The function of BTG3 in colorectal cancer cells and its possible signaling pathway

Abstract

Purpose

B-cell translocation gene 3 (BTG3) has been identified as a candidate driver gene for various cancers, but its specific role in colorectal cancer (CRC) is poorly understood. We aimed to investigate the relationship between expression of BTG3 and clinicopathological features and prognosis, as well as to explore the effects and the role of a possible BTG3 molecular mechanism on aggressive colorectal cancer behavior.

Methods

BTG3 expression was assessed by immunohistochemistry (IHC) on specimens from 140 patients with CRC. The association of BTG3 expression with clinicopathological features was examined. To confirm the biological role of BTG3 in CRC, two CRC cell lines expressing BTG3 were used and BTG3 expression was knocked down by shRNA. CCK-8, cell cycle, apoptosis, migration, and invasion assays were performed. The influence of BTG3 knockdown was further investigated by genomic microarray to uncover the potential molecular mechanisms underlying BTG3-mediated CRC development and progression.

Results

BTG3 was downregulated in colorectal cancer tissues and positively correlated with pathological classification (p = 0.037), depth of invasion (p = 0.016), distant metastasis (p = 0.024), TNM stage (p = 0.007), and overall survival (OS) and disease-free survival (DFS). BTG3 knockdown promoted cell proliferation, migration, invasion, relieved G2 arrest, and inhibited apoptosis in HCT116 and LoVo cells. A genomic microarray analysis showed that numerous tumor-associated signaling pathways and oncogenes were altered by BTG3 knockdown. At the mRNA level, nine genes referred to the extracellular-regulated kinase/mitogen-activated protein kinase pathway were differentially expressed. Western blotting revealed that BTG3 knockdown upregulated PAK2, RPS6KA5, YWHAB, and signal transducer and activator of transcription (STAT)3 protein levels, but downregulated RAP1A, DUSP6, and STAT1 protein expression, which was consistent with the genomic microarray data.

Conclusions

BTG3 expression might contribute to CRC carcinogenesis. BTG3 knockdown might strengthen the aggressive colorectal cancer behavior.

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The function of BTG3 in colorectal cancer cells and its possible signaling pathway

Abstract

Purpose

B-cell translocation gene 3 (BTG3) has been identified as a candidate driver gene for various cancers, but its specific role in colorectal cancer (CRC) is poorly understood. We aimed to investigate the relationship between expression of BTG3 and clinicopathological features and prognosis, as well as to explore the effects and the role of a possible BTG3 molecular mechanism on aggressive colorectal cancer behavior.

Methods

BTG3 expression was assessed by immunohistochemistry (IHC) on specimens from 140 patients with CRC. The association of BTG3 expression with clinicopathological features was examined. To confirm the biological role of BTG3 in CRC, two CRC cell lines expressing BTG3 were used and BTG3 expression was knocked down by shRNA. CCK-8, cell cycle, apoptosis, migration, and invasion assays were performed. The influence of BTG3 knockdown was further investigated by genomic microarray to uncover the potential molecular mechanisms underlying BTG3-mediated CRC development and progression.

Results

BTG3 was downregulated in colorectal cancer tissues and positively correlated with pathological classification (p = 0.037), depth of invasion (p = 0.016), distant metastasis (p = 0.024), TNM stage (p = 0.007), and overall survival (OS) and disease-free survival (DFS). BTG3 knockdown promoted cell proliferation, migration, invasion, relieved G2 arrest, and inhibited apoptosis in HCT116 and LoVo cells. A genomic microarray analysis showed that numerous tumor-associated signaling pathways and oncogenes were altered by BTG3 knockdown. At the mRNA level, nine genes referred to the extracellular-regulated kinase/mitogen-activated protein kinase pathway were differentially expressed. Western blotting revealed that BTG3 knockdown upregulated PAK2, RPS6KA5, YWHAB, and signal transducer and activator of transcription (STAT)3 protein levels, but downregulated RAP1A, DUSP6, and STAT1 protein expression, which was consistent with the genomic microarray data.

Conclusions

BTG3 expression might contribute to CRC carcinogenesis. BTG3 knockdown might strengthen the aggressive colorectal cancer behavior.

http://ift.tt/2kvlpSQ

Mammography screening: A major issue in medicine

Publication date: February 2018
Source:European Journal of Cancer, Volume 90
Author(s): Philippe Autier, Mathieu Boniol
Breast cancer mortality is declining in most high-income countries. The role of mammography screening in these declines is much debated.Screening impacts cancer mortality through decreasing the incidence of number of advanced cancers with poor prognosis, while therapies and patient management impact cancer mortality through decreasing the fatality of cancers. The effectiveness of cancer screening is the ability of a screening method to curb the incidence of advanced cancers in populations. Methods for evaluating cancer screening effectiveness are based on the monitoring of age-adjusted incidence rates of advanced cancers that should decrease after the introduction of screening. Likewise, cancer-specific mortality rates should decline more rapidly in areas with screening than in areas without or with lower levels of screening but where patient management is similar. These two criteria have provided evidence that screening for colorectal and cervical cancer contributes to decreasing the mortality associated with these two cancers. In contrast, screening for neuroblastoma in children was discontinued in the early 2000s because these two criteria were not met. In addition, overdiagnosis – i.e. the detection of non-progressing occult neuroblastoma that would not have been life-threatening during the subject's lifetime – is a major undesirable consequence of screening.Accumulating epidemiological data show that in populations where mammography screening has been widespread for a long time, there has been no or only a modest decline in the incidence of advanced cancers, including that of de novo metastatic (stage IV) cancers at diagnosis. Moreover, breast cancer mortality reductions are similar in areas with early introduction and high penetration of screening and in areas with late introduction and low penetration of screening. Overdiagnosis is commonplace, representing 20% or more of all breast cancers among women invited to screening and 30–50% of screen-detected cancers. Overdiagnosis leads to overtreatment and inflicts considerable physical, psychological and economic harm on many women. Overdiagnosis has also exerted considerable disruptive effects on the interpretation of clinical outcomes expressed in percentages (instead of rates) or as overall survival (instead of mortality rates or stage-specific survival). Rates of radical mastectomies have not decreased following the introduction of screening and keep rising in some countries (e.g. the United States of America (USA)). Hence, the epidemiological picture of mammography screening closely resembles that of screening for neuroblastoma.Reappraisals of Swedish mammography trials demonstrate that the design and statistical analysis of these trials were different from those of all trials on screening for cancers other than breast cancer. We found compelling indications that these trials overestimated reductions in breast cancer mortality associated with screening, in part because of the statistical analyses themselves, in part because of improved therapies and underreporting of breast cancer as the underlying cause of death in screening groups. In this regard, Swedish trials should publish the stage-specific breast cancer mortality rates for the screening and control groups separately. Results of the Greater New York Health Insurance Plan trial are biased because of the underreporting of breast cancer cases and deaths that occurred in women who did not participate in screening. After 17 years of follow-up, the United Kingdom (UK) Age Trial showed no benefit from mammography screening starting at age 39–41.Until around 2005, most proponents of breast screening backed the monitoring of changes in advanced cancer incidence and comparative studies on breast cancer mortality for the evaluation of breast screening effectiveness. However, in an attempt to mitigate the contradictions between results of mammography trials and population data, breast-screening proponents have elected to change the criteria for the evaluation of cancer screening effectiveness, giving precedence to incidence-based mortality (IBM) and case—control studies. But practically all IBM studies on mammography screening have a strong ecological component in their design. The two IBM studies done in Norway that meet all methodological requirements do not document significant reductions in breast cancer mortality associated with mammography screening. Because of their propensity to exaggerate the health benefits of screening, case–control studies may demonstrate that mammography screening could reduce the risk of death from diseases other than breast cancer.Numerous statistical model approaches have been conducted for estimating the contributions of screening and of patient management to reductions in breast cancer mortality. Unverified assumptions are needed for running these models. For instance, many models assume that if screening had not occurred, the majority of screen-detected asymptomatic cancers would have progressed to symptomatic advanced cancers. This assumption is not grounded in evidence because a large proportion of screen-detected breast cancers represent overdiagnosis and hence non-progressing tumours. The accumulation of population data in well-screened populations diminishes the relevance of model approaches.The comparison of the performance of different screening modalities – e.g. mammography, digital mammography, ultrasonography, magnetic resonance imaging (MRI), three-dimensional tomosynthesis (TDT) – concentrates on detection rates, which is the ability of a technique to detect more cancers than other techniques. However, a greater detection rate tells little about the capacity to prevent interval and advanced cancers and could just reflect additional overdiagnosis. Studies based on the incidence of advanced cancers and on the evaluation of overdiagnosis should be conducted before marketing new breast-imaging technologies.Women at high risk of breast cancer (i.e. 30% lifetime risk and more), such as women with BRCA1/2 mutations, require a close breast surveillance. MRI is the preferred imaging method until more radical risk-reduction options are eventually adopted. For women with an intermediate risk of breast cancer (i.e. 10–29% lifetime risk), including women with extremely dense breast at mammography, there is no evidence that more frequent mammography screening or screening with other modalities actually reduces the risk of breast cancer death.A plethora of epidemiological data shows that, since 1985, progress in the management of breast cancer patients has led to marked reductions in stage-specific breast cancer mortality, even for patients with disseminated disease (i.e. stage IV cancer) at diagnosis. In contrast, the epidemiological data point to a marginal contribution of mammography screening in the decline in breast cancer mortality. Moreover, the more effective the treatments, the less favourable are the harm–benefit balance of screening mammography.New, effective methods for breast screening are needed, as well as research on risk-based screening strategies.



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Outcomes in women with invasive ductal or invasive lobular early stage breast cancer treated with anastrozole or exemestane in CCTG (NCIC CTG) MA.27

Publication date: February 2018
Source:European Journal of Cancer, Volume 90
Author(s): K. Strasser-Weippl, G. Sudan, R. Ramjeesingh, L.E. Shepherd, J. O'Shaughnessy, W.R. Parulekar, P.E.R. Liedke, B.E. Chen, P.E. Goss
BackgroundHistological subtype, (invasive ductal breast cancer (IDBC)/invasive lobular breast cancer (ILBC)), might be a marker for differential response to endocrine therapy in breast cancer.MethodsClinical trial MA.27 compared 5 years of adjuvant anastrozole or exemestane in postmenopausal patients with hormone receptor positive early breast cancer. We evaluated IDBC versus ILBC (based on original pathology reports) as predictor for event-free survival (EFS) and overall survival (OS).ResultsA total of 5709 patients (5021 with IDBC and 688 with ILBC) were included (1876 were excluded because of missing or other histological subtype). Median follow-up was 4.1 years. Overall, histological subtype did not influence OS or EFS (HR (hazard ratio) 1.14, 95% confidence interval (CI) [0.79–1.63], P = 0.49 and HR 1.04, 95% CI [0.77–1.41], P = 0.81, respectively). There was no significant difference in OS between treatment with exemestane versus treatment with anastrozole in the IDBC group (HR = 0.92, 95% CI [0.73–1.16], P = 0.46). In the ILBC group, a marginally significant difference in favour of treatment with anastrozole was seen (HR = 1.79, 95% CI [0.98–3.27], P = 0.055). In multivariable analysis a prognostic effect of the interaction between treatment and histological subtype on OS (but not on EFS) was noted, suggesting a better outcome for patients with ILBC on anastrozole (HR 2.1, 95% CI [0.99–4.29], P = 0.05). After stepwise selection in the multivariable model, a marginally significant prognostic effect for the interaction variable (treatment with histological subtype) on OS (but not on EFS) was noted (Ratio of HR 2.1, 95% CI [1.00–4.31], P = 0.05).ConclusionOur data suggest an interaction effect between treatment and histology (P = 0.05) on OS. Here, patients with ILBC cancers had a better OS when treated with anastrozole versus exemestane, whereas no difference was noted for patients with IDBC.Clinical Trial informationNCT00066573.



