which are also influenced by local inflammation. Herein, we discuss clinical and experimental evidence supporting the tenet that lymphatic vessels participate in regulation of cutaneous inflammation and immunity, and are important contributors to malignancy and potential biomarkers and targets for immunotherapy.

Significance: The tumor microenvironment and tumor-associated inflammation are now appreciated not only for their role in cancer progression but also for their response to therapy. The lymphatic vasculature is a less-appreciated component of this microenvironment that coordinates local inflammation and immunity and thereby critically shapes local responses. A mechanistic understanding of the complexities of lymphatic vessel function in the unique context of skin provides a model to understand how regional immune dysfunction drives cutaneous malignancies, and as such lymphatic vessels represent a biomarker of cutaneous immunity that may provide insight into cancer prognosis and effective therapy. Cancer Discov; 6(1); 22–35. ©2015 AACR.

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Study Reveals Seeds of Metastases [News in Brief]

Rare tumor cells thought to initiate metastasis possess unique gene signatures that distinguish them from cells in primary tumors, a recent study concludes. The findings may help in developing drugs that specifically target metastasis in patients with different types of cancer.

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Barcoding Oncogene-Transformed Cells Reveals Clonal Tumor Landscape [Tumor Heterogeneity]

Clonal tumors can develop rapidly from normal human mammary cells transduced with a single oncogene.

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Targeting Mutant AKT in Cancer [News in Brief]

The results of a phase I basket trial suggest that the AKT1 E17K mutation is a valid therapeutic target. AZD5363, an investigational pan-AKT inhibitor, may benefit patients with a range of solid tumors bearing this genetic alteration.

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TRKA Mutations and Resistance to Entrectinib in Colorectal Cancer [Research Briefs]

Entrectinib is a first-in-class pan-TRK kinase inhibitor currently undergoing clinical testing in colorectal cancer and other tumor types. A patient with metastatic colorectal cancer harboring an LMNA–NTRK1 rearrangement displayed a remarkable response to treatment with entrectinib, which was followed by the emergence of resistance. To characterize the molecular bases of the patient's relapse, circulating tumor DNA (ctDNA) was collected longitudinally during treatment, and a tissue biopsy, obtained before entrectinib treatment, was transplanted in mice (xenopatient), which then received the same entrectinib regimen until resistance developed. Genetic profiling of ctDNA and xenopatient samples showed acquisition of two point mutations in the catalytic domain of NTRK1, p.G595R and p.G667C. Biochemical and pharmacologic analysis in multiple preclinical models confirmed that either mutation renders the TRKA kinase insensitive to entrectinib. These findings can be immediately exploited to design next-generation TRKA inhibitors.

Significance: We provide proof of principle that analyses of xenopatients (avatar) and liquid biopsies allow the identification of drug resistance mechanisms in parallel with clinical treatment of an individual patient. We describe for the first time that p.G595R and p.G667C TRKA mutations drive acquired resistance to entrectinib in colorectal cancers carrying NTRK1 rearrangements. Cancer Discov; 6(1); 36–44. ©2015 AACR.

See related commentary by Okimoto and Bivona, p. 14.

This article is highlighted in the In This Issue feature, p. 1

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Targeting ALK: The Ten Lives of a Tumor [In the Spotlight]

Summary: In this issue, Infarinato and colleagues report the results of preclinical testing of a novel ALK/ROS1 inhibitor, PF-06463922, in neuroblastoma. This small-molecule inhibitor was shown to efficiently inhibit the growth of patient-derived and established neuroblastoma xenograft models expressing mutated ALK. Although the in vivo data are impressive and the authors suggest that clinical trials are warranted, the presented data also suggest that it is as yet too early to welcome the new drug as a magic bullet. Cancer Discov; 6(1); 20–1. ©2016 AACR.

See related article by Infarinato et al., p. 96.

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