http://ift.tt/2AreeEg
Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Τετάρτη 29 Νοεμβρίου 2017
Primary cutaneous mucoepidermal carcinoma
Mucoepidermal carcinoma (MEC) is a tumour having mixed components of mucus secreting and epidermoid cells. Salivary glands are the the most common site of origin. Primary cutaneous MEC is a rare presentation. We report a primary cutaneous MEC in a 98-year-old woman presenting a noduloulcerative lesion over the dorsum of the nose. Histopathology of the tumour showed nests of epidermoid cells with glandular differentiation and mucin production. The diagnosis was confirmed by immunohistochemistry.
http://ift.tt/2By0S71
Systemic thrombolysis in a patient with massive pulmonary embolism and recent glioblastoma multiforme resection
While trials of systemic thrombolysis for submassive and massive pulmonary embolism (PE) report intracranial haemorrhage (ICH) rates of 2%–3%, the risk of ICH in patients with recent brain surgery or intracranial neoplasm is unknown since these patients were excluded from these trials. We report a case of massive PE treated with systemic thrombolysis in a patient with recent neurosurgery for an intracranial neoplasm. We discuss the risks and benefits of systemic thrombolysis for massive PE in the context of previous case reports, prior cohort studies and trials, and current guidelines. There may be times when the immediate risk of death from massive PE outweighs the risk of ICH from systemic thrombolysis, even when guideline-listed major contraindications exist. This case provides an example of how the haemodynamic benefit of systemic thrombolysis outweighed the impact of ICH in a patient who had undergone recent neurosurgical resection of a glioblastoma multiforme tumour.
http://ift.tt/2kar0Rf
Lyric hearing aid: a rare cause of benign necrotising otitis externa/external ear canal cholesteatoma
An 80-year-old Caucasian man presented with an incidental and asymptomatic lesion in his right ear thought to be secondary to his use of hearing aids for presbycusis. He used Lyric hearing aids, designed for 24 hours-a-day use for 4 months at a time and had no other previous otological problems. He underwent a bony meatoplasty and vascular flap reconstruction via a retroauricular approach to remove the lesion for histological analysis and regrafting of the area. The lesion was confirmed on histopathology as an ear canal cholesteatoma.
http://ift.tt/2By0PrR
Follicular bronchiolitis in an HIV-infected individual on combination antiretroviral therapy with low CD4+ cell count but sustained viral suppression
A 36-year-old Danish man, living in Asia, was diagnosed with Pneumocystis pneumonia (PCP) and HIV in 2013 (CD4+ count: 6 cells/µL; viral load: 518 000 copies/mL). He initiated combination antiretroviral therapy. Later that year, he was also diagnosed with granulomatosis with polyangiitis and was treated with prednisolone. Despite complete viral suppression and increasing CD4+ count (162 cells/µL), he was readmitted with PCP in April 2015. Subsequently, he returned to Denmark (CD4+ count: 80 cells/µL, viral suppression). Over the following months, he developed progressive dyspnoea. Lung function tests demonstrated severely reduced lung capacity with an obstructive pattern and a moderately reduced diffusion capacity. High resolution computer tomography revealed minor areas with tree-in-bud pattern and no signs of air trapping on expiratory views. Lung biopsy showed lymphocytic infiltration surrounding the bronchioles with sparing of the alveolar septa. He was diagnosed with follicular bronchiolitis. The patient spontaneously recovered along with an improvement of the immune system.
http://ift.tt/2kaTjio
Epidemiology, biology and therapy of Merkel cell carcinoma: conclusions from the EU project IMMOMEC
Abstract
Merkel cell carcinoma (MCC) is a highly aggressive, often lethal neuroendocrine cancer. Its carcinogenesis may be either caused by the clonal integration of the Merkel cell polyomavirus into the host genome or by UV-induced mutations. Notably, virally-encoded oncoproteins and UV-induced mutations affect comparable signaling pathways such as RB restriction of cell cycle progression or p53 inactivation. Despite its low incidence, MCC recently received much attention based on its exquisite immunogenicity and the resulting major success of immune modulating therapies. Here, we summarize current knowledge on epidemiology, biology and therapy of MCC as conclusion of the project 'Immune Modulating strategies for treatment of Merkel Cell Carcinoma', which was funded over a 5-year period by the European Commission to investigate innovative immunotherapies for MCC.
http://ift.tt/2zQ3kbN
Epidemiology, biology and therapy of Merkel cell carcinoma: conclusions from the EU project IMMOMEC
Abstract
Merkel cell carcinoma (MCC) is a highly aggressive, often lethal neuroendocrine cancer. Its carcinogenesis may be either caused by the clonal integration of the Merkel cell polyomavirus into the host genome or by UV-induced mutations. Notably, virally-encoded oncoproteins and UV-induced mutations affect comparable signaling pathways such as RB restriction of cell cycle progression or p53 inactivation. Despite its low incidence, MCC recently received much attention based on its exquisite immunogenicity and the resulting major success of immune modulating therapies. Here, we summarize current knowledge on epidemiology, biology and therapy of MCC as conclusion of the project 'Immune Modulating strategies for treatment of Merkel Cell Carcinoma', which was funded over a 5-year period by the European Commission to investigate innovative immunotherapies for MCC.
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Epidemiology, biology and therapy of Merkel cell carcinoma: conclusions from the EU project IMMOMEC
Abstract
Merkel cell carcinoma (MCC) is a highly aggressive, often lethal neuroendocrine cancer. Its carcinogenesis may be either caused by the clonal integration of the Merkel cell polyomavirus into the host genome or by UV-induced mutations. Notably, virally-encoded oncoproteins and UV-induced mutations affect comparable signaling pathways such as RB restriction of cell cycle progression or p53 inactivation. Despite its low incidence, MCC recently received much attention based on its exquisite immunogenicity and the resulting major success of immune modulating therapies. Here, we summarize current knowledge on epidemiology, biology and therapy of MCC as conclusion of the project 'Immune Modulating strategies for treatment of Merkel Cell Carcinoma', which was funded over a 5-year period by the European Commission to investigate innovative immunotherapies for MCC.
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Epidemiology, biology and therapy of Merkel cell carcinoma: conclusions from the EU project IMMOMEC
Abstract
Merkel cell carcinoma (MCC) is a highly aggressive, often lethal neuroendocrine cancer. Its carcinogenesis may be either caused by the clonal integration of the Merkel cell polyomavirus into the host genome or by UV-induced mutations. Notably, virally-encoded oncoproteins and UV-induced mutations affect comparable signaling pathways such as RB restriction of cell cycle progression or p53 inactivation. Despite its low incidence, MCC recently received much attention based on its exquisite immunogenicity and the resulting major success of immune modulating therapies. Here, we summarize current knowledge on epidemiology, biology and therapy of MCC as conclusion of the project 'Immune Modulating strategies for treatment of Merkel Cell Carcinoma', which was funded over a 5-year period by the European Commission to investigate innovative immunotherapies for MCC.
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Epidemiology, biology and therapy of Merkel cell carcinoma: conclusions from the EU project IMMOMEC
Abstract
Merkel cell carcinoma (MCC) is a highly aggressive, often lethal neuroendocrine cancer. Its carcinogenesis may be either caused by the clonal integration of the Merkel cell polyomavirus into the host genome or by UV-induced mutations. Notably, virally-encoded oncoproteins and UV-induced mutations affect comparable signaling pathways such as RB restriction of cell cycle progression or p53 inactivation. Despite its low incidence, MCC recently received much attention based on its exquisite immunogenicity and the resulting major success of immune modulating therapies. Here, we summarize current knowledge on epidemiology, biology and therapy of MCC as conclusion of the project 'Immune Modulating strategies for treatment of Merkel Cell Carcinoma', which was funded over a 5-year period by the European Commission to investigate innovative immunotherapies for MCC.
http://ift.tt/2zQ3kbN
Outcomes of Children and Adolescents with Advanced Hereditary Medullary Thyroid Carcinoma Treated with Vandetanib
Purpose: Vandetanib is well-tolerated in patients with advanced medullary thyroid carcinoma (MTC). Long-term outcomes and mechanisms of MTC progression have not been reported previously. Experimental Design:We monitored toxicities and disease status in patients taking vandetanib for hereditary, advanced MTC. Tumor samples were analyzed for molecular mechanisms of disease progression. Results: Seventeen patients (8 male, age 13 (9-17)* years) enrolled; 16 had a RET p.Met918Thr germline mutation. The duration of vandetanib therapy was 6.1 (0.1-9.7+)* years with treatment ongoing in nine patients. Best response was partial response (PR) in ten, stable disease (SD) in six, and progressive disease (PD) in one patient. Duration of response was 7.4 (0.6-8.7+)* and 4.9 (0.6-7.8+)* years in patients with PR and SD, respectively. Six patients died 2.0 (0.4-5.7)* years after progression. Median progression free survival (PFS) was 6.7 years (95% CI: 2.3 years-undefined) and 5-year overall survival (OS) was 88.2% (95% CI 60.6-96.9%). Of 16 patients with a RET p.Met918Thr mutation, progression free survival was 6.7 years (95% CI 3.1-undefined) and 5-year overall survival was 93.8% (95% CI 63.2-99.1%). No patients terminated treatment because of toxicity. DNA sequencing of tissue samples (n=11) identified an increase in copy number alterations across the genome as a potential mechanism of drug resistance. Conclusions:This study demonstrates that vandetanib is safe and results in sustained responses in children and adolescents with hereditary MTC. Our preliminary molecular data suggest that an increase in copy number abnormalities may be associated with tumor progression in hereditary MTC patients treated with vandetanib.
http://ift.tt/2irFU4Z
Outcomes of Children and Adolescents with Advanced Hereditary Medullary Thyroid Carcinoma Treated with Vandetanib
Purpose: Vandetanib is well-tolerated in patients with advanced medullary thyroid carcinoma (MTC). Long-term outcomes and mechanisms of MTC progression have not been reported previously. Experimental Design:We monitored toxicities and disease status in patients taking vandetanib for hereditary, advanced MTC. Tumor samples were analyzed for molecular mechanisms of disease progression. Results: Seventeen patients (8 male, age 13 (9-17)* years) enrolled; 16 had a RET p.Met918Thr germline mutation. The duration of vandetanib therapy was 6.1 (0.1-9.7+)* years with treatment ongoing in nine patients. Best response was partial response (PR) in ten, stable disease (SD) in six, and progressive disease (PD) in one patient. Duration of response was 7.4 (0.6-8.7+)* and 4.9 (0.6-7.8+)* years in patients with PR and SD, respectively. Six patients died 2.0 (0.4-5.7)* years after progression. Median progression free survival (PFS) was 6.7 years (95% CI: 2.3 years-undefined) and 5-year overall survival (OS) was 88.2% (95% CI 60.6-96.9%). Of 16 patients with a RET p.Met918Thr mutation, progression free survival was 6.7 years (95% CI 3.1-undefined) and 5-year overall survival was 93.8% (95% CI 63.2-99.1%). No patients terminated treatment because of toxicity. DNA sequencing of tissue samples (n=11) identified an increase in copy number alterations across the genome as a potential mechanism of drug resistance. Conclusions:This study demonstrates that vandetanib is safe and results in sustained responses in children and adolescents with hereditary MTC. Our preliminary molecular data suggest that an increase in copy number abnormalities may be associated with tumor progression in hereditary MTC patients treated with vandetanib.