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The subgroups of the phase III RECOURSE trial of trifluridine/tipiracil (TAS-102) versus placebo with best supportive care in patients with metastatic colorectal cancer

Publication date: February 2018
Source:European Journal of Cancer, Volume 90
Author(s): Eric Van Cutsem, Robert J. Mayer, Stéphanie Laurent, Robert Winkler, Cristina Grávalos, Manuel Benavides, Federico Longo-Munoz, Fabienne Portales, Fortunato Ciardiello, Salvatore Siena, Kensei Yamaguchi, Kei Muro, Tadamichi Denda, Yasushi Tsuji, Lukas Makris, Patrick Loehrer, Heinz-Josef Lenz, Atsushi Ohtsu
BackgroundIn the phase III RECOURSE trial, trifluridine/tipiracil (TAS-102) extended overall survival (OS) and progression-free survival (PFS) with an acceptable toxicity profile in patients with metastatic colorectal cancer refractory or intolerant to standard therapies. The present analysis investigated the efficacy and safety of trifluridine/tipiracil in RECOURSE subgroups.MethodsPrimary and key secondary end-points were evaluated using a Cox proportional hazards model in prespecified subgroups, including geographical subregion (United States of America [USA], European Union [EU], Japan), age (<65 years, ≥65 years) and v-Ki-ras2 Kirsten rat sarcoma 2 viral oncogene homologue (KRAS) status (wild type, mutant). Safety and tolerability were reported with descriptive statistics.ResultsEight-hundred patients were enrolled: USA, n = 99; EU, n = 403; Japan, n = 266. Patients aged ≥65 years and those with mutant KRAS tumours comprised 44% and 51% of all patients in the subregions, respectively. Final OS analysis (including 89% of events, compared with 72% in the initial analysis) confirmed the survival benefit associated with trifluridine/tipiracil, with a hazard ratio (HR) of 0.69 (95% confidence interval [CI] 0.59–0.81; P = 0.0001). Median OS in the three regions was 6.5–7.8 months in the trifluridine/tipiracil arm and 4.3–6.7 months in the placebo arm (USA: HR 0.56; 95% CI 0.34–0.94; P = 0.0277; EU: HR 0.62; 95% CI 0.48–0.80; P = 0.0002; Japan: HR 0.75; 95% CI 0.57–1.00; P = 0.0470). Median PFS was 2.0–2.8 months for trifluridine/tipiracil and 1.7–1.8 months for placebo; HRs favoured trifluridine/tipiracil in all regions. Similar clinical benefits of trifluridine/tipiracil were observed in elderly patients and in those with mutant KRAS tumours. There were no marked differences among subregions in terms of safety and tolerability.ConclusionsTrifluridine/tipiracil was effective in all subgroups, regardless of age, geographical origin or KRAS status.This trial is registered with ClinicalTrials.gov: NCT01607957.



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High circulating miR-18a, miR-20a, and miR-92a expression correlates with poor prognosis in patients with non-small cell lung cancer

Abstract

The purpose of this study was to assess the predictive value of angiogenic miRNAs for disease-free survival (DFS) and overall survival (OS) of patients with non-small cell lung cancer (NSCLC). In total, 196 patients with NSCLC (tumor lymph nodes metastasis (TNM) stage I–III) were enrolled and peripheral blood samples were collected. Total RNA was extracted from blood samples, and the relative expression levels of candidate miRNAs were evaluated by real time-polymerase chain reaction (RT-PCR). The median follow-up period was 56.7 months, and the final follow-up date was in August 2016. The median DFS of all patients was 30.0 (14.0–49.0) months, whereas the median OS was 41.5 (23.0–58.0) months. Furthermore, the 5-year DFS and OS rates were 11.3% and 32.3%, respectively. Kaplan–Meier (K–M) curves showed that high plasma miR-18a (P < 0.001), miR-20a (P < 0.001), miR-92a (P < 0.001), miR-126 (P < 0.001), miR-210 (P = 0.003), and miR-19a (P = 0.027) expressions levels correlated with a worse DFS. Moreover, patients with high plasma miR-18a, miR-20a, miR-92a, miR-210, and miR-126 expression levels had a shorter OS than patients with low expression levels of these miRNAs (all P <= 0.001). Furthermore, multivariate Cox regression analyses revealed that high plasma expression levels of miR-18a, miR-20a, and miR-92a as well as lymphatic node metastasis (all P < 0.001) were independent risk factors for both DFS and OS in patients with NSCLC. Thus, the circulating miR-18a, miR-20a, and miR-92a levels may serve as novel and promising prognostic biomarkers in patients with NSCLC.

Circulating miR-18a, miR-20a, and miR-92a levels may serve as novel and promising prognostic biomarkers in patients with non-small cell lung cancer.

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High circulating miR-18a, miR-20a, and miR-92a expression correlates with poor prognosis in patients with non-small cell lung cancer

Abstract

The purpose of this study was to assess the predictive value of angiogenic miRNAs for disease-free survival (DFS) and overall survival (OS) of patients with non-small cell lung cancer (NSCLC). In total, 196 patients with NSCLC (tumor lymph nodes metastasis (TNM) stage I–III) were enrolled and peripheral blood samples were collected. Total RNA was extracted from blood samples, and the relative expression levels of candidate miRNAs were evaluated by real time-polymerase chain reaction (RT-PCR). The median follow-up period was 56.7 months, and the final follow-up date was in August 2016. The median DFS of all patients was 30.0 (14.0–49.0) months, whereas the median OS was 41.5 (23.0–58.0) months. Furthermore, the 5-year DFS and OS rates were 11.3% and 32.3%, respectively. Kaplan–Meier (K–M) curves showed that high plasma miR-18a (P < 0.001), miR-20a (P < 0.001), miR-92a (P < 0.001), miR-126 (P < 0.001), miR-210 (P = 0.003), and miR-19a (P = 0.027) expressions levels correlated with a worse DFS. Moreover, patients with high plasma miR-18a, miR-20a, miR-92a, miR-210, and miR-126 expression levels had a shorter OS than patients with low expression levels of these miRNAs (all P <= 0.001). Furthermore, multivariate Cox regression analyses revealed that high plasma expression levels of miR-18a, miR-20a, and miR-92a as well as lymphatic node metastasis (all P < 0.001) were independent risk factors for both DFS and OS in patients with NSCLC. Thus, the circulating miR-18a, miR-20a, and miR-92a levels may serve as novel and promising prognostic biomarkers in patients with NSCLC.

Circulating miR-18a, miR-20a, and miR-92a levels may serve as novel and promising prognostic biomarkers in patients with non-small cell lung cancer.

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Endodontic management of taurodontism with a complex root canal anatomy in mandibular posterior teeth

One of the biggest challenges in endodontic treatment is to comprehensively understand the variation of tooth root canal anatomy. To a large degree, the anatomy and furcation distribution of teeth, which vary from nationality and ethnic groups, will influence the clinical diagnosis, treatment plan and even prognosis. Taurodontism, as one of anatomic variation in tooth structures, is relatively hard to be seen in dental clinics. Two special cases of taurodontism with varied root canal anatomies in mandibular second premolar and first molar are reported in this paper.

http://ift.tt/2oZ449G

Subacute combined degeneration of the spinal cord in vitamin B12 and copper deficiency

Description

A 67-year-old man with a medical history of pancreatoduodenectomy (Whipple procedure) in September 2015 due to a pancreatic cancer was admitted to our department of neurology 1 year later with a progressively disturbed gait. He reported weakness and numbness of both legs. Clinical examination revealed a spastic sensomotoric tetraparesis with ataxia and bladder dysfunction. MRI showed longitudinal myelopathy exactly limited to the posterior tracts (fasciculus gracilis and fasciculus cuneatus) indicating a metabolic origin (subacute combined degeneration of the spinal cord; figure 1A,B).

Figure 1

(A) Axial T2-weighted and (B) sagittal short T1 inversion recovery (STIR) MRI of the cervical spine showing longitudinal myelopathy exactly limited to the posterior tracts (fasciculus gracilis and fasciculus cuneatus, arrows). (C) Sagittal STIR MRI of the cervical spine 4 months later.

Consistently and according to the medical history of the Whipple procedure, a moderate vitamin B₁₂ deficiency...

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Interstitial lung disease secondary to Cetuximab in bladder cancer: an Oncologists perspective

A wide variety of cytotoxic medications cause interstitial lung disease (ILD). For the first time, we describe ILD in an 82-year-old woman with muscle invasive bladder cancer 10 days after receiving cetuximab as part of a novel trial. She had no significant medical history or drug allergies, had good exercise tolerance and a 5 pack-year smoking history. She received neoadjuvant chemotherapy (gemcitabine, cisplatin) with a good response on MRI. She was eligible for a phase 2 trial of cetuximab with chemotherapy and radiotherapy for muscle invasive bladder cancer (TUXEDO), in which the trial arm used cetuximab plus standard chemoradiotherapy to the bladder (64 grey in 32 fractions plus mitomycinandfluorouracil). Ten days after her third infusion of cetuximab, she was presented with type 1 respiratory failure. Thoracic CT scan demonstrated new widespread ground glass change in the lungs. She received high-dose steroids (prednisolone 1 mg/kg), broad spectrum antibacterial cover and non-invasive ventilation. She survived to be discharged with residual respiratory failure.

http://ift.tt/2p0Cskh

Deliberate self-poisoning with long-acting anticoagulant rodenticides

Long-acting anticoagulant rodenticides, also called superwarfarins, are known for their greater potency, longer half-life and delayed onset of symptoms. Cases of superwarfarin poisoning can pose a diagnostic and clinical challenge due to a wide array of presentations and prolonged severe coagulopathy requiring months of high-dose oral vitamin K therapy. The most common presentation of long-acting anticoagulant rodenticide poisoning is mucocutaneous bleeding, with other common presentations including haematuria, gingival bleeding, epistaxis and gastrointestinal bleeding. We discuss a case of deliberate self-poisoning with long-acting anticoagulant rodenticides presenting with haematuria and coagulation values above measurable limits. This case is important as it required immediate and maintenance therapy in order to prevent profound bleeding, as well as the evaluation of the patient's psychosocial factors to ensure medical compliance and to prevent refractory complications or repeated self-harm.