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Modeling the subclonal evolution of cancer cell populations
Increasing evidence shows that tumor clonal architectures are often the consequence of a complex branching process, yet little is known about the expected dynamics and extent to which these divergent subclonal expansions occur. Here we develop and implement more than 88,000 instances of a stochastic evolutionary model simulating genetic drift and neoplastic progression. Under different combinations of population genetic parameter values, including those estimated for colorectal cancer and glioblastoma multiforme, the distribution of sizes of subclones carrying driver mutations had a heavy right tail at the time of tumor detection, with only 1-4 dominant clones present at ≥10% frequency. In contrast, the vast majority of subclones were present at <10% frequency, many of which had higher fitness than currently dominant clones. The number of dominant clones (≥10% frequency) in a tumor correlated strongly with the number of subclones (<10% of the tumor). Overall, these subclones were frequently below current standard detection thresholds, frequently harbored treatment-resistant mutations and were more common in slow-growing tumors.
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HER2-driven Breast Tumorigenesis Relies upon Interactions of the Estrogen Receptor with Coactivator MED1
Studies of the estrogen receptor (ER) coactivator protein MED1 have revealed its specific roles in pubertal mammary gland development and potential contributions to breast tumorigenesis, based on co-amplification of MED1 and HER2 in certain breast cancers. In this study, we generated a mouse model of mammary tumorigenesis harboring the MMTV-HER2 oncogene and mutation of MED1 to evaluate its role in HER2-driven tumorigenesis. MED1 mutation in its ER-interacting LxxLL motifs was sufficient to delay tumor onset and impair tumor growth, metastasis and cancer stem-like cell formation in this model. Mechanistic investigations revealed that MED1 acted directly to regulate ER signaling through the downstream IGF-1 pathway but not the AREG pathway. Our findings show that MED1 is critical for HER2-driven breast tumorigenesis, suggesting its candidacy as a disease-selective therapeutic target.
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LSR antibody therapy inhibits ovarian epithelial tumor growth by inhibiting lipid uptake
Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy but it still lacks effective treatment options. In this study, we utilized proteomic technology to identify lipolysis-stimulated lipoprotein receptor (LSR) as a new tumor antigen of EOC. Immunohistochemical analysis of EOC tissues in conjunction with survival analysis of EOC patients showed that high expression of LSR is associated with poor prognosis. High LSR expression also occurred in tumor metastases including to the lymph node and omentum. To evaluate the possible benefits of blocking this antigen in EOC, we raised a new monoclonal antibody (mAb) to human LSR (hLSR). In mouse xenograft models of hLSR-positive EOC (cell lines or patient-derived tumors), we found that administration of anti-hLSR mAb inhibited tumor growth in a manner independent of both antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity. Mechanistic investigations showed that hLSR expression increased incorporation of very low-density lipoprotein (VLDL) into EOC cells and that anti-hLSR mAb inhibited lipid uptake in vitro and in vivo. Moreover, VLDL promoted cell proliferation in hLSR-positive EOC cells in vitro and this effect was inhibited by anti-hLSR mAb. While the anti-hLSR mAb studied cross-reacted with the mouse antigen, we observed no adverse effects on normal organs and lipid metabolism in murine hosts. Our findings suggest that hLSR plays a key functional role in EOC development and that this antigen can be therapeutically targeted by specific mAb to improve EOC treatment.
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Photodynamic priming mitigates chemotherapeutic selection pressures and improves drug delivery
Physiological barriers to drug delivery and selection for drug resistance limit survival outcomes in cancer patients. In this study, we present preclinical evidence that a subtumoricidal photodynamic priming (PDP) strategy can relieve drug delivery barriers in the tumor microenvironment to safely widen the therapeutic window of a nanoformulated cytotoxic drug. In orthotopic xenograft models of pancreatic cancer, combining PDP with nanoliposomal irinotecan (nal-IRI) prevented tumor relapse, reduce metastasis and increase both progression-free survival and 1-year disease-free survival. PDP enabled these durable improvements by targeting multiple tumor compartments to (1) increase intratumoral drug accumulation by >10-fold, (2) increase the duration of drug exposure above a critical therapeutic threshold, and (3) attenuate surges in CD44 and CXCR4 expression which mediate chemoresistance often observed after multi-cycle chemotherapy. Overall, our results offer preclinical proof of concept for the effectiveness of PDP to minimize risks of tumor relapse, progression and drug resistance and to extend patient survival.
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The E3 ligase RING1 targets p53 for degradation and promotes cancer cell proliferation and survival
As a component of the transcriptional repression complex 1 (PRC1), the ring finger protein RING1 participates in the epigenetic regulation in cancer. However, the contributions of RING1 to cancer etiology or development are unknown. In this study, we report that RING1 is a critical negative regulator of p53 homeostasis in human hepatocellular and colorectal carcinomas. RING1 acts as an E3 ubiquitin (Ub) ligase to directly interact with and ubiquitinate p53, resulting in its proteasome-dependent degradation. The RING domain of RING1 was required for its E3 Ub ligase activity. RING1 depletion inhibited the proliferation and survival of the p53 wild-type cancer cells by inducing cell cycle arrest, apoptosis and senescence, with only modest effects on p53-deficient cells. Its growth inhibitory effect was partially rescued by p53 silencing, suggesting an important role for the RING1-p53 complex in human cancer. In clinical specimens of hepatocellular carcinoma, RING1 upregulation was evident in association with poor clinical outcomes. Collectively, our results elucidate a novel PRC1-independent function of RING1 and provide a mechanistic rationale for its candidacy as a new prognostic marker and/or therapeutic target in human cancer.
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PPAR{delta} elicits ligand-independent repression of Trefoil Factor Family to limit prostate cancer growth
The nuclear receptor PPAR-β/δ (PPARD) has essential roles in fatty acid catabolism and energy homeostasis as well as cell differentiation, inflammation and metabolism. However, its contributions to tumorigenesis are uncertain and have been disputed. Here we provide evidence of tumor suppressive activity of PPARD in prostate cancer through a non-canonical and ligand-independent pathway. PPARD was downregulated in prostate cancer specimens. In murine prostate epithelium, PPARD gene deletion resulted in increased cellularity. Genetic modulation of PPARD in human prostate cancer cell lines validated the tumor suppressive activity of this gene in vitro and in vivo. Mechanistically, PPARD exerted its activity in a DNA binding-dependent and ligand-independent manner. We identified a novel set of genes repressed by PPARD that failed to respond to ligand-mediated activation. Among these genes, we observed robust regulation of the secretory trefoil factor family (TFF) members, including a causal and correlative association of TFF1 to prostate cancer biology in vitro and in patient specimens. Overall, our results illuminate the oncosuppressive function of PPARD and understanding of the pathogenic molecular pathways elicited by this nuclear receptor.
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Delivering type I interferon to dendritic cells empowers tumor eradication and immune combination treatments
An ideal generic cancer immunotherapy should mobilize the immune system to destroy tumor cells without harming healthy cells and remain active in case of recurrence. Furthermore, it should preferably not rely on tumor-specific surface markers, as these are only available in a limited set of malignancies. Despite approval for treatment of various cancers, clinical application of cytokines is still impeded by their multiple toxic side effects. Type I interferon (IFN) has a long history in the treatment of cancer, but its multifaceted activity pattern and complex side effects prevent its clinical use. Here we develop AcTakines (Activity-on-Target cytokines), optimized (mutated) immunocytokines that are up to 1000-fold more potent on target cells, allowing specific signaling in selected cell types only. Type I IFN-derived AcTaferon-targeting Clec9A+ dendritic cells (DC) displayed strong antitumor activity in murine melanoma, breast carcinoma, and lymphoma models and against human lymphoma in humanized mice without any detectable toxic side effects. Combined with immune checkpoint blockade, chemotherapy, or low-dose TNF, complete tumor regression and long-lasting tumor immunity were observed, still without adverse effects. Our findings indicate that DC-targeted AcTaferons provide a novel class of highly efficient, safe, and broad-spectrum off-the-shelf cancer immunotherapeutics with no need for a tumor marker.
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Disparities in Prostate, Lung, Breast, and Colorectal Cancer Survival and Comorbidity Status among Urban American Indians and Alaskan Natives
Cancer is the second leading cause of death among American Indians and Alaskan Natives (AIAN), although cancer survival information in this population is limited, particularly among urban AIAN. In this retrospective cohort study, we compared all-cause and prostate, breast, lung, and colorectal cancer–specific mortality among AIAN (n = 582) and non-Hispanic white (NHW; n = 82,696) enrollees of Kaiser Permanente Northern California (KPNC) diagnosed with primary invasive breast, prostate, lung, or colorectal cancer from 1997 to 2015. Tumor registry and other electronic health records provided information on sociodemographic, comorbidity, tumor, clinical, and treatment characteristics. Cox regression models were used to estimate adjusted survival curves and hazard ratios (HR) with 95% confidence intervals (CI). AIAN had a significantly higher comorbidity burden compared with NHW (P < 0.05). When adjusting for patient, disease characteristics, and Charlson comorbidity scores, all-cause mortality and cancer-specific mortality were significantly higher for AIAN than NHW patients with breast cancer (HR, 1.47; 95% CI, 1.13–1.92) or with prostate cancer (HR, 1.87; 95% CI, 1.14–3.06) but not for AIAN patients with lung and colorectal cancer. Despite approximately equal access to preventive services and cancer care in this setting, we found higher mortality for AIAN than NHW with some cancers, and a greater proportion of AIAN cancer patients with multiple comorbid conditions. This study provides severely needed information on the cancer experience of the 71% of AIANs who live in urban areas and access cancer care outside of the Indian Health Services, from which the vast majority of AIAN cancer information comes. Cancer Res; 77(23); 1–7. ©2017 AACR.