http://ift.tt/2DlxuBN

Stenotrophomonas maltophilia: an emerging multidrug-resistant opportunistic pathogen in the immunocompromised host

Stenotrophomonas maltophilia is a multidrug-resistant opportunistic pathogen with increasing prevalence and high morbidity and mortality. In addition to its classic association with pulmonary infections, S. maltophilia can cause skin and soft tissue infections with varying clinical presentations. We describe the case of a man in his 30s with B-cell acute lymphoblastic leukaemia who presented with a solitary patch of faint but tender purpura found to have rapidly progressive S. maltophilia infection diagnosed on skin biopsy. S. maltophilia infection should be considered in the cutaneous evaluation of the immunocompromised host.

http://ift.tt/2oVQ1S2

Colonic perforation by an intrathecal baclofen pump catheter causing delayed Escherichia coli meningitis

Intrathecal baclofen (ITB) delivery via an implanted pump is frequently used for the treatment of spasticity. This is an effective and safe neurosurgical and pharmacological intervention associated with an improvement in patient quality of life. There is, however, a risk of device-related infection. We present a patient with pump-site infection and Escherichia coli meningitis secondary to transcolonic perforation of an intrathecal baclofen pump catheter. While this is rare, we review the intraoperative precautions and best practices that should be taken to prevent and manage this unusual complication.

http://ift.tt/2Dfkwp7

A disclosed diagnosis for 24 years unknown illness

IgG4-related disease (IgG4-RD) is a newly described illness over the last several years. A 57-year-old man, who had been followed for chronic kidney disease (CKD), chronic pancreatitis and history of operated cholangitis, was admitted to our hospital for abdominal pain and worsening renal function. Serum levels of IgG and IgG4 were elevated. CT scan showed the characteristic findings of IgG4-related retroperitoneal fibrosis, pancreas and kidney disease. An endoscopic biopsy revealed the finding compatible with IgG4-RD. Steroid therapy led to the remission of his abdominal pain. Patients with CKD of unknown aetiology may have IgG4-RD.

http://ift.tt/2p4aqoi

A surgeons nightmare: pyoderma gangrenosum with pathergy effect mimicking necrotising fasciitis

A 53-year-old woman was admitted for vulval swelling and fever. She was initially diagnosed with vulval cellulitis and given parenteral antibiotics. Within 1 week, she developed necrotic-looking skin lesions extending from her vulva to her buttock. Emergency surgical debridement with diversion colostomy was performed in view of suspected necrotising fasciitis. Shortly after the surgery, she developed necrotic-looking skin lesions at the peripheral venous cannula insertion site, central line insertion site, and around her surgical wounds and stoma. A second surgical debridement was performed and shortly afterwards, similar skin lesions appeared around her surgical wounds. Her clinical progression was suggestive of pyoderma gangrenosum with pathergy effect. Hence, she was started on topical steroid, systemic steroid and immunosuppressant. The skin lesions responded well to medical therapy. Further systemic workup for conditions associated with this disease revealed findings suspicious for myelodysplastic syndrome.

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Management of atypical femoral fracture in a patient with osteogenesis imperfecta

Osteogenesis imperfecta (OI) is a generalised connective tissue disorder associated with low bone mass, bone fragility and increased susceptibility to fractures. First-line treatment to improve bone mineral density (BMD) is usually with bisphosphonates but long-term usage has been associated with uncommon complications such as atypical femoral fractures (AFF). Treatment with teriparatide in this situation has been reported with positive outcomes. However, choice of treatment after 2 years of teriparatide has not been well studied or reported. We describe a patient with OI treated with bisphosphonates for 9 years, who then suffered a spontaneous AFF, was subsequently started on teriparatide for 2 years followed by 6 monthly Denosumab. 1 year post-treatment with Denosumab, there was significant improvement in BMD, good fracture healing and no new fractures. This case highlights the potential use of denosumab following 2 years of teriparatide treatment in patients with OI with AFF.

http://ift.tt/2oYsYWR

Spinal cord abscess secondary to infected dorsal dermal sinus in an infant: uncommon presentation of a known entity

Infection along the congenital dermal sinus tract is well known. However, congenital dorsal dermal sinus presenting with intramedullary abscess is quite rare. The sinus tract usually presents in the midline and acts as a portal of entry for infection that may manifest as meningitis, extradural or subdural abscess and may further involve the cord. Surgical drainage of pus and complete excision of the sinus tract is the standard treatment. Here we describe an infant with an infected congenital dorsal dermal sinus with atypical presentation as large paracentral abscess in the upper back. We further highlight the importance of recognising and treating these skin dimples even when clinically silent to avoid catastrophic complications.

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Uvular necrosis following diagnostic gastroscopy

Uvular necrosis is an extremely rare complication of gastroscopy. We describe the fifth published case of uvular necrosis following an uncomplicated diagnostic gastroscopy in a young man. Presentation with severe sore throat and inability to swallow saliva occurred within 24 hours of gastroscopy and resolved with conservative treatment.

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Auditory agnosia caused by bilateral putamen haemorrhage

A 55-year-old right-handed man with a history of hypertension suddenly fell and developed right hemiparesis. Neurological examination revealed that he was alert, but did not appropriately respond to verbal questions and commands. Detailed examination revealed that he could correctly respond to written commands. His speech was almost fluent, showing no paraphasia and normal articulation. His written sentences were legible. Pure tone audiometry showed that his auditory acuity was relatively preserved. His brainstem auditory evoked potential components from I to V were recorded bilaterally with normal latency. Cerebral CT demonstrated fresh bleeding in the left putamen and an old haemorrhage on the opposite side. He was treated by antihypertensive therapy and rehabilitation. Although there remained mild sensory deficit on his right extremities and he felt a slight noise during conversation, he had little difficulty with verbal communication when he was transferred to another hospital on day 38.

http://ift.tt/2Dmb97m

Successful embolisation of an intracranial meningioma via a right-sided aortic arch

Right aortic arch is an unusual arch variation. Supra-aortic neurointervention in such cases has been sparingly reported. This case highlights the unusual association of a left hemispheric convexity meningioma with a right aortic arch which was successfully navigated. Particle embolisation of the meningioma produced good results followed by complete surgical excision and gratifying overall final outcome in this challenging scenario.

http://ift.tt/2oXWVWZ

Primary apocrine carcinoma of an unusual site

Primary apocrine carcinoma is a rare malignancy most commonly occurring in apocrine dense areas like axilla. There are only about 200 cases reported to date. We report a case of primary apocrine carcinoma present at an unusual site, that is, the arm. A wide local excision of the mass was done and was diagnosed as apocrine carcinoma on histopathological examination and was confirmed by immunohistochemistry. Wide local excision is the treatment required.

http://ift.tt/2DjIYpi

Mystery ring: a case of TIPS stent migration

Description

We present a 50-year-old man with history of end-stage liver disease secondary to hepatitis C, who frequently presents to the hospital with ascites. He recently underwent Trans jugular Intrahepatic Portosystemic Shunt (TIPS) stent placement after becoming resistant to diuresis and large volume therapeutic paracentesis. He presented to the emergency room with altered mental status due to hepatic encephalopathy. On physical exam, he was noted to have a systolic murmur; hence, a transthoracic echocardiogram was ordered. It showed an echo dense ring-like shadow in the right atrium close to intra-atrial septum (figure 1). Transoesophageal echocardiogram was obtained for better visualisation, and it showed a migrated TIPS stent entering the right atrium from the inferior vena cava with its cephalad end close to the intra-atrial septum (figure 2). There was no evidence of mechanical complication related to stent migration by echocardiography. The patient declined percutaneous retrieval....

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Ultrawide field imaging with navigable magnifier for diagnosis of diffuse unilateral subacute neuroretinitis

Description

A 52-year-old female presented with painless loss of vision in right eye since 3–4 years. Visual acuity was counting fingers close to face in right eye and 20/20 in left eye. Anterior segment examination and intraocular pressure were normal in both eyes. Right eye had multiple areas of pigment mottling and deep retinal scarring scattered throughout the fundus, along with optic disc atrophy (figure 1). Fundus examination of left eye was unremarkable. Window defects were detected on ultrawide field fluorescein angiography. Diffuse unilateral subacute neuroretinitis (DUSN) was suspected due to the ultrawide field imaging (UWFI) characteristics. The clinical UWFI was scanned with a navigable magnifier available in the software (Optos PLC, Dunfermline, UK). A slender, white-coloured, minimally curved structure was identified in the temporal pre-equatorial region with an adjoining scar (figure 2).

Figure 1

UWFI of the right eye depicting multiple...

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Recurrent lower gastrointestinal bleeding in an 87-year-old woman

Description

An 87-year-old woman presented to an outside hospital with a complaint of bright red blood per rectum (BRBPR), where her haemoglobin was found to be 4.6 g/dL. An extensive gastrointestinal (GI) work was performed, including oesophagogastroduodenoscopy, colonoscopy and a video capsule endoscopy, followed by a superior mesenteric artery (SMA) angiogram which showed no active extravasation. The patient continued to have BRBPR and was transferred to our hospital for further work-up. Her medical history was significant for hypertension, hyperlipidaemia and coronary artery disease. Her surgical history included knee arthroplasty, hernia repair, hysterectomy, cholecystectomy and appendectomy. Physical examination of the abdomen was soft, non-distended and non-tender. On transfer, a CT enterography was obtained and could not identify the source of bleeding but did note some stenosis of the superior mesenteric artery (SMA). A colonoscopy was then performed, which revealed old blood in her colon, but no active bleeding was found. A subsequent nuclear tagged...

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Giant ductal pseudoaneurysm in infancy: a lesson learnt the hard way

Description

A 7-month-old girl, ex-preterm (26-weeker), 4.5 kg, with 4 mm patent ductus arteriosus (PDA) underwent PDA device closure (Amplatzer duct occluder - ADO II 4x6 mm) elsewhere and was readmitted 4 days later with pericardial effusion. Needle pericardiocentesis drained 50 mL of haemorrhagic fluid. Septic screen was negative. Severe dyspnoea ensued 2 weeks later. Chest X-ray excluded lung pathology. Bedside echocardiogram showed PDA device in situ (online ), no residual ductus, vegetation or pericardial recollection, unobstructed flow in the pulmonary artery and descending aorta, normal pulmonary arterial pressures, and normal biventricular function. Curiously, a giant anechoic mass (22x25 mm) (online ) was visualised posteroinferior to the device with its neck communicating with lesser curvature of the thoracic aorta at the level of origin of the left subclavian artery (figure 1A,B). Intra-aneurysmal thrombus or aortic dissection was absent. We diagnosed giant ductal pseudoaneurysm with possible left bronchial compression.

Figure 1

(A) Parasternal short-axis transthoracic two-dimensional echocardiogram...

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Sensory neuronopathy associated with cholangiocarcinoma diagnosed 6 years after symptom onset

A pure sensory neuronopathy (also referred to as a sensory ganglionopathy) is one of a handful of classical neurological paraneoplastic syndromes. Current guidelines recommend that in cases of sensory neuronopathy, a search for an underlying malignancy be pursued for up to 4 years. We report the case of a 52-year-old woman with a sensory neuronopathy who was eventually diagnosed with a cholangiocarcinoma 6 years after the onset of her disease. A CT fluorodeoxyglucose positron emission tomography (FDG-PET) scan performed 18 and 24 months after disease onset failed to identify an underlying neoplasm. Immunomodulatory treatment with corticosteroids, intravenous immunoglobulins and plasma exchange were ineffective. Investigations for Sjogren's disease were negative. A third FDG-PET performed 6 years after symptom onset identified a cholangiocarcinoma, which was confirmed histologically following open resection. Since the tumour was removed, our patient's condition has not progressed, but there has been no improvement and she remains severely disabled.

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Nasal tip schwannoma mimicking rhinophyma

Description

Rhinophyma meaning 'nose growth' in Greek is a relatively common condition that describes thickening of the nasal skin with enlargement of the sebaceous glands. While not fully understood, it is believed to be a result of vascular instability causing leakage of fluid into the tissues. This subsequently triggers inflammation and scarring.1 Treatment is initially medical; systemic isotretinoin has been shown to reduce the bulk of rhinophyma. Many surgical techniques have also been described, all of which involve tissue removal. Previous literature has demonstrated other skin conditions mimicking this diagnosis including angiosarcoma, squamous cell carcinoma and sarcoidosis.2

A 52-year-old woman was referred to ear, nose and throat (ENT) from dermatology for surgical management of rhinophyma. She described a 3-year history of an increasing swelling on the tip of her nose (figure 1). During this time, she underwent extensive conservative treatment with...

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CTLA-4 polymorphisms are associated with treatment outcomes of patients with multiple myeloma receiving bortezomib-based regimens

Abstract

Single-nucleotide polymorphisms (SNPs) of cytotoxic T lymphocyte antigen-4 (CTLA-4) are important risk factors associated with autoimmune diseases and malignancies. This study explored the association of CTLA-4SNPs with the development of myeloma and evaluated the outcome of patients receiving bortezomib-based regimens in relation to CTLA-4SNPs. Peripheral blood samples from 86 patients with multiple myeloma (MM) and 154 healthy controls were obtained to investigate CTLA4 polymorphisms. Five SNP genotypes of CTLA-4, namely, −1772 (rs733618), −1661 (rs4553808), −318 (rs5742909), CT60 (rs3087243), and +49 (rs231775), were evaluated through TaqMan SNP genotyping assays (Applied Biosystems). Some of the CTLA-4 polymorphisms displayed frequencies that vary among ethnic groups. Kaplan–Meier analysis revealed that patients with rs733618 GG showed a significantly lower disease-free survival (0 vs. 57.4%, P = 0.020) and overall survival (46.3 vs. 83.3%, P = 0.026) than those with GA+AA following bortezomib-based therapy. Multivariate analyses showed that rs733618 GG was a risk factor for OS (HR = 0.012; 95% CI = 0.001–0.199; P = 0.002). The incidence of nonhematologic grade 3/4 adverse events significantly increased in the rs4553808 GG+GA group compared with that in the AA group (P = 0.036). CTLA-4 rs733618 GG reduced the progression-free survival and the overall survival of patients with MM who received bortezomib-based therapy. Information regarding CTLA-4 polymorphisms and haplotypes may be used to improve MM therapy. Future studies must determine the precise effect of CTLA-4 polymorphisms and haplotypes on MM therapy outcomes by using different cohorts with a large number of subjects.

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MUC1-C Induces PD-L1 and Immune Evasion in Triple-Negative Breast Cancer

The immune checkpoint ligand PD-L1 and the transmembrane mucin MUC1 are upregulated in triple-negative breast cancer (TNBC), where they contribute to its aggressive pathogenesis. Here, we report that genetic or pharmacological targeting of the oncogenic MUC1 subunit MUC1-C is sufficient to suppress PD-L1 expression in TNBC cells. Mechanistic investigations showed that MUC1-C acted to elevate PD-L1 transcription by recruitment of MYC and NF-κB p65 to the PD-L1 promoter. In an immunocompetent model of TNBC in which Eo771/MUC1-C cells were engrafted into MUC1 transgenic mice, we showed that targeting MUC1-C associated with PD-L1 suppression, increases in tumor-infiltrating CD8+ T cells and tumor cell killing. MUC1 expression in TNBCs also correlated inversely with CD8, CD69, and GZMB, and downregulation of these markers associated with decreased survival. Taken together, our findings show how MUC1 contributes to immune escape in TNBC, and they offer a rationale to target MUC1-C as a novel immunotherapeutic approach for TNBC treatment.Significance: These findings show how upregulation of the transmembrane mucin MUC1 contributes to immune escape in an aggressive form of breast cancer, with potential implications for a novel immunotherapeutic approach. Cancer Res; 78(1); 1–11. ©2017 AACR.

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KRAS Oncogenic Signaling Extends beyond Cancer Cells to Orchestrate the Microenvironment

KRAS is one of the most frequently mutated oncogenes in cancer, being a potent initiator of tumorigenesis, a strong inductor of malignancy, and a predictive biomarker of response to therapy. Despite the large investment to understand the effects of KRAS activation in cancer cells, pharmacologic targeting of KRAS or its downstream effectors has not yet been successful at the clinical level. Recent studies are now describing new mechanisms of KRAS-induced tumorigenesis by analyzing its effects on the components of the tumor microenvironment. These studies revealed that the activation of KRAS on cancer cells extends to the surrounding microenvironment, affecting the properties and functions of its constituents. Herein, we discuss the most emergent perspectives on the relationship between KRAS-mutant cancer cells and their microenvironment components. Cancer Res; 78(1); 1–8. ©2017 AACR.

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MUC1-C Induces PD-L1 and Immune Evasion in Triple-Negative Breast Cancer

The immune checkpoint ligand PD-L1 and the transmembrane mucin MUC1 are upregulated in triple-negative breast cancer (TNBC), where they contribute to its aggressive pathogenesis. Here, we report that genetic or pharmacological targeting of the oncogenic MUC1 subunit MUC1-C is sufficient to suppress PD-L1 expression in TNBC cells. Mechanistic investigations showed that MUC1-C acted to elevate PD-L1 transcription by recruitment of MYC and NF-κB p65 to the PD-L1 promoter. In an immunocompetent model of TNBC in which Eo771/MUC1-C cells were engrafted into MUC1 transgenic mice, we showed that targeting MUC1-C associated with PD-L1 suppression, increases in tumor-infiltrating CD8+ T cells and tumor cell killing. MUC1 expression in TNBCs also correlated inversely with CD8, CD69, and GZMB, and downregulation of these markers associated with decreased survival. Taken together, our findings show how MUC1 contributes to immune escape in TNBC, and they offer a rationale to target MUC1-C as a novel immunotherapeutic approach for TNBC treatment.Significance: These findings show how upregulation of the transmembrane mucin MUC1 contributes to immune escape in an aggressive form of breast cancer, with potential implications for a novel immunotherapeutic approach. Cancer Res; 78(1); 1–11. ©2017 AACR.

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KRAS Oncogenic Signaling Extends beyond Cancer Cells to Orchestrate the Microenvironment

KRAS is one of the most frequently mutated oncogenes in cancer, being a potent initiator of tumorigenesis, a strong inductor of malignancy, and a predictive biomarker of response to therapy. Despite the large investment to understand the effects of KRAS activation in cancer cells, pharmacologic targeting of KRAS or its downstream effectors has not yet been successful at the clinical level. Recent studies are now describing new mechanisms of KRAS-induced tumorigenesis by analyzing its effects on the components of the tumor microenvironment. These studies revealed that the activation of KRAS on cancer cells extends to the surrounding microenvironment, affecting the properties and functions of its constituents. Herein, we discuss the most emergent perspectives on the relationship between KRAS-mutant cancer cells and their microenvironment components. Cancer Res; 78(1); 1–8. ©2017 AACR.

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Epigenetic Reprogramming Strategies to Reverse Global Loss of 5-Hydroxymethylcytosine, a Prognostic Factor for Poor Survival in High-grade Serous Ovarian Cancer

PURPOSE: A major challenge in platinum-based cancer therapy is the clinical management of chemoresistant tumors, which have a largely unknown pathogenesis at the level of epigenetic regulation. EXPERIMENTAL DESIGN: We evaluated the potential of using global loss of 5-hydroxymethylcytosine (5-hmC) levels as a novel diagnostic and prognostic epigenetic marker to better assess platinum-based chemotherapy response and clinical outcome in high-grade serous tumors (HGSOC), the most common and deadliest subtype of ovarian cancer. Furthermore, we identified a targetable pathway to reverse these epigenetic changes, both genetically and pharmacologically. RESULTS: This study shows that decreased 5-hmC levels are an epigenetic hallmark for malignancy and tumor progression in HGSOC. In addition, global 5-hmC loss is associated with a decreased response to platinum-based chemotherapy, shorter time to relapse, and poor overall survival in newly diagnosed HGSOC patients. Interestingly, the rescue of 5-hmC loss restores sensitivity to platinum chemotherapy in vitro and in vivo, decreases the percentage of tumor cells with cancer stem cell markers, and increases overall survival in an aggressive animal model of platinum resistant disease. CONCLUSIONS: Consequently, a global analysis of patient 5-hmC levels should be included in future clinical trials, which use pretreatment with epigenetic adjuvants to elevate 5-hmC levels and improve the efficacy of current chemotherapies. Identifying prognostic epigenetic markers and altering chemotherapeutic regimens to incorporate DNMTi pretreatment in tumors with low 5-hmC levels could have important clinical implications for newly diagnosed HGSOC disease.

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Loss-of-function mutations in Calcitonin receptor (CALCR) identify highly aggressive glioblastoma with poor outcome

Purpose Despite significant advances in the understanding of the biology, the prognosis of glioblastoma (GBM) remains dismal. The objective was to carry out whole exome sequencing (WES) of Indian glioma and integrate with that of TCGA to find clinically relevant mutated pathways. Experimental Design WES of different astrocytoma samples (n=42; Indian cohort) was carried out and compared to that of TCGA cohort. An integrated analysis of mutated genes from Indian and TCGA cohorts was carried out to identify survival association of pathways with genetic alterations. Patient-derived glioma stem-like cells, glioma cell lines and mouse xenograft models were used for functional characterization of Calcitonin Receptor (CALCR) and establish it as a therapeutic target. Results A similar mutation spectrum between Indian cohort and TCGA cohort was demonstrated. An integrated analysis identified GBMs with defective "Neuroactive ligand-receptor interaction" pathway (n=23; 9.54%) have significantly poor prognosis (p0.0001). Further, GBMs with mutated Calcitonin receptor (CALCR) or reduced transcripts levels predicted poor prognosis. Exogenously added Calcitonin (CT) inhibited various properties of glioma cells and pro-oncogenic signaling pathways in a CALCR-dependent manner. Patient-derived mutations in CALCR abolished these functions with the degree of loss-of-function negatively correlating with patient survival. WT CALCR, but not the mutant versions, inhibited Ras-mediated transformation of immortalized astrocytes in vitro. Further, CT inhibited patient derived neurospheres growth and in vivo glioma tumor growth in a mouse model. Conclusions We demonstrate CT-CALCR signaling axis is an important tumor suppressor pathway in glioma and establish CALCR as a novel therapeutic target for GBM.