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PTBP3-mediated regulation of ZEB1 mRNA stability promotes epithelial-mesenchymal transition in breast cancer
The RNA polypyrimidine tract binding protein PTBP3 is a little studied paralog of PTBP1 which has oncogenic properties. In this study, we demonstrate that PTBP3 induces epithelial-mesenchymal transition (EMT) in breast tumor cells and promotes their invasive growth and metastasis. Elevated expression of PTBP3 associated significantly with lymph node metastasis, advanced histology grade, TNM stage, and poor 5-year overall survival of patients. In human mammary epithelial cells, PTBP3 overexpression was sufficient to induce EMT and enhance cell migration, invasion, and cancer stem-like cell properties. PTBP3 regulated expression of the EMT regulatory transcription factor ZEB1 by binding the 3'UTR of its mRNA, thereby preventing its degradation. Conversely, ZEB1 ablation blocked the ability of PTBP3 to induce EMT. Overall, our findings define PTBP3 as a regulator of EMT that acts by governing expression of ZEB1, and they establish an oncogenic function of PTBP3 suggesting its candidacy as a theranostic target.
http://ift.tt/2AnA4sf
Modeling the subclonal evolution of cancer cell populations
Increasing evidence shows that tumor clonal architectures are often the consequence of a complex branching process, yet little is known about the expected dynamics and extent to which these divergent subclonal expansions occur. Here we develop and implement more than 88,000 instances of a stochastic evolutionary model simulating genetic drift and neoplastic progression. Under different combinations of population genetic parameter values, including those estimated for colorectal cancer and glioblastoma multiforme, the distribution of sizes of subclones carrying driver mutations had a heavy right tail at the time of tumor detection, with only 1-4 dominant clones present at ≥10% frequency. In contrast, the vast majority of subclones were present at <10% frequency, many of which had higher fitness than currently dominant clones. The number of dominant clones (≥10% frequency) in a tumor correlated strongly with the number of subclones (<10% of the tumor). Overall, these subclones were frequently below current standard detection thresholds, frequently harbored treatment-resistant mutations and were more common in slow-growing tumors.
http://ift.tt/2ioDOTk
HER2-driven Breast Tumorigenesis Relies upon Interactions of the Estrogen Receptor with Coactivator MED1
Studies of the estrogen receptor (ER) coactivator protein MED1 have revealed its specific roles in pubertal mammary gland development and potential contributions to breast tumorigenesis, based on co-amplification of MED1 and HER2 in certain breast cancers. In this study, we generated a mouse model of mammary tumorigenesis harboring the MMTV-HER2 oncogene and mutation of MED1 to evaluate its role in HER2-driven tumorigenesis. MED1 mutation in its ER-interacting LxxLL motifs was sufficient to delay tumor onset and impair tumor growth, metastasis and cancer stem-like cell formation in this model. Mechanistic investigations revealed that MED1 acted directly to regulate ER signaling through the downstream IGF-1 pathway but not the AREG pathway. Our findings show that MED1 is critical for HER2-driven breast tumorigenesis, suggesting its candidacy as a disease-selective therapeutic target.
http://ift.tt/2AmXs9s
LSR antibody therapy inhibits ovarian epithelial tumor growth by inhibiting lipid uptake
Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy but it still lacks effective treatment options. In this study, we utilized proteomic technology to identify lipolysis-stimulated lipoprotein receptor (LSR) as a new tumor antigen of EOC. Immunohistochemical analysis of EOC tissues in conjunction with survival analysis of EOC patients showed that high expression of LSR is associated with poor prognosis. High LSR expression also occurred in tumor metastases including to the lymph node and omentum. To evaluate the possible benefits of blocking this antigen in EOC, we raised a new monoclonal antibody (mAb) to human LSR (hLSR). In mouse xenograft models of hLSR-positive EOC (cell lines or patient-derived tumors), we found that administration of anti-hLSR mAb inhibited tumor growth in a manner independent of both antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity. Mechanistic investigations showed that hLSR expression increased incorporation of very low-density lipoprotein (VLDL) into EOC cells and that anti-hLSR mAb inhibited lipid uptake in vitro and in vivo. Moreover, VLDL promoted cell proliferation in hLSR-positive EOC cells in vitro and this effect was inhibited by anti-hLSR mAb. While the anti-hLSR mAb studied cross-reacted with the mouse antigen, we observed no adverse effects on normal organs and lipid metabolism in murine hosts. Our findings suggest that hLSR plays a key functional role in EOC development and that this antigen can be therapeutically targeted by specific mAb to improve EOC treatment.
http://ift.tt/2ioDunA
Photodynamic priming mitigates chemotherapeutic selection pressures and improves drug delivery
Physiological barriers to drug delivery and selection for drug resistance limit survival outcomes in cancer patients. In this study, we present preclinical evidence that a subtumoricidal photodynamic priming (PDP) strategy can relieve drug delivery barriers in the tumor microenvironment to safely widen the therapeutic window of a nanoformulated cytotoxic drug. In orthotopic xenograft models of pancreatic cancer, combining PDP with nanoliposomal irinotecan (nal-IRI) prevented tumor relapse, reduce metastasis and increase both progression-free survival and 1-year disease-free survival. PDP enabled these durable improvements by targeting multiple tumor compartments to (1) increase intratumoral drug accumulation by >10-fold, (2) increase the duration of drug exposure above a critical therapeutic threshold, and (3) attenuate surges in CD44 and CXCR4 expression which mediate chemoresistance often observed after multi-cycle chemotherapy. Overall, our results offer preclinical proof of concept for the effectiveness of PDP to minimize risks of tumor relapse, progression and drug resistance and to extend patient survival.
http://ift.tt/2AmXePE
The E3 ligase RING1 targets p53 for degradation and promotes cancer cell proliferation and survival
As a component of the transcriptional repression complex 1 (PRC1), the ring finger protein RING1 participates in the epigenetic regulation in cancer. However, the contributions of RING1 to cancer etiology or development are unknown. In this study, we report that RING1 is a critical negative regulator of p53 homeostasis in human hepatocellular and colorectal carcinomas. RING1 acts as an E3 ubiquitin (Ub) ligase to directly interact with and ubiquitinate p53, resulting in its proteasome-dependent degradation. The RING domain of RING1 was required for its E3 Ub ligase activity. RING1 depletion inhibited the proliferation and survival of the p53 wild-type cancer cells by inducing cell cycle arrest, apoptosis and senescence, with only modest effects on p53-deficient cells. Its growth inhibitory effect was partially rescued by p53 silencing, suggesting an important role for the RING1-p53 complex in human cancer. In clinical specimens of hepatocellular carcinoma, RING1 upregulation was evident in association with poor clinical outcomes. Collectively, our results elucidate a novel PRC1-independent function of RING1 and provide a mechanistic rationale for its candidacy as a new prognostic marker and/or therapeutic target in human cancer.
http://ift.tt/2in0Ytz
PPAR{delta} elicits ligand-independent repression of Trefoil Factor Family to limit prostate cancer growth
The nuclear receptor PPAR-β/δ (PPARD) has essential roles in fatty acid catabolism and energy homeostasis as well as cell differentiation, inflammation and metabolism. However, its contributions to tumorigenesis are uncertain and have been disputed. Here we provide evidence of tumor suppressive activity of PPARD in prostate cancer through a non-canonical and ligand-independent pathway. PPARD was downregulated in prostate cancer specimens. In murine prostate epithelium, PPARD gene deletion resulted in increased cellularity. Genetic modulation of PPARD in human prostate cancer cell lines validated the tumor suppressive activity of this gene in vitro and in vivo. Mechanistically, PPARD exerted its activity in a DNA binding-dependent and ligand-independent manner. We identified a novel set of genes repressed by PPARD that failed to respond to ligand-mediated activation. Among these genes, we observed robust regulation of the secretory trefoil factor family (TFF) members, including a causal and correlative association of TFF1 to prostate cancer biology in vitro and in patient specimens. Overall, our results illuminate the oncosuppressive function of PPARD and understanding of the pathogenic molecular pathways elicited by this nuclear receptor.
http://ift.tt/2Anjrgt
Delivering type I interferon to dendritic cells empowers tumor eradication and immune combination treatments
An ideal generic cancer immunotherapy should mobilize the immune system to destroy tumor cells without harming healthy cells and remain active in case of recurrence. Furthermore, it should preferably not rely on tumor-specific surface markers, as these are only available in a limited set of malignancies. Despite approval for treatment of various cancers, clinical application of cytokines is still impeded by their multiple toxic side effects. Type I interferon (IFN) has a long history in the treatment of cancer, but its multifaceted activity pattern and complex side effects prevent its clinical use. Here we develop AcTakines (Activity-on-Target cytokines), optimized (mutated) immunocytokines that are up to 1000-fold more potent on target cells, allowing specific signaling in selected cell types only. Type I IFN-derived AcTaferon-targeting Clec9A+ dendritic cells (DC) displayed strong antitumor activity in murine melanoma, breast carcinoma, and lymphoma models and against human lymphoma in humanized mice without any detectable toxic side effects. Combined with immune checkpoint blockade, chemotherapy, or low-dose TNF, complete tumor regression and long-lasting tumor immunity were observed, still without adverse effects. Our findings indicate that DC-targeted AcTaferons provide a novel class of highly efficient, safe, and broad-spectrum off-the-shelf cancer immunotherapeutics with no need for a tumor marker.
http://ift.tt/2in0vrj
Disparities in Prostate, Lung, Breast, and Colorectal Cancer Survival and Comorbidity Status among Urban American Indians and Alaskan Natives
Cancer is the second leading cause of death among American Indians and Alaskan Natives (AIAN), although cancer survival information in this population is limited, particularly among urban AIAN. In this retrospective cohort study, we compared all-cause and prostate, breast, lung, and colorectal cancer–specific mortality among AIAN (n = 582) and non-Hispanic white (NHW; n = 82,696) enrollees of Kaiser Permanente Northern California (KPNC) diagnosed with primary invasive breast, prostate, lung, or colorectal cancer from 1997 to 2015. Tumor registry and other electronic health records provided information on sociodemographic, comorbidity, tumor, clinical, and treatment characteristics. Cox regression models were used to estimate adjusted survival curves and hazard ratios (HR) with 95% confidence intervals (CI). AIAN had a significantly higher comorbidity burden compared with NHW (P < 0.05). When adjusting for patient, disease characteristics, and Charlson comorbidity scores, all-cause mortality and cancer-specific mortality were significantly higher for AIAN than NHW patients with breast cancer (HR, 1.47; 95% CI, 1.13–1.92) or with prostate cancer (HR, 1.87; 95% CI, 1.14–3.06) but not for AIAN patients with lung and colorectal cancer. Despite approximately equal access to preventive services and cancer care in this setting, we found higher mortality for AIAN than NHW with some cancers, and a greater proportion of AIAN cancer patients with multiple comorbid conditions. This study provides severely needed information on the cancer experience of the 71% of AIANs who live in urban areas and access cancer care outside of the Indian Health Services, from which the vast majority of AIAN cancer information comes. Cancer Res; 77(23); 1–7. ©2017 AACR.
http://ift.tt/2AlIlwR
Re-irradiation for recurrent glioma- the NCI experience in tumor control, OAR toxicity and proposal of a novel prognostic scoring system
Despite mounting evidence for the use of re-irradiation (re-RT) in recurrent high grade glioma, optimal patient selection criteria for re-RT remain unknown. We present a novel scoring system based on radiobiol...
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Re-irradiation for recurrent glioma- the NCI experience in tumor control, OAR toxicity and proposal of a novel prognostic scoring system
Despite mounting evidence for the use of re-irradiation (re-RT) in recurrent high grade glioma, optimal patient selection criteria for re-RT remain unknown. We present a novel scoring system based on radiobiol...
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Irinotecan and Oxaliplatin Might Provide Equal Benefit as Adjuvant Chemotherapy for Patients with Resectable Synchronous Colon Cancer and Liver-confined Metastases: A Nationwide Database Study
Background: Although irinotecan and oxaliplatin are both standard treatments for advanced colon cancer, it remains unknown whether either is effective for patients with resectable synchronous colon cancer and liver-confined metastasis (SCCLM) after curative surgery. Patients and Methods: A population-based cohort of patients diagnosed with de novo SCCLM between 2004 and 2009 was established by searching the database of the Taiwan Cancer Registry and the National Health Insurance Research Database of Taiwan. Patients who underwent curative surgery as their first therapy followed by chemotherapy doublets were classified into the irinotecan group or oxaliplatin group accordingly. Patients who received radiotherapy or did not receive chemotherapy doublets were excluded. Results: We included 6,533 patients with de novo stage IV colon cancer. Three hundred and nine of them received chemotherapy doublets after surgery; 77 patients received irinotecan and 232 patients received oxaliplatin as adjuvant chemotherapy. The patients in both groups exhibited similar overall survival (median: not reached vs. 40.8 months, p=0.151) and time to the next line of treatment (median: 16.5 vs. 14.3 months, p=0.349) in both univariate and multivariate analyses. Additionally, patients with resectable SCCLM had significantly shorter median overall survival than patients with stage III colon cancer who underwent curative surgery and subsequent adjuvant chemotherapy, but longer median overall survival than patients with de novo stage IV colon cancer who underwent surgery only at the primary site followed by standard systemic chemotherapy (p<0.001). Conclusion: Irinotecan and oxaliplatin exhibited similar efficacy in patients who underwent curative surgery for resectable SCCLM.