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Epigenetic Reprogramming Strategies to Reverse Global Loss of 5-Hydroxymethylcytosine, a Prognostic Factor for Poor Survival in High-grade Serous Ovarian Cancer

PURPOSE: A major challenge in platinum-based cancer therapy is the clinical management of chemoresistant tumors, which have a largely unknown pathogenesis at the level of epigenetic regulation. EXPERIMENTAL DESIGN: We evaluated the potential of using global loss of 5-hydroxymethylcytosine (5-hmC) levels as a novel diagnostic and prognostic epigenetic marker to better assess platinum-based chemotherapy response and clinical outcome in high-grade serous tumors (HGSOC), the most common and deadliest subtype of ovarian cancer. Furthermore, we identified a targetable pathway to reverse these epigenetic changes, both genetically and pharmacologically. RESULTS: This study shows that decreased 5-hmC levels are an epigenetic hallmark for malignancy and tumor progression in HGSOC. In addition, global 5-hmC loss is associated with a decreased response to platinum-based chemotherapy, shorter time to relapse, and poor overall survival in newly diagnosed HGSOC patients. Interestingly, the rescue of 5-hmC loss restores sensitivity to platinum chemotherapy in vitro and in vivo, decreases the percentage of tumor cells with cancer stem cell markers, and increases overall survival in an aggressive animal model of platinum resistant disease. CONCLUSIONS: Consequently, a global analysis of patient 5-hmC levels should be included in future clinical trials, which use pretreatment with epigenetic adjuvants to elevate 5-hmC levels and improve the efficacy of current chemotherapies. Identifying prognostic epigenetic markers and altering chemotherapeutic regimens to incorporate DNMTi pretreatment in tumors with low 5-hmC levels could have important clinical implications for newly diagnosed HGSOC disease.

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Loss-of-function mutations in Calcitonin receptor (CALCR) identify highly aggressive glioblastoma with poor outcome

Purpose Despite significant advances in the understanding of the biology, the prognosis of glioblastoma (GBM) remains dismal. The objective was to carry out whole exome sequencing (WES) of Indian glioma and integrate with that of TCGA to find clinically relevant mutated pathways. Experimental Design WES of different astrocytoma samples (n=42; Indian cohort) was carried out and compared to that of TCGA cohort. An integrated analysis of mutated genes from Indian and TCGA cohorts was carried out to identify survival association of pathways with genetic alterations. Patient-derived glioma stem-like cells, glioma cell lines and mouse xenograft models were used for functional characterization of Calcitonin Receptor (CALCR) and establish it as a therapeutic target. Results A similar mutation spectrum between Indian cohort and TCGA cohort was demonstrated. An integrated analysis identified GBMs with defective "Neuroactive ligand-receptor interaction" pathway (n=23; 9.54%) have significantly poor prognosis (p0.0001). Further, GBMs with mutated Calcitonin receptor (CALCR) or reduced transcripts levels predicted poor prognosis. Exogenously added Calcitonin (CT) inhibited various properties of glioma cells and pro-oncogenic signaling pathways in a CALCR-dependent manner. Patient-derived mutations in CALCR abolished these functions with the degree of loss-of-function negatively correlating with patient survival. WT CALCR, but not the mutant versions, inhibited Ras-mediated transformation of immortalized astrocytes in vitro. Further, CT inhibited patient derived neurospheres growth and in vivo glioma tumor growth in a mouse model. Conclusions We demonstrate CT-CALCR signaling axis is an important tumor suppressor pathway in glioma and establish CALCR as a novel therapeutic target for GBM.

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BET Proteins as Targets for Anticancer Treatment [Review]

Bromodomain and extraterminal domain (BET) proteins are epigenetic readers that regulate gene expression and are involved in cancer pathogenesis. Over the last years, several BET inhibitors have been developed and clinically tested. Results from the first clinical trials show limited single-agent activity in a small subset of patients with hematologic malignancies and in NUT carcinoma. Adverse events have been observed and may limit treatment compliance. Here, we review the preclinical rationale for targeting BET proteins in cancer and the preliminary results from clinical trials, and outline future directions for the use of BET inhibitors as antitumor agents.

Significance: BET inhibitors represent a new class of anticancer agents. Results from the first clinical trials confirm the antitumor potential of BET inhibitors, but their efficacy as single agents seems to be limited. Based on preclinical data, combination therapies with other anticancer agents and the development of a new generation of compounds may open new possibilities for targeting BET proteins as effective anticancer strategies. Cancer Discov; 8(1); 1–13. ©2017 AACR.

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Effectiveness of Pharmaceutical Smoking Cessation Aids in a Nationally Representative Cohort of American Smokers

Abstract

Background

Despite strong efficacy in randomized trials, the population effectiveness of pharmaceutical aids in long-term smoking cessation is lacking, possibly because of confounding (factors that are associated with both pharmaceutical aid use and difficulty quitting). Matching techniques in longitudinal studies can remove this confounding bias.

Methods

Using the nationally representative Tobacco Use Supplement to the Current Population Survey (TUS-CPS), we assessed the effectiveness of medications to aid quitting among baseline adult smokers who attempted to quit prior to one year of follow-up in two longitudinal studies: 2002–2003 and 2010–2011. Pharmaceutical aid users and nonusers with complete data (n = 2129) were matched using propensity score models with 12 potential confounders (age, sex, race-ethnicity, education, smoking intensity, nicotine dependence, previous quit history, self-efficacy to quit, smoke-free homes, survey year, and cessation aid use). Using matched data sets, logistic regression models were fit to assess whether use of any individual pharmaceutical aid increased the proportion of patients who were abstinent for 30 days or more at follow-up.

Results

Propensity score matching markedly improved balance on the potential confounders between the pharmaceutical aid use groups. Using matched samples to provide a balanced comparison, there was no evidence that use of varenicline (adjusted risk difference [aRD] = 0.01, 95% confidence interval [CI] = –0.07 to 0.11), bupropion (aRD = 0.02, 95% CI = –0.04 to 0.09), or nicotine replacement (aRD = 0.01, 95% CI = –0.03 to 0.06) increased the probability of 30 days or more smoking abstinence at one-year follow-up.

Conclusions

The lack of effectiveness of pharmaceutical aids in increasing long-term cessation in population samples is not an artifact caused by confounded analyses. A possible explanation is that counseling and support interventions provided in efficacy trials are rarely delivered in the general population.

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Smoking Cessation Pharmacotherapy, Even Without Counseling, Remains a Cornerstone of Treatment

In this issue of the Journal, Leas and colleagues report results from a prospective observational study of smokers making a quit attempt that concludes, "…the simple provision of pharmaceutical aids to smokers does not appear to be an effective way to increase the proportion who successfully quit for the long term" (1). Despite the rigorous methodological aspects of this study, we believe this conclusion is overstated for three main reasons: the conflicting body of evidence from large effectiveness randomized controlled trials (RCTs), which do not suffer from confounding; residual confounding, particularly by smoker type; and recall bias tending to under capture failed quit attempts that did not involve pharmacotherapy. While this study could bring useful attention to the benefits of counseling, it would be harmful if it discouraged cessation medication use when counseling was unavailable.

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The Antagonistic Effect of Selenium on Lead-Induced Immune Dysfunction via Recovery of Cytokine and Heat Shock Protein Expression in Chicken Neutrophils

Abstract

Lead (Pb) is a ubiquitous and toxic heavy metal and it can damage the immune system in humans and animals. Many researchers have reported that Selenium (Se) could possess various pharmacological effects in mammals. However, few studies have been carried out to investigate the protective role of Se in birds, especially in chickens. In this study, we investigated the protective effects of Se against Pb-induced inflammatory responses and the expression of heat shock proteins (HSPs) in peripheral blood neutrophils. One hundred eighty Hy-Line brown chickens were randomly divided into the control group (Con group), Se supplementation group (+Se group), Pb supplementation group (+Pb group), and the Se and Pb compound group (Se+Pb group). On the 90th day of the experiment, the peripheral blood was collected to extract neutrophils, and then, the levels of HSPs and cytokines were examined. The results showed that, after Pb treatment, the levels of IL-(1β, 1R, 4, 8, 10, and 12β), TGF-β4, and HSP (27, 40, 60, 70, and 90) mRNA were significantly increased and levels of IL-2 and IFN-γ mRNA were decreased compared with those in the control group. Compared with the control group, the protein levels of HSP60 and HSP70 were also increased in the Pb treatment group. Co-administration of Se (1 mg/kg/day) and Pb resulted in a reversal of the Pb-induced cytokine changes in neutrophils accompanied by a significant decrease in HSPs. Our study demonstrated that Pb could decrease the immune function via changing the expression of cytokines and HSPs in chicken neutrophils, but Se could relieve the toxic effect induced by Pb.

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The Antagonistic Effect of Selenium on Lead-Induced Immune Dysfunction via Recovery of Cytokine and Heat Shock Protein Expression in Chicken Neutrophils

Abstract

Lead (Pb) is a ubiquitous and toxic heavy metal and it can damage the immune system in humans and animals. Many researchers have reported that Selenium (Se) could possess various pharmacological effects in mammals. However, few studies have been carried out to investigate the protective role of Se in birds, especially in chickens. In this study, we investigated the protective effects of Se against Pb-induced inflammatory responses and the expression of heat shock proteins (HSPs) in peripheral blood neutrophils. One hundred eighty Hy-Line brown chickens were randomly divided into the control group (Con group), Se supplementation group (+Se group), Pb supplementation group (+Pb group), and the Se and Pb compound group (Se+Pb group). On the 90th day of the experiment, the peripheral blood was collected to extract neutrophils, and then, the levels of HSPs and cytokines were examined. The results showed that, after Pb treatment, the levels of IL-(1β, 1R, 4, 8, 10, and 12β), TGF-β4, and HSP (27, 40, 60, 70, and 90) mRNA were significantly increased and levels of IL-2 and IFN-γ mRNA were decreased compared with those in the control group. Compared with the control group, the protein levels of HSP60 and HSP70 were also increased in the Pb treatment group. Co-administration of Se (1 mg/kg/day) and Pb resulted in a reversal of the Pb-induced cytokine changes in neutrophils accompanied by a significant decrease in HSPs. Our study demonstrated that Pb could decrease the immune function via changing the expression of cytokines and HSPs in chicken neutrophils, but Se could relieve the toxic effect induced by Pb.