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Robotic-assisted Transperitoneal Infrarenal Para-aortic Lymphadenectomy for Gynecological Malignancies: Comparison with a Laparoscopic Approach
Background/Aim: We evaluated the clinical feasibility and surgical outcomes of robotic-assisted transperitoneal infrarenal para-aortic lymphadenectomy (TIPAL) in patients with gynecological malignancies. Patients and Methods: The perioperative outcomes in 90 patients with gynecological malignancies who underwent laparoscopic (n=43) or robotic-assisted (n=47) TIPAL were compared retrospectively. Results: The operative time for pelvic and total lymphadenectomy were significantly shorter in the robotic-assisted approach, whereas the time for infrarenal para-aortic lymphadenectomy did not differ statistically. In contrast, the number of infrarenal para-aortic lymph nodes was significantly higher in the robotic-assisted approach. We compared the time per retrieved lymph node in both approaches, and those for pelvic, infrarenal para-aortic, and total lymphadenectomy were significantly shorter in the robotic-assisted approach. Conclusion: In our study, the robotic-assisted TIPAL took less time to retrieve a lymph node than the laparoscopic approach. The robotic-assisted approach for TIPAL is feasible for the staging and treatment of patients with gynecological malignancies.
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Anastomotic Leakage Using Linear Stapling Device with Pre-attached Bioabsorbable Polyglycolic Acid Felt After Laparoscopic Anterior Resection
Aim: Many studies have evaluated the risk factors for anastomotic leakage after laparoscopic anterior resection. In this study in order to increase the tightness of anastomoses and prevent bleeding from their staple lines, a linear stapler with pre-attached bioabsorbable polyglycolic acid (PGA) felt was used for rectal transection, and the short-term surgical outcomes were evaluated. Patients and Methods: A prospective registry of 62 patients with rectosigmoidal or rectal carcinoma who initially underwent laparoscopic anterior resection using PGA felt for rectal transection was reviewed. Results: The overall frequency of anastomotic leakage was 1.6% (1/62), and none of the patients developed postoperative staple line bleeding or other adverse events related to the use of PGA felt. Conclusion: The frequency of anastomotic leakage was relatively low, and therefore the use of a linear stapler with pre-attached bioabsorbable PGA felt might reduce the risk of adverse events related to anastomosis, especially anastomotic leakage.
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Association Between PD-L1 Expression and Metabolic Activity on 18F-FDG PET/CT in Patients with Small-sized Lung Cancer
Aim: We evaluated the metabolic characteristics of small-sized lung cancer using 18F-fluorodeoxyglucose positron-emission tomography/computed tomography (18F-FDG PET/CT) with regard to programmed cell death ligand 1 (PD-L1) expression. Materials and Methods: PD-L1 expression was evaluated by immunohistochemistry with the antibody clone SP142 in 263 patients with surgically resected primary small-sized lung cancer. Specimens with <5% tumor membrane staining were considered negative. We examined the association between the frequency of PD-L1 expression and the maximum standardized uptake value (SUVmax) in preoperative 18F-FDG PET/CT. Results: Among patients with non-small cell lung cancer (NSCLC), the SUVmax was significantly higher in those with PD-L1 expression than in those without (p<0.0001). However, there was no correlation between SUVmax and PD-L1 expression in patients with neuroendocrine tumors (p=0.9638). Multivariate analysis revealed that smoking and a high SUVmax were independent predictors of PD-L1 expression. Conclusion: PD-L1 expression was related to high glucose metabolism in small-sized NSCLC.
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A Glissonean Approach with Individual Isolation During Right Hemi-Hepatectomy After Portal Vein Embolization
Background/Aim: Although the Glissonean approach in hemi-hepatectomy is a very useful technique, right hemi-hepatectomy with Glissonean approach after portal vein embolization (PVE) is difficult because of the obstructing materials located at the right portal branch. The aim of this study was to evaluate the utility of the Glissonean approach with an individual isolation technique (GI technique) in right hemi-hepatectomies after PVE. Patients and Methods: We retrospectively analyzed 21 patients who underwent the GI technique between March 2007 and June 2012. Results: In one of the 21 patients, we could not perform the GI technique because of severe adhesions following previous operation; however, there were no troubles in the remaining 20 cases. In addition, none of the patients that were treated using this method developed massive ascites after right hemi-hepatectomy, despite 8 patients (40%) exhibiting severe fibrosis (F3 or F4). Conclusion: Even in right hemi-hepatectomy following PVE, our GI technique may be a useful procedures for patients.
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Mucinous Cystic Neoplasms Lined by Abundant Mucinous Epithelium Frequently Involve KRAS Mutations and Malignant Progression
Background: Pancreatic and hepatic mucinous cyst neoplasms (MCNs) have a malignant potential, but indolent MCNs are not uncommon. Materials and Methods: The pathological and genetic characteristics of resected MCNs (n=15) categorized by the amount of mucin of the lining epithelium were investigated. Results: MCNs were divided into two groups: (i) a rich (r)-MCN group (n=6), in which more than half of the epithelium was lined by abundant mucinous epithelium; and (ii) a poor (p)-MCN group (n=9), which consisted of the remaining cases. Three patients in the r-MCN group showed invasive carcinoma or high-grade dysplasia, whereas all patients in the p-MCN group showed low-grade dysplasia. Mutations of Kirsten rat sarcoma viral oncogene homolog (KRAS) were more frequent in the r-MCN group (83%) (p-MCN; 11%, p<0.05). Conclusion: Mucinous MCNs more frequently have KRAS mutations and higher risk of malignant progression.
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Outcome Evaluation of HER2 Breast Cancer Patients with Limited Brain Metastasis
Background/Aim: To appraise the outcome of limited brain metastasis (BMs) from HER2 breast cancer. Patients and Methods: The study cohort included sixty-six patients Treatments consisted of surgery followed by radiotherapy (RT), or radiosurgery (SRS/HSRS) or whole brain radiotherapy (WBRT). Results: Surgery followed by RT was performed in 25.8% of patients, SRS/HSRS alone in 48.5%, and WBRT alone in 25.7%. The median follow-up time was 23.4 months and 32.5 months for alive patients. Local recurrence occurred in 16 (24.2%) patients. The median, 1-, 2-, 3-year local control were (median not reached=nr), 87.5%, 71.2%, and 63.0%. The median 1-, 2-, 3-year overall survival were 30.7 months (95%CI: 18.9-42.6 months), 78.5%, 57.4%, 43.3%. Karnofsky Performance Scale (KPS), number of BMs, local treatment performed, the presence of extracranial (EC) metastases at the time of BMs diagnosis, and the administration of trastuzumab affected survival. Conclusion: HER2BC patients with good performance status, controlled EC disease and single BM had better outcome. In this long-term survivor patients, local BMs treatment can affect survival.
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Characterization of Prognostic Factors and the Efficacy of Adjuvant S-1 Chemotherapy in Patients with Post-surgery Extrahepatic Bile Duct Cancer
Background/Aim: There is no clear consensus on the type of adjuvant therapy that should be used for patients with extrahepatic bile duct cancer. Patients and Methods: Two hundred and seventy-one patients that had undergone surgical resection for extrahepatic bile duct cancer composed the study cohort. Demographics, treatments, and relationships between the potential prognostic factors and survival rates were analyzed. Results: The overall 3-year and 5-year survival rates for post-surgery extrahepatic bile duct cancer patients were 49.0% and 35.4%, respectively. Multivariate analysis revealed that regional lymph node metastasis was an independent negative prognostic factor. We observed a significant correlation between node-positive extrahepatic bile duct cancer and postoperative local recurrence, liver metastasis, peritoneal dissemination, and post-surgery lymph node metastasis. Adjuvant S-1 chemotherapy showed a favorable hazard ratio in patients with lymph node metastases or positive vascular invasion. Conclusion: We recommend the use of adjuvant S-1 therapy in patients with lymph node metastases or microvascular invasion.
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BRAF, NRAS and C-KIT Advanced Melanoma: Clinico-pathological Features, Targeted-Therapy Strategies and Survival
Background/Aim: The mutational status of stage III and IV melanomas should be recognized in order to allow for targeted therapies. The aim of our study was the characterization of BRAF, NRAS and C-KIT melanoma patients, in order to define their optimal management. Patients and Methods: Between 1991 and 2015, 63 mutated melanoma patients were treated and monitored during their diagnostic and therapeutic management at a single institution. Results: BRAF-mutated melanoma patients were the most common, representing 70% of the study population, while NRAS- and C-KIT-mutated melanoma represented 19% and 11% respectively. BRAF-mutated melanomas were mostly located at sites of intermittent sun exposure, and were associated with higher Breslow thickness and an increased number of mitosis. NRAS mutated melanoma were mainly observed in chronic sun-damaged areas and had a negative prognostic value, with shorter time to progression and a high incidence of central nervous system involvement. C-KIT mutated melanoma were located at acral and mucosal sites. Overall survival observed in the three groups of patients revealed wide differences. Conclusion: BRAF, NRAS and C-KIT melanomas constitute distinct clinico-pathological entities. BRAF-mutated melanoma benefit from both anti-BRAF and anti-MEK targeted therapies while triple-negative melanomas could benefit from novel anti-CTLA-4 and anti-PD-L1 immunotherapeutic approaches.
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FOLFOX as First-line Therapy for Gastric Cancer with Severe Peritoneal Metastasis
Background/Aim: Severe peritoneal metastasis (PM) from advanced gastric cancer (AGC) causes massive ascites and inadequate oral intake. Because patients with severe PM are often not included in clinical trials, little is known regarding the efficacy and safety of oxaliplatin with l-leucovorin and bolus/continuous infusion of 5-fluorouracil (FOLFOX) for them. Patients and Methods: We retrospectively studied AGC patients with massive ascites and/or inadequate oral intake due to severe PM treated with FOLFOX as the first-line treatment. Results: Only 39 (10%) of 378 AGC patients had severe PM; 10 received FOLFOX. The median progression-free and overall survivals were 7.5 and 13.2 months, respectively. Ascites decreased in seven of nine patients with ascites, and oral intake improved in four of seven patients with an inadequate oral intake. Common grade 3-4 adverse events included neutropenia and anemia. Conclusion: This study suggests that FOLFOX is effective and manageable for AGC patients with severe PM.