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The PRKD1 E710D hotspot mutation is highly specific in separating polymorphous adenocarcinoma of the palate from adenoid cystic carcinoma and pleomorphic adenoma on FNA

BACKGROUND

Polymorphous adenocarcinoma (PAC) of the palatal minor salivary glands, previously known as polymorphous low-grade adenocarcinoma, is the second most common intraoral malignant salivary gland carcinoma after adenoid cystic carcinoma (ACC) and carries an excellent prognosis. Unfortunately, PAC demonstrates cytological overlap with 2 other salivary gland tumors frequently encountered in the same location, namely ACC and pleomorphic adenoma (PA). Recently, the protein kinase D1 (PRKD1) hotspot mutation E710D was demonstrated to be specific for PAC and to be present in the majority of cases. The objective of the current study was to investigate the value of PRKD1 hotspot sequencing in identifying PAC in paired fine-needle aspiration (FNA) and surgical specimens from cases of PAC, ACC, and PA.

METHODS

Paired May-Grunwald-Giemsa-stained FNA and corresponding surgical specimens were collected from 18 PAC cases, 25 ACC cases, and 21 PA cases. Both sets of specimens were subjected to dideoxynucleotide sequencing of PRKD1 exon 15, including the PRKD1 E710D hotspot.

RESULTS

Of the PAC cases, approximately 50% demonstrated identical PRKD1 E710D hotspot mutations on the FNA specimen and corresponding surgical specimen. Two ACC specimens had point mutations within the sequenced region in the FNA specimen as well as the surgical specimen, but none were located in the hotspot region. None of the PA cases demonstrated PRKD1 mutations. The specificity of the PRKD1 hotspot mutation for identifying PAC among ACC and PA cases was 100% whereas the sensitivity was 50%.

CONCLUSIONS

The PRKD1 E710D hotspot mutation is highly specific for identifying PAC on FNA among cases of ACC and PA, whereas the sensitivity is only modest. Alternative PRKD1 mutations exclude PAC, and are more suggestive of ACC. Cancer Cytopathol 2017. © 2017 American Cancer Society.

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The PRKD1 E710D hotspot mutation is highly specific in separating polymorphous adenocarcinoma of the palate from adenoid cystic carcinoma and pleomorphic adenoma on FNA

BACKGROUND

Polymorphous adenocarcinoma (PAC) of the palatal minor salivary glands, previously known as polymorphous low-grade adenocarcinoma, is the second most common intraoral malignant salivary gland carcinoma after adenoid cystic carcinoma (ACC) and carries an excellent prognosis. Unfortunately, PAC demonstrates cytological overlap with 2 other salivary gland tumors frequently encountered in the same location, namely ACC and pleomorphic adenoma (PA). Recently, the protein kinase D1 (PRKD1) hotspot mutation E710D was demonstrated to be specific for PAC and to be present in the majority of cases. The objective of the current study was to investigate the value of PRKD1 hotspot sequencing in identifying PAC in paired fine-needle aspiration (FNA) and surgical specimens from cases of PAC, ACC, and PA.

METHODS

Paired May-Grunwald-Giemsa-stained FNA and corresponding surgical specimens were collected from 18 PAC cases, 25 ACC cases, and 21 PA cases. Both sets of specimens were subjected to dideoxynucleotide sequencing of PRKD1 exon 15, including the PRKD1 E710D hotspot.

RESULTS

Of the PAC cases, approximately 50% demonstrated identical PRKD1 E710D hotspot mutations on the FNA specimen and corresponding surgical specimen. Two ACC specimens had point mutations within the sequenced region in the FNA specimen as well as the surgical specimen, but none were located in the hotspot region. None of the PA cases demonstrated PRKD1 mutations. The specificity of the PRKD1 hotspot mutation for identifying PAC among ACC and PA cases was 100% whereas the sensitivity was 50%.

CONCLUSIONS

The PRKD1 E710D hotspot mutation is highly specific for identifying PAC on FNA among cases of ACC and PA, whereas the sensitivity is only modest. Alternative PRKD1 mutations exclude PAC, and are more suggestive of ACC. Cancer Cytopathol 2017. © 2017 American Cancer Society.

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Prediction for sustained deep molecular response of BCR-ABL1 levels in patients with chronic myeloid leukemia in chronic phase

BACKGROUND

The achievement of a sustained deep molecular response is a goal of increasing relevance because it opens the possibility of treatment discontinuation. The objective of this analysis was to develop a prediction model for a sustained molecular response with BCR-ABL1 level <0.0032% on the international scale (MR^4.5) for at least 2 years according to BCR-ABL1 levels achieved within the first 12 months of therapy.

METHODS

Data for 603 patients with newly diagnosed chronic myeloid leukemia in chronic phase in consecutive prospective clinical trials were analyzed. The best fit average molecular response was defined by robust linear regression models, with which the average molecular levels were defined. The minimum acceptable molecular response was defined by quantile regression for the 95th percentile, with which the worst 5% BCR-ABL1 levels were identified.

RESULTS

In 603 patients with a median follow-up of 103 months, 2002 BCR-ABL1–level data points within 1 year of tyrosine kinase inhibitors were identified. The regression equation for the best fit average levels for a sustained MR^4.5 was Log₁₀(PCR) = −0.1424 × (Months) – 0.8668, and the regression equation for minimum acceptable levels was Log₁₀(PCR) = −0.1403 × (Months) + 0.6142 (where PCR indicates polymerase chain reaction). To achieve a sustained MR^4.5, the best fit average levels were 0.051%, 0.019%, 0.007%, and 0.003% at 3, 6, 9, and 12 months, respectively; the minimum acceptable levels were 1.561%, 0.592%, 0.225%, and 0.085% at 3, 6, 9, and 12 months, respectively.

CONCLUSIONS

This model proposes optimal values that predict the highest probability of reaching such a goal. These values can be used to guide therapy when a sustained MR^4.5 is the objective. Cancer 2017. © 2017 American Cancer Society.

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Low testosterone at first prostate-specific antigen failure and assessment of risk of death in men with unfavorable-risk prostate cancer treated on prospective clinical trials

BACKGROUND

Low testosterone at the time of diagnosis of prostate cancer has been associated with a worse prognosis. Whether this is true and how to define the best treatment approach at the time of first prostate-specific antigen (PSA) failure to the authors' knowledge has not been elucidated to date and was studied herein.

METHODS

Between 1995 and 2001, a total of 58 men with unfavorable-risk PC who were treated on clinical trials with radiotherapy and androgen deprivation therapy (ADT) had available testosterone levels at the time of PSA failure. Cox and Fine and Gray regressions were performed to ascertain whether low versus normal testosterone was associated with the risk of PC-specific mortality, other-cause mortality, and all-cause mortality adjusting for age, salvage ADT, and known PC prognostic factors.

RESULTS

After a median follow-up of 6.68 years after PSA failure, 31 men (53.4%) had died; 10 of PC (32.3%), of which 8 of 11 (72.7%) versus 2 of 47 (4.3%) deaths occurred in men with low versus normal testosterone at the time of PSA failure, respectively. A significant increase in the risk of all-cause mortality (adjusted hazard ratio [AHR], 2.54; 95% confidence interval [95% CI], 1.04-6.21 [P = .04]) and PC-specific mortality (AHR, 13.71; 95% CI, 2.4-78.16 [P = .003]), with a reciprocal trend toward a decreased risk of other-cause mortality (AHR, 0.18; 95% CI, 0.02-1.55 [P = .12]) was observed in men with low versus normal testosterone.

CONCLUSIONS

Low, but not necessarily castrate, testosterone levels at the time of PSA failure confer a very poor prognosis. These observations provide evidence to support testosterone testing at the time of PSA failure. Given prolonged survival when abiraterone or docetaxel is added to ADT in men with castrate-sensitive metastatic PC and possibly localized high-risk PC provides a rationale supporting their use with ADT in men with low testosterone in the setting of a phase 2 trial. Cancer 2017. © 2017 American Cancer Society.

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Bovine leukemia virus linked to breast cancer but not coinfection with human papillomavirus: Case-control study of women in Texas

BACKGROUND

Bovine leukemia virus (BLV) and human papillomavirus (HPV) were previously identified in human breast tissue and have been associated with breast cancer in independent studies. The objective of the current study was to test for the presence of BLV and HPV in the same breast tissue specimens to determine whether the viruses were associated with breast cancer either singly or together.

METHODS

Archival formalin-fixed paraffin-embedded breast tissue sections from 216 women were received from The University of Texas MD Anderson Cancer Center along with patient diagnosis. In situ polymerase chain reaction and/or DNA hybridization methods were used to detect targeted DNA segments of BLV and HPV. Standard statistical methods were used to calculate age-adjusted odds ratios, attributable risk, and P values for the trend related to the association between presence of a virus and a diagnosis of breast disease.

RESULTS

Women diagnosed with breast cancer were significantly more likely to have BLV DNA in their breast tissue compared with women with benign diagnoses and no history of breast cancer. Women with breast pathology classified as premalignant and no history of breast cancer also were found to have an elevated risk of harboring BLV DNA in their breast tissue. HPV status was not associated with malignancy, premalignant breast disease, or the presence of BLV in the breast tissues.

CONCLUSIONS

The data from the current study supported previous findings of a significant association between BLV DNA in breast tissue and a diagnosis of breast cancer, but did not demonstrate oncogenic strains of HPV associated with breast cancer or the presence of BLV DNA in breast tissue. The authors believe the findings of the current study contribute to overall knowledge regarding a possible causal role for viruses in human breast cancer. Cancer 2017. © 2017 American Cancer Society.

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Pooled analysis of stereotactic ablative radiotherapy for primary renal cell carcinoma: A report from the International Radiosurgery Oncology Consortium for Kidney (IROCK)

BACKGROUND

Stereotactic ablative radiotherapy (SABR) is an emerging therapy for primary renal cell carcinoma. The authors assessed safety, efficacy, and survival in a multi-institutional setting. Outcomes between single-fraction and multifraction SABR were compared.

METHODS

Individual patient data sets from 9 International Radiosurgery Oncology Consortium for Kidney institutions across Germany, Australia, the United States, Canada, and Japan were pooled. Toxicities were recorded using Common Terminology Criteria for Adverse Events, version 4.0. Patient, tumor, and treatment characteristics were stratified according to the number of radiotherapy fractions (single vs multiple). Survival outcomes were examined using Kaplan-Meier estimates and Cox proportional-hazards regression.