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Incidence and Risk Factors of Symptomatic Hiatal Hernia Following Resection for Gastric and Esophageal Cancer
Background/Aim: Symptomatic hiatal hernia (HH) following resection for gastric or esophageal cancer is a potentially life-threatening event that may lead to emergent surgery. However, the incidence and risk factors of this complication remain unclear. Patients and Methods: Data of patients who underwent resection for gastric or esophageal cancer between 2005 and 2012 were assessed and the incidence of symptomatic HH was evaluated. Factors associated with an increased risk for HH were investigated. Results: Resection of gastric or esophageal cancer was performed in 471 patients. The primary tumor was located in the stomach, cardia and esophagus in 36%, 24%, and 40% of patients, respectively. The incidence of symptomatic HH was 2.8% (n=13). All patients underwent surgical hernia repair, 8 patients (61.5%) required emergent procedure, and 3 patients (23%) underwent bowel resection. Morbidity and mortality after HH repair was 38% and 8%, respectively. Factors associated with increased risk for symptomatic HH included Body-Mass-Index (median BMI with HH 27 (23-35) vs. BMI without HH 25 (15-51), p=0.043), diabetes (HH rate: with diabetes, 6.3% vs. without diabetes, 2%, p=0.034), tumor location (HH rate: stomach, 1.2% vs. esophagus, 1.1% vs. cardia, 7.9%, p=0.001), and resection type (HH rate: total/subtotal gastrectomy, 0.7% vs. transthoracic esophagectomy, 2.7% vs. extended gastrectomy, 6.1%, p=0.038). Conclusion: HH is a major adverse event after resection for gastric or esophageal cancer especially among patients undergoing extended gastrectomy for cardia cancer requiring a high rate of repeat surgery. Therefore, intensive follow-up examinations for high-risk patients and early diagnosis of asymptomatic patients are essential for selecting patients for elective surgery to avoid unpredictable emergent events with high morbidity and mortality.
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A Prospective Study of Intensity-modified Radiation Therapy in Comparison with Conventional 3D-RT for BR Pancreatic Cancer Patients with Arterial Involvement
Background/Aim: Intensity-modulated radiation therapy (IMRT) is a form of radiation therapy that allows accurate irradiation with reduced damage to surrounding tissues. Here, we analyzed borderline-resectable pancreatic cancer (BRPC) with arterial abutment (BR-A) patients with IMRT as neoadjuvant therapy and performed comparisons with patients with conventional RT to clarify the advantages of IMRT as a neoadjuvant therapy. Patients and Methods: Thirty BR-A patients treated at our hospital between January 2012 and December 2015 were divided into two groups: 12 patients underwent conventional 3D-RT before resection (RT group); and 18 patients underwent IMRT before resection (IMRT group). We analyzed safety, tumor resection rate, histological classification of the tumor and overall survival. Results: The R0 rate was 84% for the IMRT group and 83% for the RT group. Local therapeutic effects as assessed by Evans classification showed a higher local control rate in the IMRT group (Grade: 1, 0%; 2a, 25%; 2b, 41.6%; 3, 17%; 4, 8%) than in the RT group (Grade: 1, 17%; 2a, 50%; 2b, 17%; 3, 17%; 4, 0%). The cumulative dose of S1 treatment as adjuvant therapy was much smaller in the RT group (18.3%) compared to that in the IMRT group (57.1%, p=0.047), and with better subsequent overall survival rate (MST 32 months vs. 13.8 months, p=0.0273). Conclusion: The IMRT group showed a better control rate than the RT group. The neoadjuvant IMRT has advantages of higher completion rate of adjuvant chemotherapy with better nutritional status and better subsequent overall survival rate (OS).
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Pancreatic Mucinous Cystic Neoplasm Communicating with Main Pancreatic Duct: An Unrecognized Presentation of Pancreatic Mucinous Neoplasm?
Mucinous cystic neoplasms (MCNs) and intraductal papillary mucinous neoplasms (IPMNs) are two well recognized entities of precursor cystic lesions of pancreatic duct adenocarcinoma. The characteristic features of MCNs are the lined mucinous epithelium with underlying ovarian-type stroma, but without communication with the ducts, while that for IPMNs are the communication with the ducts but without the underlying ovarian-type stroma. Here we report a case of MCN communicating with the main pancreatic duct in a 68-year-old woman. The initial radiographic diagnosis was pancreatic IPMN with main pancreatic involvement and this was also confirmed during gross examination. Histologically, the pancreatic cystic neoplasm was lined with mucinous epithelium with underlying ovarian-type of stroma. Immunohistochemical stains confirmed that the stroma cells were positive for ER, PR, alpha-inhibin and focally positive for CD10. The final pathologic diagnosis was pancreatic mucinous cystic neoplasm communicating with the main pancreatic duct. To the best of our knowledge, this is the second pathology confirmed case of MCN communicating with the main pancreatic duct. A careful gross examination and bivalvation of the main duct communicating with the cystic neoplasm helps render the correct diagnosis. If more cases are reported in the future, the MCN communicating with duct could become a new entity of pancreatic mucinous neoplasm.
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Predictive Factors and a Survival Score for Patients Irradiated for Metastatic Spinal Cord Compression from Carcinoma of the Salivary Glands
Aim: To our knowledge, this is the first study focusing on metastatic spinal cord compression (MSCC) from carcinoma of the salivary glands. Patients and Methods: Nine patients receiving radiation alone were evaluated for improvement of motor deficits, post-radiation gait function and survival. Results: Of nine characteristics (radiation program, age, sex, additional metastases to bone or to other organs, dynamic of motor deficits, pre-radiation gait function, number of vertebrae affected by MSCC, general condition), strong trends were found for associations between improved motor deficits and their dynamic (p=0.05), post-radiation gait function and pre-treatment ambulatory status (p=0.08) and between survival and additional metastases to other organs (p=0.07), dynamic of motor deficits (p=0.07) and general condition (p=0.07). In addition, a survival score was created. Patients with 2-3 points had a significantly better 6-month survival than those with 0-1 points (100% vs. 0%, p=0.027). Conclusion: Characteristics predicting outcomes identified in this study and the new survival score can guide physicians when making treatment decisions.
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Stereotactic Body Radiation Therapy in Primary and Metastatic Liver Disease
Background/Aim: The aim of this study was to investigate the treatment outcomes and toxicities in patients with liver disease treated by Stereotactic Body Radiation Therapy (SBRT). Patients and Methods: From 2007 to 2016, 43 patients with 58 lesions (6 primary and 37 metastatic liver tumors) were treated with SBRT. Results: Local Control was reached in 47 out of 58 (81%) treated lesions with 12 and 24-month rates of 81% and 74% respectively. The progression-free survival at 12 and 24 months was 42% and 36%, respectively. The disease specific survival at 12 and 24 months was 74% and 46% respectively. Median overall survival (OS) was 20 months and the rates of OS were 74% and 46% at 12 and 24 months respectively. Toxicity was very low consisting mainly of Grade 1 and 2. Conclusion: SBRT provides good local control for both primary and metastatic liver lesions, with minimal toxicity.
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Irinotecan and Oxaliplatin Might Provide Equal Benefit as Adjuvant Chemotherapy for Patients with Resectable Synchronous Colon Cancer and Liver-confined Metastases: A Nationwide Database Study
Background: Although irinotecan and oxaliplatin are both standard treatments for advanced colon cancer, it remains unknown whether either is effective for patients with resectable synchronous colon cancer and liver-confined metastasis (SCCLM) after curative surgery. Patients and Methods: A population-based cohort of patients diagnosed with de novo SCCLM between 2004 and 2009 was established by searching the database of the Taiwan Cancer Registry and the National Health Insurance Research Database of Taiwan. Patients who underwent curative surgery as their first therapy followed by chemotherapy doublets were classified into the irinotecan group or oxaliplatin group accordingly. Patients who received radiotherapy or did not receive chemotherapy doublets were excluded. Results: We included 6,533 patients with de novo stage IV colon cancer. Three hundred and nine of them received chemotherapy doublets after surgery; 77 patients received irinotecan and 232 patients received oxaliplatin as adjuvant chemotherapy. The patients in both groups exhibited similar overall survival (median: not reached vs. 40.8 months, p=0.151) and time to the next line of treatment (median: 16.5 vs. 14.3 months, p=0.349) in both univariate and multivariate analyses. Additionally, patients with resectable SCCLM had significantly shorter median overall survival than patients with stage III colon cancer who underwent curative surgery and subsequent adjuvant chemotherapy, but longer median overall survival than patients with de novo stage IV colon cancer who underwent surgery only at the primary site followed by standard systemic chemotherapy (p<0.001). Conclusion: Irinotecan and oxaliplatin exhibited similar efficacy in patients who underwent curative surgery for resectable SCCLM.
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Robotic-assisted Transperitoneal Infrarenal Para-aortic Lymphadenectomy for Gynecological Malignancies: Comparison with a Laparoscopic Approach
Background/Aim: We evaluated the clinical feasibility and surgical outcomes of robotic-assisted transperitoneal infrarenal para-aortic lymphadenectomy (TIPAL) in patients with gynecological malignancies. Patients and Methods: The perioperative outcomes in 90 patients with gynecological malignancies who underwent laparoscopic (n=43) or robotic-assisted (n=47) TIPAL were compared retrospectively. Results: The operative time for pelvic and total lymphadenectomy were significantly shorter in the robotic-assisted approach, whereas the time for infrarenal para-aortic lymphadenectomy did not differ statistically. In contrast, the number of infrarenal para-aortic lymph nodes was significantly higher in the robotic-assisted approach. We compared the time per retrieved lymph node in both approaches, and those for pelvic, infrarenal para-aortic, and total lymphadenectomy were significantly shorter in the robotic-assisted approach. Conclusion: In our study, the robotic-assisted TIPAL took less time to retrieve a lymph node than the laparoscopic approach. The robotic-assisted approach for TIPAL is feasible for the staging and treatment of patients with gynecological malignancies.
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Anastomotic Leakage Using Linear Stapling Device with Pre-attached Bioabsorbable Polyglycolic Acid Felt After Laparoscopic Anterior Resection
Aim: Many studies have evaluated the risk factors for anastomotic leakage after laparoscopic anterior resection. In this study in order to increase the tightness of anastomoses and prevent bleeding from their staple lines, a linear stapler with pre-attached bioabsorbable polyglycolic acid (PGA) felt was used for rectal transection, and the short-term surgical outcomes were evaluated. Patients and Methods: A prospective registry of 62 patients with rectosigmoidal or rectal carcinoma who initially underwent laparoscopic anterior resection using PGA felt for rectal transection was reviewed. Results: The overall frequency of anastomotic leakage was 1.6% (1/62), and none of the patients developed postoperative staple line bleeding or other adverse events related to the use of PGA felt. Conclusion: The frequency of anastomotic leakage was relatively low, and therefore the use of a linear stapler with pre-attached bioabsorbable PGA felt might reduce the risk of adverse events related to anastomosis, especially anastomotic leakage.
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Association Between PD-L1 Expression and Metabolic Activity on 18F-FDG PET/CT in Patients with Small-sized Lung Cancer
Aim: We evaluated the metabolic characteristics of small-sized lung cancer using 18F-fluorodeoxyglucose positron-emission tomography/computed tomography (18F-FDG PET/CT) with regard to programmed cell death ligand 1 (PD-L1) expression. Materials and Methods: PD-L1 expression was evaluated by immunohistochemistry with the antibody clone SP142 in 263 patients with surgically resected primary small-sized lung cancer. Specimens with <5% tumor membrane staining were considered negative. We examined the association between the frequency of PD-L1 expression and the maximum standardized uptake value (SUVmax) in preoperative 18F-FDG PET/CT. Results: Among patients with non-small cell lung cancer (NSCLC), the SUVmax was significantly higher in those with PD-L1 expression than in those without (p<0.0001). However, there was no correlation between SUVmax and PD-L1 expression in patients with neuroendocrine tumors (p=0.9638). Multivariate analysis revealed that smoking and a high SUVmax were independent predictors of PD-L1 expression. Conclusion: PD-L1 expression was related to high glucose metabolism in small-sized NSCLC.
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A Glissonean Approach with Individual Isolation During Right Hemi-Hepatectomy After Portal Vein Embolization
Background/Aim: Although the Glissonean approach in hemi-hepatectomy is a very useful technique, right hemi-hepatectomy with Glissonean approach after portal vein embolization (PVE) is difficult because of the obstructing materials located at the right portal branch. The aim of this study was to evaluate the utility of the Glissonean approach with an individual isolation technique (GI technique) in right hemi-hepatectomies after PVE. Patients and Methods: We retrospectively analyzed 21 patients who underwent the GI technique between March 2007 and June 2012. Results: In one of the 21 patients, we could not perform the GI technique because of severe adhesions following previous operation; however, there were no troubles in the remaining 20 cases. In addition, none of the patients that were treated using this method developed massive ascites after right hemi-hepatectomy, despite 8 patients (40%) exhibiting severe fibrosis (F3 or F4). Conclusion: Even in right hemi-hepatectomy following PVE, our GI technique may be a useful procedures for patients.
http://ift.tt/2kahCNA
Mucinous Cystic Neoplasms Lined by Abundant Mucinous Epithelium Frequently Involve KRAS Mutations and Malignant Progression
Background: Pancreatic and hepatic mucinous cyst neoplasms (MCNs) have a malignant potential, but indolent MCNs are not uncommon. Materials and Methods: The pathological and genetic characteristics of resected MCNs (n=15) categorized by the amount of mucin of the lining epithelium were investigated. Results: MCNs were divided into two groups: (i) a rich (r)-MCN group (n=6), in which more than half of the epithelium was lined by abundant mucinous epithelium; and (ii) a poor (p)-MCN group (n=9), which consisted of the remaining cases. Three patients in the r-MCN group showed invasive carcinoma or high-grade dysplasia, whereas all patients in the p-MCN group showed low-grade dysplasia. Mutations of Kirsten rat sarcoma viral oncogene homolog (KRAS) were more frequent in the r-MCN group (83%) (p-MCN; 11%, p<0.05). Conclusion: Mucinous MCNs more frequently have KRAS mutations and higher risk of malignant progression.
http://ift.tt/2By0HJ0
Outcome Evaluation of HER2 Breast Cancer Patients with Limited Brain Metastasis
Background/Aim: To appraise the outcome of limited brain metastasis (BMs) from HER2 breast cancer. Patients and Methods: The study cohort included sixty-six patients Treatments consisted of surgery followed by radiotherapy (RT), or radiosurgery (SRS/HSRS) or whole brain radiotherapy (WBRT). Results: Surgery followed by RT was performed in 25.8% of patients, SRS/HSRS alone in 48.5%, and WBRT alone in 25.7%. The median follow-up time was 23.4 months and 32.5 months for alive patients. Local recurrence occurred in 16 (24.2%) patients. The median, 1-, 2-, 3-year local control were (median not reached=nr), 87.5%, 71.2%, and 63.0%. The median 1-, 2-, 3-year overall survival were 30.7 months (95%CI: 18.9-42.6 months), 78.5%, 57.4%, 43.3%. Karnofsky Performance Scale (KPS), number of BMs, local treatment performed, the presence of extracranial (EC) metastases at the time of BMs diagnosis, and the administration of trastuzumab affected survival. Conclusion: HER2BC patients with good performance status, controlled EC disease and single BM had better outcome. In this long-term survivor patients, local BMs treatment can affect survival.
http://ift.tt/2kaPWYI
Characterization of Prognostic Factors and the Efficacy of Adjuvant S-1 Chemotherapy in Patients with Post-surgery Extrahepatic Bile Duct Cancer
Background/Aim: There is no clear consensus on the type of adjuvant therapy that should be used for patients with extrahepatic bile duct cancer. Patients and Methods: Two hundred and seventy-one patients that had undergone surgical resection for extrahepatic bile duct cancer composed the study cohort. Demographics, treatments, and relationships between the potential prognostic factors and survival rates were analyzed. Results: The overall 3-year and 5-year survival rates for post-surgery extrahepatic bile duct cancer patients were 49.0% and 35.4%, respectively. Multivariate analysis revealed that regional lymph node metastasis was an independent negative prognostic factor. We observed a significant correlation between node-positive extrahepatic bile duct cancer and postoperative local recurrence, liver metastasis, peritoneal dissemination, and post-surgery lymph node metastasis. Adjuvant S-1 chemotherapy showed a favorable hazard ratio in patients with lymph node metastases or positive vascular invasion. Conclusion: We recommend the use of adjuvant S-1 therapy in patients with lymph node metastases or microvascular invasion.
http://ift.tt/2BxEOtd
BRAF, NRAS and C-KIT Advanced Melanoma: Clinico-pathological Features, Targeted-Therapy Strategies and Survival
Background/Aim: The mutational status of stage III and IV melanomas should be recognized in order to allow for targeted therapies. The aim of our study was the characterization of BRAF, NRAS and C-KIT melanoma patients, in order to define their optimal management. Patients and Methods: Between 1991 and 2015, 63 mutated melanoma patients were treated and monitored during their diagnostic and therapeutic management at a single institution. Results: BRAF-mutated melanoma patients were the most common, representing 70% of the study population, while NRAS- and C-KIT-mutated melanoma represented 19% and 11% respectively. BRAF-mutated melanomas were mostly located at sites of intermittent sun exposure, and were associated with higher Breslow thickness and an increased number of mitosis. NRAS mutated melanoma were mainly observed in chronic sun-damaged areas and had a negative prognostic value, with shorter time to progression and a high incidence of central nervous system involvement. C-KIT mutated melanoma were located at acral and mucosal sites. Overall survival observed in the three groups of patients revealed wide differences. Conclusion: BRAF, NRAS and C-KIT melanomas constitute distinct clinico-pathological entities. BRAF-mutated melanoma benefit from both anti-BRAF and anti-MEK targeted therapies while triple-negative melanomas could benefit from novel anti-CTLA-4 and anti-PD-L1 immunotherapeutic approaches.
http://ift.tt/2k8A7BY
FOLFOX as First-line Therapy for Gastric Cancer with Severe Peritoneal Metastasis
Background/Aim: Severe peritoneal metastasis (PM) from advanced gastric cancer (AGC) causes massive ascites and inadequate oral intake. Because patients with severe PM are often not included in clinical trials, little is known regarding the efficacy and safety of oxaliplatin with l-leucovorin and bolus/continuous infusion of 5-fluorouracil (FOLFOX) for them. Patients and Methods: We retrospectively studied AGC patients with massive ascites and/or inadequate oral intake due to severe PM treated with FOLFOX as the first-line treatment. Results: Only 39 (10%) of 378 AGC patients had severe PM; 10 received FOLFOX. The median progression-free and overall survivals were 7.5 and 13.2 months, respectively. Ascites decreased in seven of nine patients with ascites, and oral intake improved in four of seven patients with an inadequate oral intake. Common grade 3-4 adverse events included neutropenia and anemia. Conclusion: This study suggests that FOLFOX is effective and manageable for AGC patients with severe PM.
http://ift.tt/2By0BB8
Incidence and Risk Factors of Symptomatic Hiatal Hernia Following Resection for Gastric and Esophageal Cancer
Background/Aim: Symptomatic hiatal hernia (HH) following resection for gastric or esophageal cancer is a potentially life-threatening event that may lead to emergent surgery. However, the incidence and risk factors of this complication remain unclear. Patients and Methods: Data of patients who underwent resection for gastric or esophageal cancer between 2005 and 2012 were assessed and the incidence of symptomatic HH was evaluated. Factors associated with an increased risk for HH were investigated. Results: Resection of gastric or esophageal cancer was performed in 471 patients. The primary tumor was located in the stomach, cardia and esophagus in 36%, 24%, and 40% of patients, respectively. The incidence of symptomatic HH was 2.8% (n=13). All patients underwent surgical hernia repair, 8 patients (61.5%) required emergent procedure, and 3 patients (23%) underwent bowel resection. Morbidity and mortality after HH repair was 38% and 8%, respectively. Factors associated with increased risk for symptomatic HH included Body-Mass-Index (median BMI with HH 27 (23-35) vs. BMI without HH 25 (15-51), p=0.043), diabetes (HH rate: with diabetes, 6.3% vs. without diabetes, 2%, p=0.034), tumor location (HH rate: stomach, 1.2% vs. esophagus, 1.1% vs. cardia, 7.9%, p=0.001), and resection type (HH rate: total/subtotal gastrectomy, 0.7% vs. transthoracic esophagectomy, 2.7% vs. extended gastrectomy, 6.1%, p=0.038). Conclusion: HH is a major adverse event after resection for gastric or esophageal cancer especially among patients undergoing extended gastrectomy for cardia cancer requiring a high rate of repeat surgery. Therefore, intensive follow-up examinations for high-risk patients and early diagnosis of asymptomatic patients are essential for selecting patients for elective surgery to avoid unpredictable emergent events with high morbidity and mortality.
http://ift.tt/2k8A5tQ
A Prospective Study of Intensity-modified Radiation Therapy in Comparison with Conventional 3D-RT for BR Pancreatic Cancer Patients with Arterial Involvement
Background/Aim: Intensity-modulated radiation therapy (IMRT) is a form of radiation therapy that allows accurate irradiation with reduced damage to surrounding tissues. Here, we analyzed borderline-resectable pancreatic cancer (BRPC) with arterial abutment (BR-A) patients with IMRT as neoadjuvant therapy and performed comparisons with patients with conventional RT to clarify the advantages of IMRT as a neoadjuvant therapy. Patients and Methods: Thirty BR-A patients treated at our hospital between January 2012 and December 2015 were divided into two groups: 12 patients underwent conventional 3D-RT before resection (RT group); and 18 patients underwent IMRT before resection (IMRT group). We analyzed safety, tumor resection rate, histological classification of the tumor and overall survival. Results: The R0 rate was 84% for the IMRT group and 83% for the RT group. Local therapeutic effects as assessed by Evans classification showed a higher local control rate in the IMRT group (Grade: 1, 0%; 2a, 25%; 2b, 41.6%; 3, 17%; 4, 8%) than in the RT group (Grade: 1, 17%; 2a, 50%; 2b, 17%; 3, 17%; 4, 0%). The cumulative dose of S1 treatment as adjuvant therapy was much smaller in the RT group (18.3%) compared to that in the IMRT group (57.1%, p=0.047), and with better subsequent overall survival rate (MST 32 months vs. 13.8 months, p=0.0273). Conclusion: The IMRT group showed a better control rate than the RT group. The neoadjuvant IMRT has advantages of higher completion rate of adjuvant chemotherapy with better nutritional status and better subsequent overall survival rate (OS).
http://ift.tt/2BydmLI
Pancreatic Mucinous Cystic Neoplasm Communicating with Main Pancreatic Duct: An Unrecognized Presentation of Pancreatic Mucinous Neoplasm?