RESULTS

Of 223 patients, 118 received single-fraction SABR, and 105 received multifraction SABR. The mean patient age was 72 years, and 69.5% of patients were men. There were 83 patients with grade 1 and 2 toxicity (35.6%) and 3 with grade 3 and 4 toxicities (1.3%). The rates of local control, cancer-specific survival, and progression-free survival were 97.8%, 95.7%, and 77.4%, respectively, at 2 years; and they were 97.8%, 91.9%, and 65.4%, respectively, at 4 years. On multivariable analysis, tumors with a larger maximum dimension and the receipt of multifraction SABR were associated with poorer progression-free survival (hazard ratio, 1.16 [P < .01] and 1.13 [P = .02], respectively) and poorer cancer-specific survival (hazard ratio, 1.28 [P < .01] and 1.33 [P = .01], respectively). There were no differences in local failure between the single-fraction cohort (n = 1) and the multifraction cohort (n = 2; P = .60). The mean ( ± standard deviation) estimated glomerular filtration rate at baseline was 59.9 ± 21.9 mL per minute, and it decreased by 5.5 ± 13.3 mL per minute (P < .01).

CONCLUSIONS

SABR is well tolerated and locally effective for treating patients who have primary renal cell carcinoma and has an acceptable impact on renal function. An interesting observation is that patients who receive single-fraction SABR appear to be less likely to progress distantly or to die of cancer. Cancer 2017. © 2017 American Cancer Society.

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Personal history of proliferative breast disease with atypia and risk of multifocal breast cancer

BACKGROUND

A history of proliferative breast disease with atypia (PBDA) may be indicative of an increased risk not just of breast cancer but also of a more aggressive form of breast cancer.

METHODS

Multifocal breast cancer (MFBC), defined as 2 or more tumors in the same breast upon a diagnosis of cancer, is associated with a poorer prognosis than unifocal (single-tumor) breast cancer. PBDA, including atypical ductal hyperplasia and atypical lobular hyperplasia, is a known risk factor for breast cancer. Using New Hampshire Mammography Network data collected for 3567 women diagnosed with incident breast cancer from 2004 to 2014, this study assessed the risk of MFBC associated with a previous diagnosis of PBDA.

RESULTS

Women with a history of PBDA were found to be twice as likely to be subsequently diagnosed with MFBC as women with no history of benign breast disease (BBD; odds ratio [OR], 2.23; 95% confidence interval [CI], 1.08-4.61). Ductal carcinoma in situ on initial biopsy was associated with a 2-fold increased risk of MFBC in comparison with invasive cancer (OR, 2.13; 95% CI, 1.58-2.88). BBD and proliferative BBD without atypia were not associated with MFBC.

CONCLUSIONS

Women with a history of previous PBDA may be at increased risk for MFBC. Women with a history of PBDA may benefit from additional presurgical clinical workup. Cancer 2017. © 2017 American Cancer Society.

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Prediction for sustained deep molecular response of BCR-ABL1 levels in patients with chronic myeloid leukemia in chronic phase

BACKGROUND

The achievement of a sustained deep molecular response is a goal of increasing relevance because it opens the possibility of treatment discontinuation. The objective of this analysis was to develop a prediction model for a sustained molecular response with BCR-ABL1 level <0.0032% on the international scale (MR^4.5) for at least 2 years according to BCR-ABL1 levels achieved within the first 12 months of therapy.

METHODS

Data for 603 patients with newly diagnosed chronic myeloid leukemia in chronic phase in consecutive prospective clinical trials were analyzed. The best fit average molecular response was defined by robust linear regression models, with which the average molecular levels were defined. The minimum acceptable molecular response was defined by quantile regression for the 95th percentile, with which the worst 5% BCR-ABL1 levels were identified.

RESULTS

In 603 patients with a median follow-up of 103 months, 2002 BCR-ABL1–level data points within 1 year of tyrosine kinase inhibitors were identified. The regression equation for the best fit average levels for a sustained MR^4.5 was Log₁₀(PCR) = −0.1424 × (Months) – 0.8668, and the regression equation for minimum acceptable levels was Log₁₀(PCR) = −0.1403 × (Months) + 0.6142 (where PCR indicates polymerase chain reaction). To achieve a sustained MR^4.5, the best fit average levels were 0.051%, 0.019%, 0.007%, and 0.003% at 3, 6, 9, and 12 months, respectively; the minimum acceptable levels were 1.561%, 0.592%, 0.225%, and 0.085% at 3, 6, 9, and 12 months, respectively.

CONCLUSIONS

This model proposes optimal values that predict the highest probability of reaching such a goal. These values can be used to guide therapy when a sustained MR^4.5 is the objective. Cancer 2017. © 2017 American Cancer Society.

http://ift.tt/2kSdDln

Low testosterone at first prostate-specific antigen failure and assessment of risk of death in men with unfavorable-risk prostate cancer treated on prospective clinical trials

BACKGROUND

Low testosterone at the time of diagnosis of prostate cancer has been associated with a worse prognosis. Whether this is true and how to define the best treatment approach at the time of first prostate-specific antigen (PSA) failure to the authors' knowledge has not been elucidated to date and was studied herein.

METHODS

Between 1995 and 2001, a total of 58 men with unfavorable-risk PC who were treated on clinical trials with radiotherapy and androgen deprivation therapy (ADT) had available testosterone levels at the time of PSA failure. Cox and Fine and Gray regressions were performed to ascertain whether low versus normal testosterone was associated with the risk of PC-specific mortality, other-cause mortality, and all-cause mortality adjusting for age, salvage ADT, and known PC prognostic factors.

RESULTS

After a median follow-up of 6.68 years after PSA failure, 31 men (53.4%) had died; 10 of PC (32.3%), of which 8 of 11 (72.7%) versus 2 of 47 (4.3%) deaths occurred in men with low versus normal testosterone at the time of PSA failure, respectively. A significant increase in the risk of all-cause mortality (adjusted hazard ratio [AHR], 2.54; 95% confidence interval [95% CI], 1.04-6.21 [P = .04]) and PC-specific mortality (AHR, 13.71; 95% CI, 2.4-78.16 [P = .003]), with a reciprocal trend toward a decreased risk of other-cause mortality (AHR, 0.18; 95% CI, 0.02-1.55 [P = .12]) was observed in men with low versus normal testosterone.

CONCLUSIONS

Low, but not necessarily castrate, testosterone levels at the time of PSA failure confer a very poor prognosis. These observations provide evidence to support testosterone testing at the time of PSA failure. Given prolonged survival when abiraterone or docetaxel is added to ADT in men with castrate-sensitive metastatic PC and possibly localized high-risk PC provides a rationale supporting their use with ADT in men with low testosterone in the setting of a phase 2 trial. Cancer 2017. © 2017 American Cancer Society.

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Bovine leukemia virus linked to breast cancer but not coinfection with human papillomavirus: Case-control study of women in Texas

BACKGROUND

Bovine leukemia virus (BLV) and human papillomavirus (HPV) were previously identified in human breast tissue and have been associated with breast cancer in independent studies. The objective of the current study was to test for the presence of BLV and HPV in the same breast tissue specimens to determine whether the viruses were associated with breast cancer either singly or together.

METHODS

Archival formalin-fixed paraffin-embedded breast tissue sections from 216 women were received from The University of Texas MD Anderson Cancer Center along with patient diagnosis. In situ polymerase chain reaction and/or DNA hybridization methods were used to detect targeted DNA segments of BLV and HPV. Standard statistical methods were used to calculate age-adjusted odds ratios, attributable risk, and P values for the trend related to the association between presence of a virus and a diagnosis of breast disease.

RESULTS

Women diagnosed with breast cancer were significantly more likely to have BLV DNA in their breast tissue compared with women with benign diagnoses and no history of breast cancer. Women with breast pathology classified as premalignant and no history of breast cancer also were found to have an elevated risk of harboring BLV DNA in their breast tissue. HPV status was not associated with malignancy, premalignant breast disease, or the presence of BLV in the breast tissues.

CONCLUSIONS

The data from the current study supported previous findings of a significant association between BLV DNA in breast tissue and a diagnosis of breast cancer, but did not demonstrate oncogenic strains of HPV associated with breast cancer or the presence of BLV DNA in breast tissue. The authors believe the findings of the current study contribute to overall knowledge regarding a possible causal role for viruses in human breast cancer. Cancer 2017. © 2017 American Cancer Society.

http://ift.tt/2kRg73i

Pooled analysis of stereotactic ablative radiotherapy for primary renal cell carcinoma: A report from the International Radiosurgery Oncology Consortium for Kidney (IROCK)

BACKGROUND

Stereotactic ablative radiotherapy (SABR) is an emerging therapy for primary renal cell carcinoma. The authors assessed safety, efficacy, and survival in a multi-institutional setting. Outcomes between single-fraction and multifraction SABR were compared.

METHODS

Individual patient data sets from 9 International Radiosurgery Oncology Consortium for Kidney institutions across Germany, Australia, the United States, Canada, and Japan were pooled. Toxicities were recorded using Common Terminology Criteria for Adverse Events, version 4.0. Patient, tumor, and treatment characteristics were stratified according to the number of radiotherapy fractions (single vs multiple). Survival outcomes were examined using Kaplan-Meier estimates and Cox proportional-hazards regression.

RESULTS

Of 223 patients, 118 received single-fraction SABR, and 105 received multifraction SABR. The mean patient age was 72 years, and 69.5% of patients were men. There were 83 patients with grade 1 and 2 toxicity (35.6%) and 3 with grade 3 and 4 toxicities (1.3%). The rates of local control, cancer-specific survival, and progression-free survival were 97.8%, 95.7%, and 77.4%, respectively, at 2 years; and they were 97.8%, 91.9%, and 65.4%, respectively, at 4 years. On multivariable analysis, tumors with a larger maximum dimension and the receipt of multifraction SABR were associated with poorer progression-free survival (hazard ratio, 1.16 [P < .01] and 1.13 [P = .02], respectively) and poorer cancer-specific survival (hazard ratio, 1.28 [P < .01] and 1.33 [P = .01], respectively). There were no differences in local failure between the single-fraction cohort (n = 1) and the multifraction cohort (n = 2; P = .60). The mean ( ± standard deviation) estimated glomerular filtration rate at baseline was 59.9 ± 21.9 mL per minute, and it decreased by 5.5 ± 13.3 mL per minute (P < .01).

CONCLUSIONS

SABR is well tolerated and locally effective for treating patients who have primary renal cell carcinoma and has an acceptable impact on renal function. An interesting observation is that patients who receive single-fraction SABR appear to be less likely to progress distantly or to die of cancer. Cancer 2017. © 2017 American Cancer Society.

http://ift.tt/2ktQoyx

Personal history of proliferative breast disease with atypia and risk of multifocal breast cancer

BACKGROUND

A history of proliferative breast disease with atypia (PBDA) may be indicative of an increased risk not just of breast cancer but also of a more aggressive form of breast cancer.

METHODS

Multifocal breast cancer (MFBC), defined as 2 or more tumors in the same breast upon a diagnosis of cancer, is associated with a poorer prognosis than unifocal (single-tumor) breast cancer. PBDA, including atypical ductal hyperplasia and atypical lobular hyperplasia, is a known risk factor for breast cancer. Using New Hampshire Mammography Network data collected for 3567 women diagnosed with incident breast cancer from 2004 to 2014, this study assessed the risk of MFBC associated with a previous diagnosis of PBDA.

RESULTS

Women with a history of PBDA were found to be twice as likely to be subsequently diagnosed with MFBC as women with no history of benign breast disease (BBD; odds ratio [OR], 2.23; 95% confidence interval [CI], 1.08-4.61). Ductal carcinoma in situ on initial biopsy was associated with a 2-fold increased risk of MFBC in comparison with invasive cancer (OR, 2.13; 95% CI, 1.58-2.88). BBD and proliferative BBD without atypia were not associated with MFBC.

CONCLUSIONS

Women with a history of previous PBDA may be at increased risk for MFBC. Women with a history of PBDA may benefit from additional presurgical clinical workup. Cancer 2017. © 2017 American Cancer Society.

http://ift.tt/2kRfOpa

Pathological and Radiological Splenic Vein Involvement are Predictors of Poor Prognosis and Early Liver Metastasis After Surgery in Patients with Pancreatic Adenocarcinoma of the Body and Tail

Abstract

Background

The prognostic impact of pancreatic ductal adenocarcinoma (PDAC) invasion to the splenic vessel is controversial.

Objective

The aim of this study was to assess the clinical value of pathological and radiological splenic vessel invasion in PDACs of the body and tail.

Methods

Medical records of patients with resectable PDAC of the body and tail who underwent distal pancreatectomy between 2003 and 2016 at the Kobe University Hospital were retrospectively analyzed.

Results

Overall, 68 patients (29 female and 39 male patients) were enrolled. Pathologically determined splenic vein invasion (p-SV) and splenic artery invasion (p-SA) were identified in 21 (30.9%) and 5 (7.4%) patients, respectively. The p-SV (but not p-SA) was an independent prognostic factor in multivariate analysis (p = 0.009). On analysis of recurrence patterns, patients with PDAC positive for p-SV were at a higher risk for liver metastasis (p = 0.022); however, the associations were not significant for other recurrence patterns. Liver metastasis occurred earlier in patients who were positive for p-SV (p = 0.015). Preoperative computed tomography effectively diagnosed pathological vessel invasion (SV: sensitivity, 95.2%, specificity, 72.3%; SA: sensitivity, 100%, specificity, 84.1%). Radiological SV invasion remained significant in multivariate analysis regarding postoperative survival (p = 0.007), and was also associated with early liver metastases (p = 0.008).

Conclusions

Pathological/radiological SV invasion were independent adverse prognostic factors associated with early liver metastasis in patients with PDAC of the body/tail. Assessment of these findings may be useful in determining optimal therapeutic options in these patients.

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Validation of the Symptom Screening in Pediatrics Tool in Children Receiving Cancer Treatments

Abstract

Background

The objective was to evaluate the reliability and validity of the self-report Symptom Screening in Pediatrics Tool (SSPedi) from the perspective of children with cancer and pediatric hematopoietic stem cell transplant (HSCT) recipients.

Methods

In this multicenter study, respondents were children age eight to 18 years who had cancer or had received HSCT, and their parents. Two different child respondent populations were targeted. More symptomatic respondents were receiving active treatment for cancer, admitted to the hospital, and expected to be in the hospital three days later. Less symptomatic respondents were in maintenance therapy for acute lymphoblastic leukemia or had completed cancer therapy. Children completed SSPedi and then responded to validated self-report measures of mucositis, nausea, pain, and global quality of life. Children in the more symptomatic group repeated SSPedi and a global symptom change scale three days later. Parent proxy-report was optional. Reliability was evaluated using intraclass correlations while convergent validity was evaluated using Spearman correlations.

Results

Of 502 children enrolled, 302 were in the more symptomatic group and 200 were in the less symptomatic group. Intraclass correlation coefficients were 0.88 (95% confidence interval [CI] = 0.82 to 0.92) for test-retest reliability and 0.76 (95% CI = 0.71 to 0.80) for inter-rater reliability. The mean difference in SSPedi scores between more and less symptomatic groups was 7.8 (95% CI = 6.4 to 9.2). SSPedi was responsive to change in global symptoms. All hypothesized relationships among measures were observed.

Conclusions

SSPedi is a self-report symptom bother tool for children with cancer and HSCT recipients that is reliable, valid, and responsive to change. SSPedi can be used for clinical and research purposes. Future work should focus on integration into care delivery.

http://ift.tt/2kRYqRj

Pathological and Radiological Splenic Vein Involvement are Predictors of Poor Prognosis and Early Liver Metastasis After Surgery in Patients with Pancreatic Adenocarcinoma of the Body and Tail

Abstract

Background

The prognostic impact of pancreatic ductal adenocarcinoma (PDAC) invasion to the splenic vessel is controversial.

Objective

The aim of this study was to assess the clinical value of pathological and radiological splenic vessel invasion in PDACs of the body and tail.

Methods

Medical records of patients with resectable PDAC of the body and tail who underwent distal pancreatectomy between 2003 and 2016 at the Kobe University Hospital were retrospectively analyzed.

Results

Overall, 68 patients (29 female and 39 male patients) were enrolled. Pathologically determined splenic vein invasion (p-SV) and splenic artery invasion (p-SA) were identified in 21 (30.9%) and 5 (7.4%) patients, respectively. The p-SV (but not p-SA) was an independent prognostic factor in multivariate analysis (p = 0.009). On analysis of recurrence patterns, patients with PDAC positive for p-SV were at a higher risk for liver metastasis (p = 0.022); however, the associations were not significant for other recurrence patterns. Liver metastasis occurred earlier in patients who were positive for p-SV (p = 0.015). Preoperative computed tomography effectively diagnosed pathological vessel invasion (SV: sensitivity, 95.2%, specificity, 72.3%; SA: sensitivity, 100%, specificity, 84.1%). Radiological SV invasion remained significant in multivariate analysis regarding postoperative survival (p = 0.007), and was also associated with early liver metastases (p = 0.008).

Conclusions

Pathological/radiological SV invasion were independent adverse prognostic factors associated with early liver metastasis in patients with PDAC of the body/tail. Assessment of these findings may be useful in determining optimal therapeutic options in these patients.

http://ift.tt/2krT3c6

Utility of Routine Surveillance Imaging for Diffuse Large B-Cell Lymphoma Post Autologous Transplant: A Single Center Experience

Publication date: Available online 19 December 2017
Source:Hematology/Oncology and Stem Cell Therapy
Author(s): Ghulam Rehman Mohyuddin, Ashley Elizabeth Clark, John Roller, Leyla Shune, Tara Lin, Neil Dunavin, Ajoy Dias, Siddhartha Ganguly, Sunil Abhyankar, Joseph McGuirk, Anurag Singh
Surveillance scans after autologous stem cell transplant (auto-HCT) for patients with relapsed/refractory (RR) diffuse large B Cell lymphoma (DLBCL) have no proven survival benefit. We studied survival differences among patients with RR DLBCL post auto-HCT whose recurrences were detected clinically versus with routine surveillance imaging. Among the 139 patients with RR DLBCL that underwent auto-HCT from 2000-2014 at our institution, 37 relapsed: 21 clinical and 16 radiological. The median time to progression was 167 days for the clinical cohort and 565 days for the radiological cohort (p= 0.03), and median overall survival (OS) was 587 days and not reached, respectively (p=0.006). Most patients with relapsed DLBCL after auto-HCT were diagnosed clinically and were likely to be detected earlier and have a shorter OS. Relapse in patients with aggressive disease will likely be detected when clinically apparent, and the outcome of these patients is independent of the way the relapse is diagnosed. Thus, universal scanning after auto-HCT appears to have little benefit.



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Radiation Oncology: What's in a name?

Publication date: Available online 19 December 2017
Source:Practical Radiation Oncology
Author(s): Trevor J. Royce




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“It's The Disease of Not Listening That I Am Troubled With” – Henry IV

Publication date: Available online 19 December 2017
Source:Practical Radiation Oncology
Author(s): William T. Sause




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A letter to my children

Publication date: Available online 19 December 2017
Source:Practical Radiation Oncology
Author(s): Mordechai Reich




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Chest wall dose reduction using non-coplanar volumetric modulated arc radiotherapy for lung stereotactic ablative radiotherapy

Publication date: Available online 19 December 2017
Source:Practical Radiation Oncology
Author(s): Amy S. Yu, Peter G Maxim, Billy W Loo, Michael F Gensheimer
PurposeStereotactic ablative radiotherapy (SABR) to lung tumors close to the chest wall can cause rib fractures or chest wall pain. We evaluated and propose a clinically practical solution of using non-coplanar volumetric modulated arc radiotherapy (VMAT) to reduce chest wall dose from lung SABR.Methods and materialsTwenty lung SABR VMAT plans in which the chest wall volume receiving 30Gy or higher (V30) exceeded 30cc were re-planned by non-coplanar VMAT with opposite 15-degree couch kicks. Dosimetric parameters including chest wall V30 and V40, lung V5, V10, V20, and mean dose, Paddick high-dose conformity index, intermediate-dose conformity index, and monitor units (MU) for each plan were used to evaluate the plan quality. The treatment time was also estimated by delivering the entire treatment. Two-sided paired t-test was used to evaluate the difference of the dosimetric parameters between coplanar one arc (cVMAT1), coplanar two arcs (cVMAT2), and non-coplanar two arcs (nVMAT2) plans, and differences with p < 0.05 were considered statistically significant.ResultsV30 and V40 for chest wall were reduced on average by 20%±9% and 15%±11% (mean±SD) from cVMAT2 plans to nVMAT2 plans (p < 0.01 for both comparisons), and 8%±7% and 16%±13% from cVMAT1 plans to cVMAT2 plans (p < 0.003 for both comparisons). The differences in lung mean dose were less than 0.2Gy among cVMAT1, cVMAT2 and nVMAT2. There were no significant differences in lung V5, V10, and V20. On average, the number of MU increased 14% for nVMAT2 compared to cVMAT2. The Paddick high-dose conformity indexes were 0.88±0.03, 0.89±0.04 and 0.91±0.03, and intermediate-dose conformity indexes were 3.88±0.49, 3.80±0.44 and 3.51±0.38 for cVMAT1, cVMAT2 and nVMAT2, respectively.ConclusionsWe found that non-coplanar VMAT plans are feasible, clinically practical to deliver, and significantly reduce V30 and V40 of chest wall without increasing lung dose.



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“It's The Disease of Not Listening That I Am Troubled With” – Henry IV

Publication date: Available online 19 December 2017
Source:Practical Radiation Oncology
Author(s): William T. Sause




http://ift.tt/2kRcvhN

A letter to my children

Publication date: Available online 19 December 2017
Source:Practical Radiation Oncology
Author(s): Mordechai Reich




http://ift.tt/2kvVn1Z