Mucinous cystic neoplasms (MCNs) and intraductal papillary mucinous neoplasms (IPMNs) are two well recognized entities of precursor cystic lesions of pancreatic duct adenocarcinoma. The characteristic features of MCNs are the lined mucinous epithelium with underlying ovarian-type stroma, but without communication with the ducts, while that for IPMNs are the communication with the ducts but without the underlying ovarian-type stroma. Here we report a case of MCN communicating with the main pancreatic duct in a 68-year-old woman. The initial radiographic diagnosis was pancreatic IPMN with main pancreatic involvement and this was also confirmed during gross examination. Histologically, the pancreatic cystic neoplasm was lined with mucinous epithelium with underlying ovarian-type of stroma. Immunohistochemical stains confirmed that the stroma cells were positive for ER, PR, alpha-inhibin and focally positive for CD10. The final pathologic diagnosis was pancreatic mucinous cystic neoplasm communicating with the main pancreatic duct. To the best of our knowledge, this is the second pathology confirmed case of MCN communicating with the main pancreatic duct. A careful gross examination and bivalvation of the main duct communicating with the cystic neoplasm helps render the correct diagnosis. If more cases are reported in the future, the MCN communicating with duct could become a new entity of pancreatic mucinous neoplasm.
http://ift.tt/2k8A35c
Predictive Factors and a Survival Score for Patients Irradiated for Metastatic Spinal Cord Compression from Carcinoma of the Salivary Glands
Aim: To our knowledge, this is the first study focusing on metastatic spinal cord compression (MSCC) from carcinoma of the salivary glands. Patients and Methods: Nine patients receiving radiation alone were evaluated for improvement of motor deficits, post-radiation gait function and survival. Results: Of nine characteristics (radiation program, age, sex, additional metastases to bone or to other organs, dynamic of motor deficits, pre-radiation gait function, number of vertebrae affected by MSCC, general condition), strong trends were found for associations between improved motor deficits and their dynamic (p=0.05), post-radiation gait function and pre-treatment ambulatory status (p=0.08) and between survival and additional metastases to other organs (p=0.07), dynamic of motor deficits (p=0.07) and general condition (p=0.07). In addition, a survival score was created. Patients with 2-3 points had a significantly better 6-month survival than those with 0-1 points (100% vs. 0%, p=0.027). Conclusion: Characteristics predicting outcomes identified in this study and the new survival score can guide physicians when making treatment decisions.
http://ift.tt/2BAlvPV
Stereotactic Body Radiation Therapy in Primary and Metastatic Liver Disease
Background/Aim: The aim of this study was to investigate the treatment outcomes and toxicities in patients with liver disease treated by Stereotactic Body Radiation Therapy (SBRT). Patients and Methods: From 2007 to 2016, 43 patients with 58 lesions (6 primary and 37 metastatic liver tumors) were treated with SBRT. Results: Local Control was reached in 47 out of 58 (81%) treated lesions with 12 and 24-month rates of 81% and 74% respectively. The progression-free survival at 12 and 24 months was 42% and 36%, respectively. The disease specific survival at 12 and 24 months was 74% and 46% respectively. Median overall survival (OS) was 20 months and the rates of OS were 74% and 46% at 12 and 24 months respectively. Toxicity was very low consisting mainly of Grade 1 and 2. Conclusion: SBRT provides good local control for both primary and metastatic liver lesions, with minimal toxicity.
http://ift.tt/2ke1UkB
[Corrections] Correction to Lancet Oncol 2017; 18: 1061–75
Perl AE, Altman JK, Cortes J, et al. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1–2 study. Lancet Oncol 2017; 18: 1061–75—In table S9 in the supplementary appendix of this Article, the composite remission in patients with ITD and D835 mutations should have been 7 (54%). The appendix has been corrected as of Nov 29, 2017.
http://ift.tt/2kacAka
[Comment] Checkpoint inhibitors and aspergillosis in AML: the double hit hypothesis
Despite improvements in outcomes, mortality due to invasive aspergillosis remains high in patients with acute myeloid leukaemia (AML). The poorer survival of patients with invasive aspergillosis and AML is partly due to the suboptimal diagnostic tools available and the relative ineffectiveness of existing antifungal drugs in the setting of ongoing immunosuppression. Because no new antifungals have been commercialised since 2001, the need to develop novel strategies to enhance immune function and synergise with existing antifungal drugs is pressing.
http://ift.tt/2Bw0oy6
[Policy Review] Defining a global research and policy agenda for betel quid and areca nut
Betel quid and areca nut are known risk factors for many oral and oesophageal cancers, and their use is highly prevalent in the Asia-Pacific region. Additionally, betel quid and areca nut are associated with health effects on the cardiovascular, nervous, gastrointestinal, metabolic, respiratory, and reproductive systems. Unlike tobacco, for which the WHO Framework Convention on Tobacco Control provides evidence-based policies for reducing tobacco use, no global policy exists for the control of betel quid and areca nut use.
http://ift.tt/2AkHCtw
[Clinical Picture] A polymorphous bullous dermatosis
A 50-year-old woman with an advanced high-grade serous ovarian cancer was admitted to the oncology department at Gustave Roussy Institute (Villejuif, France) in October 2016 because of large and painful supraclavicular erosions. Initially diagnosed as radiodermatitis, the erosions appeared 4 weeks after a localised palliative radiotherapy on a supraclavicular metastatic lymphadenopathy. Subsequently, erosions of the oral mucosa and widespread cutaneous lesions occurred in November, 2016. The patient was referred by her oncologist to our dermatology department at Henri Mondor Hospital (Créteil, France).
http://ift.tt/2AhaR2n
[Corrections] Correction to Lancet Oncol 2017; 18: 1493–1501
Tawbi HA, Burgess M, Bolejack V, et al. Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. Lancet Oncol 2017; 18: 1493–1501—In this Article (published online on Oct 4, 2017), the Interpretation in the Summary should have read "The primary endpoint of overall response was not met for either cohort. However, pembrolizumab showed encouraging a ctivity in patients with undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma.
http://ift.tt/2AlAr4o
[Review] De-novo and acquired resistance to immune checkpoint targeting
Use of immune checkpoint inhibitors targeting the programmed cell death protein-1/programmed cell death-ligand 1 and cytotoxic T lymphocyte-associated protein-4 axes has yielded impressive results in some clinical trials. However, only a subset of patients initially respond to these inhibitors, and increasing clinical evidence indicates that a substantial proportion of initial responders ultimately relapse with lethal, drug-resistant disease months or years later. Studies that have used massively parallel sequencing have shed light on the rich functional landscape of mutations that endow tumour cells with the ability to evade T-cell-mediated immunosurveillance.
http://ift.tt/2Agj4Uu
[Policy Review] European position statement on lung cancer screening
Lung cancer screening with low-dose CT can save lives. This European Union (EU) position statement presents the available evidence and the major issues that need to be addressed to ensure the successful implementation of low-dose CT lung cancer screening in Europe. This statement identified specific actions required by the European lung cancer screening community to adopt before the implementation of low-dose CT lung cancer screening. This position statement recommends the following actions: a risk stratification approach should be used for future lung cancer low-dose CT programmes; that individuals who enter screening programmes should be provided with information on the benefits and harms of screening, and smoking cessation should be offered to all current smokers; that management of detected solid nodules should use semi-automatically measured volume and volume-doubling time; that national quality assurance boards should be set up to oversee technical standards; that a lung nodule management pathway should be established and incorporated into clinical practice with a tailored screening approach; that non-calcified baseline lung nodules greater than 300 mm3, and new lung nodules greater than 200 mm3, should be managed in multidisciplinary teams according to this EU position statement recommendations to ensure that patients receive the most appropriate treatment; and planning for implementation of low-dose CT screening should start throughout Europe as soon as possible.
http://ift.tt/2BwU35J
[Corrections] Correction to Lancet Oncol 2016; 17: 1637–38
Guyton KZ, Loomis D, Grosse Y, et al, on behalf of the International Agency for Research on Cancer Monograph Working Group. Carcinogenicity of pentachlorophenol and some related compounds. Lancet Oncol 2016; 17: 1637–38—In this News piece (IARC monograph 117), one of the contributors has a potential conflict of interest that should have been declared. Warren Foster (a member of the Monograph Working Group) has previously contributed to the literature on endocrine disruption, for which he was compensated by Exponent through funds provided by the American Chemistry Council.
http://ift.tt/2k9C7Kj
[Review] Radiotherapy in the setting of breast reconstruction: types, techniques, and timing
As the use of breast reconstruction and postmastectomy radiotherapy (PMRT) has increased over the past decade, the typical approach to integrating radiotherapy with breast reconstruction has provoked intense controversy in the management of breast cancer. PMRT can lead to an increased frequency of complications in the reconstructed breast. Conversely, the reconstructed breast can increase the complexity of radiotherapy delivery. How to minimise the frequency of complications without compromising oncological or cosmetic outcomes of the reconstructed breast is an important shared multidisciplinary goal for oncologists and their patients.
http://ift.tt/2ByiX51
[Correspondence] Go, no-go decision making for phase 3 clinical trials: ACT IV revisited
We read with great interest the Article by Michael Weller and colleagues1 and the Comment by Elizabeth R Gerstner2 regarding the negative phase 3 study of rindopepimut in newly diagnosed glioblastoma. Gerstner notes that the ACT IV trial did not confirm the previous results of three phase 2 studies (ACTIVATE, ACT II, and ACT III), which were compared with a historical control that served as the basis for the phase 3 study. Her thoughtful speculation that temozolomide-induced lymphopenia or heterogeneity of EGFRvIII expression, or both,2 might provide a partial explanation of the failure of the ACT IV study.
http://ift.tt/2Bv392V
[Correspondence] Go, no-go decision making for phase 3 clinical trials: ACT IV revisited – Authors' reply
We appreciate not only the interest of H Ian Robins and colleagues in the ACT IV trial,1 but also the thoughtful commentary by Elizbeth R Gerstner. From the perspective of several years' additional experience with clinical trial conduct in newly diagnosed glioblastoma relative to the time when ACT IV was designed, we feel that the failure to adequately estimate efficacy with a new treatment based on historical controls (even when matched for eligibility) provides a good lesson to be learned.
http://ift.tt/2k9MOfS
[Cancer and Society] The art of death
Edwidge Danticat's The Art of Death, Writing the Final Story is an intimate look at one woman's journey to make sense of death, including the recent loss of her mother to stage IV ovarian cancer. To understand death, the novelist turns to her innate comfort, the written word. Drawing on the great authors and their representations of death, she begins to make sense of the great loss she has seen in her life.
http://ift.tt/2Bw0p58
[Cancer and Society] Make Blood Cancer Visible
Walking through Paternoster Square near London's St Paul's Cathedral during the month of September, you are greeted by an unusual and striking array of blood-red, three-dimensional sculptures of names standing vertically. This public installation is the launch of a campaign run by Janssen Oncology to raise awareness and education about blood cancer; to, in effect, make blood cancer visible. Janssen Oncology, in partnership with nine other blood cancer patient groups, conducted both a public survey and a survey of patients diagnosed with blood cancer to generate statistics about perceptions surrounding blood cancer.
http://ift.tt/2kc5CuZ
[Comment] Lung cancer in Asian women and health system implications for Australia
In 2017, an estimated 12 434 Australians will be diagnosed with lung cancer and 9012 will die from the disease. Tobacco smoking remains the largest single cause of lung cancer in Australia, being responsible for approximately 90% of cases in men and 65% in women. Globally, lung cancer accounts for 13% of all cancer diagnoses and is the leading cause of cancer deaths in men overall and in women in developed countries.1
http://ift.tt/2Bxwk5d
[Editorial] Clinical decision making: more than just an algorithm
November, 2017, has seen two seemingly contradictory stories in the headlines: in the UK, the Government has unveiled plans to accelerate access to medicines under a new Accelerated Access pathway; while a recent study published in the Journal of the American Medical Informatics Association (JAMIA) has shown that more than 70% of clinicians override e-prescribing alerts when being warned of potential drug–drug interactions. This somewhat ironic paradox—in which more drugs are being pushed through to the market, only to be bottlenecked through a system that relies on an automated system of prescription—has potentially conflicting consequences.
http://ift.tt/2kbju8L
[Review] An integrated multidisciplinary algorithm for the management of spinal metastases: an International Spine Oncology Consortium report
Spinal metastases are becoming increasingly common because patients with metastatic disease are living longer. The close proximity of the spinal cord to the vertebral column limits many conventional therapeutic options that can otherwise be used to treat cancer. In response to this problem, an innovative multidisciplinary approach has been developed for the management of spinal metastases, leveraging the capabilities of image-guided stereotactic radiosurgery, separation surgery, vertebroplasty, and minimally invasive local ablative approaches.
http://ift.tt/2kaQqxW
[Correspondence] Cancer in two Renaissance families
We read with great interest the letter published by Raffaele Gaeta and colleagues1 describing a supposed concentration of cancer cases in the Renaissance court of Naples. However, this short report lacks important physiopathological and bibliographical data. First, more than five cases of malignant tumours have been published in the paleopathological literature.2 The authors focused exclusively on soft-tissue tumours in mummified human remains1,3 without mentioning bone cancer cases,2 therefore giving a biased view of cancer frequencies in past populations.
http://ift.tt/2BxW7KO
[Cancer and Society] Die young with me
In the refreshingly unconventional Die Young With Me, Rob Rufus has reinvigorated the cancer memoir genre. Readers discovering this book outside of the strictly categorised worlds of bookshops and libraries could be forgiven for thinking they had discovered a work of fiction, something akin to John Green's The Fault in our Stars. The first person narrative coupled with the high school setting and cast of teenage characters serve to further this fiction-like tone, as does the introductory storyline: boy meets girl, the outcast and the cheerleader.
http://ift.tt/2kaQkq4
[Cancer and Society] Island
A lot of mist can settle over the Solent, the straits that separate the Isle of Wight from the English mainland. On some days, you hear the passenger ferry before you see it; whirring and clanking, and the blast of the horn. The ship slowly assumes shape, shimmering and uncertain at first, and finally emerging from the fog. After it docks, the passengers stream out. Some are on bicycles, most are on foot. After a while, the ferry leaves again.
http://ift.tt/2BzUA75
[Corrections] Correction to Lancet Oncol 2017; 18: 1555–56
Bestvina CM and Vokes E. ALK and ROS1 rearrangement in NSCLC: rapidly evolving standards. Lancet Oncol 2017; 18: 1555–56—In this Comment, the sixth sentence in the third paragraph should have read "Grade 3 or worse pulmonary toxicity occurred in 3% of patients treated with brigatinib." This correction has been made as of Nov 29, 2017, and the printed version is correct.
http://ift.tt/2kaQde8
The Smurf transition: new insights on ageing from end-of-life studies in animal models
Purpose of review Over the past 5 years, many articles were published concerning the prediction of high risk of mortality in apparently healthy adults, echoing the first description in 2011 of the Smurf phenotype, a harbinger of natural death in drosophila. Recent findings These recent findings suggest that the end-of-life is molecularly and physiologically highly stereotyped, evolutionarily conserved and predictable. Summary Taken altogether, these results from independent teams using multiple organisms including humans draw the lines of future directions in ageing research. The ability to identify and study individuals about to die of natural causes with no apparent diseases is a game-changer in this field. In addition, the public health applications are potentially of tremendous impact in our ageing societies and raise important ethical questions.http://ift.tt/2AorNV2
An update on noninvasive follicular thyroid neoplasm with papillary-like nuclear features
Purpose of review Noninvasive encapsulated follicular variant of papillary thyroid carcinoma (PTC) has been established in the literature as a clinically indolent tumor. Despite this, it was traditionally treated like all other PTCs. In an attempt to reduce overtreatment of this entity, a panel of experts reclassified this entity as noninvasive follicular neoplasm with papillary-like nuclear features (NIFTP). This reclassification has led to a flurry of literature elucidating the molecular, cytologic and clinical parameters of this 'new' entity and the implications for patient management. The purpose of this review is to examine the latest literature on this tumor and explore how its emergence has impacted our current understanding of the diagnosis, management and outcomes in this entity. Recent findings NIFTP is a low grade tumor with an indolent clinical course. Recent studies have begun to document the variable incidence of NIFTP, the ultrasound and cytologic findings, and the impact of the NIFTP terminology on established rates of malignancy in fine-needle aspiration and clinical outcome studies. Summary The recent literature on molecular, radiographic and cytologic characteristics of NIFTP are building our understanding of this neoplasm and support its indolent nature.http://ift.tt/2AoR6pU
Targeting the perivascular niche in brain tumors
Purpose of review Brain tumors are composed of primary tumors of the central nervous system, such us glioblastoma (GBM), and secondary metastatic tumors, such as melanoma, non-Hodgkin lymphoma as well as lung and breast cancers. Brain tumors are highly deadly, and unfortunately not many improvements have been achieved to improve the survival of patients with brain tumors. Chemoradiation resistance is one of the most clinically relevant challenges faced in patients with brain tumors. The perivascular niche is one of the most relevant microenvironment hubs in brain tumors. The understanding of the cellular crosstalk established within the brain tumor perivascular niche might provide us with key discoveries of new brain tumor vulnerabilities. Recent findings Radio and chemoresistance in GBM and brain metastases is attributed to cancer stem cells (CSCs), which intrinsically modulate several pathways that make them resistant to therapy. Growing evidence, however, highlights the perivascular space as a niche for CSC survival, resistance to therapy, progression and dissemination. Here, I review the latest discoveries on the components and features of brain tumor vascular niches and the possible therapeutic strategies aimed at targeting its vulnerabilities, thus preventing GBM and metastasis chemoradiation resistance and recurrence. Summary Recent discoveries suggest that targeting the brain perivascular niche has the potential of sensitizing brain tumors to therapies and reducing the occurrence of metastases.http://ift.tt/2Aosfmc
An update on the status of molecular testing for the indeterminate thyroid nodule and risk stratification of differentiated thyroid cancer
Purpose of review Correct identification of malignancy in cytologically indeterminate thyroid nodules is a diagnostic challenge, leading to potentially unnecessary surgery in patients for whom final histology is benign. Similarly, many patients with differentiated thyroid cancer (DTC) undergo aggressive surgical management of tumors, which may ultimately have low-risk histologic features. Use of molecular testing strategies can aid in both the diagnosis of indeterminate thyroid nodules and preoperative risk stratification of DTC. Recent findings Validation studies of both the Afirma Gene Expression Classifier and Thyroseq Next-Generation Sequencing panel are ongoing. Both tests can be used to help rule out malignancy in indeterminate thyroid nodules. Recent additions to available molecular testing for indeterminate thyroid nodules include the Rosetta microRNA classifier and the augmentation of the ThyGenX gene panel with a microRNA reflex test (ThyraMIR). Mutational analysis of DTC shows that mutation in TERT alone, and in combination with other mutations, portends advanced disease. Summary Currently available molecular testing modalities are useful for ruling out malignancy in indeterminate thyroid nodules; however, longer-term follow-up studies are needed to confirm that test-negative nodules are truly benign. Analysis of specific gene mutations helps identify aggressive disease to guide prognostication and management, but further study is needed.http://ift.tt/2AorwkY
Lysine methylation signaling in pancreatic cancer
Purpose of review Despite better knowledge of its genetic basis, pancreatic cancer is still highly lethal with very few therapeutic options. In this review, we discuss the potential impact of epigenetic therapies, focusing on lysine methylation signaling and its implication in pancreatic cancer. Recent findings Protein lysine methylation, a key mechanism of posttranslational modifications of histone proteins, has emerged as a major cell signaling mechanism regulating physiologic and pathologic processes including cancer. This finely tuned and dynamic signaling mechanism is regulated by lysine methyltransferases (KMT), lysine demethylases (KDM) and signal transducers harboring methyl-binding domains. Recent evidence demonstrates that overexpression of cytoplasmic KMT and resulting enhanced lysine methylation is a reversible event that enhances oncogenic signaling through the Ras and Mitogen-Activated Protein Kinases pathway in pancreatic cancer, opening perspectives for new anticancer chemotherapeutics aimed at controlling these activities. Summary The development of potent and specific inhibitors of lysine methylation signaling may represent a hitherto largely unexplored avenue for new forms of targeted therapy in cancer, with great potential for yet hard-to-treat cancers such as pancreatic cancer.http://ift.tt/2AorpG4
Advances in understanding the molecular underpinnings of adrenocortical tumors
Purpose of review Adrenocortical tumors are divided into benign adenomas and malignant carcinomas. The former is relatively common and carries a favorable prognosis, whereas the latter is rare and frequently presents at an advanced stage, with poor outcomes. Advances in next-generation sequencing, genome analysis, and bioinformatics have allowed for high-throughput molecular characterization of adrenal tumorigenesis. Recent findings Although recent genomic, epigenomic, and transcriptomic studies in large tumor cohorts have confirmed the central roles of aberrant Wnt/ß-catenin signaling, constitutive protein kinase A pathway activation, cell cycle dysregulation, and ion channelopathies in adrenal tumorigenesis, these studies also revealed novel signature events underlying malignant differentiation of adrenocortical carcinomas. Summary Recent advances in understanding of the molecular mechanisms underlying adrenocortical tumorigenesis provide new molecular diagnostic and prognostic tools and opportunities for novel therapeutic approaches. These findings are particularly important in adrenocortical carcinoma, for which current treatment options are limited.http://ift.tt/2AmFHXP
Paracrine interactions of cancer-associated fibroblasts, macrophages and endothelial cells: tumor allies and foes
Purpose of review Tumor stroma is composed of many cellular subtypes, of which the most abundant are fibroblasts, macrophages and endothelial cells. During the process of tissue injury, these three cellular subtypes must coordinate their activity to efficiently contribute to tissue regeneration. In tumor, this mechanism is hijacked by cancer cells, which rewire the interaction of stromal cells to benefit tumor development. The present review aims at summarizing most relevant information concerning both pro-tumorigenic and anti-tumorigenic actions implicating the three stromal cell subtypes as well as their mutual interactions. Recent findings Although stromal cells are generally regarded as tumor-supportive and at will manipulated by cancer cells, several novel studies point at many defaults in cancer cell-mediated stromal reprograming. Indeed, parts of initial tissue-protective and homeostatic functions of the stromal cells remain in place even after tumor development. Both tumor-supportive and tumor-suppressive functions have been well described for macrophages, whereas similar results are emerging for fibroblasts and endothelial cells. Summary Recent success of immunotherapies have finally brought the long awaited proof that stroma is key for efficient tumor targeting. However, a better understanding of paracrine stromal interactions is needed in order to encourage drug development not only aiming at disruption of tumor-supportive communication but also re-enforcing, existing, tumor-suppressive mechanisms.http://ift.tt/2AmFzrj
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