Aneuploidy, TP53 mutation, and amplification of MYC correlate with increased intratumor heterogeneity and poor prognosis of breast cancer patients

Abstract

The clinical course of breast cancer varies from one patient to another. Currently, the choice of therapy relies on clinical parameters and histological and molecular tumor features. Alas, these markers are informative in only a subset of patients. Therefore, additional predictors of disease outcome would be valuable for treatment stratification. Extensive studies showed that the degree of variation of the nuclear DNA content, i.e., aneuploidy determines prognosis. Our aim was to further elucidate the molecular basis of aneuploidy. We analyzed five diploid and six aneuploid tumors with more than 20 years of follow-up. By performing FISH with a multiplexed panel of 10 probes to enumerate copy numbers in individual cells, and by sequencing 563 cancer-related genes, we analyzed how aneuploidy is linked to intratumor heterogeneity. In our cohort, none of the patients with diploid tumors died of breast cancer during follow-up in contrast to four of six patients with aneuploid tumors (mean survival 86.4 months). The FISH analysis showed markedly increased genomic instability and intratumor heterogeneity in aneuploid tumors. MYC gain was observed in only 20% of the diploid cancers, while all aneuploid cases showed a gain. The mutation burden was similar in diploid and aneuploid tumors, however, TP53 mutations were not observed in diploid tumors, but in all aneuploid tumors in our collective.

We conclude that quantitative measurements of intratumor heterogeneity by multiplex FISH, detection of MYC amplification and TP53 mutation could augment prognostication in breast cancer patients. This article is protected by copyright. All rights reserved.

http://ift.tt/2AjKQO5

Functions of the multi-interacting protein KIDINS220/ARMS in cancer and other pathologies

Abstract

Development of an organ and subsequently the whole system from an embryo is a highly integrated process. Although there are evidence that different systems are interconnected during developmental stages, the molecular understanding of this relationship is either not known or only to a limited extent. Nervous system development, amongst all, is maybe the most crucial and complex process. It relies on the correct distribution of specific neuronal growth factors and hormones to the specific receptors. Among the plethora of proteins that are involved in downstream signalling of neuronal growth factors, we find the Kinase-D Interacting Substrate of 220 kDa (KIDINS220), also known as Ankyrin-rich Repeat Membrane Spanning (ARMS) protein. KIDINS220 has been shown to play a substantial role in the nervous system and vascular system development as well as in neuronal survival and differentiation. It serves as a downstream regulator for many important neuronal and vascular growth factors such as Vascular Endothelial Growth Factor (VEGF), the neurotrophin family, glutamate receptors and ephrin receptors. Moreover, activation and differentiation of B- and T-cells, as well as tumour cell proliferation has also shown to be related KIDINS220. This review comprehensively summarises the existing research data on this protein, with a particular interest in its role in cancer and in other pathologies. This article is protected by copyright. All rights reserved.

http://ift.tt/2zvCMs4

Aneuploidy, TP53 mutation, and amplification of MYC correlate with increased intratumor heterogeneity and poor prognosis of breast cancer patients

Abstract

The clinical course of breast cancer varies from one patient to another. Currently, the choice of therapy relies on clinical parameters and histological and molecular tumor features. Alas, these markers are informative in only a subset of patients. Therefore, additional predictors of disease outcome would be valuable for treatment stratification. Extensive studies showed that the degree of variation of the nuclear DNA content, i.e., aneuploidy determines prognosis. Our aim was to further elucidate the molecular basis of aneuploidy. We analyzed five diploid and six aneuploid tumors with more than 20 years of follow-up. By performing FISH with a multiplexed panel of 10 probes to enumerate copy numbers in individual cells, and by sequencing 563 cancer-related genes, we analyzed how aneuploidy is linked to intratumor heterogeneity. In our cohort, none of the patients with diploid tumors died of breast cancer during follow-up in contrast to four of six patients with aneuploid tumors (mean survival 86.4 months). The FISH analysis showed markedly increased genomic instability and intratumor heterogeneity in aneuploid tumors. MYC gain was observed in only 20% of the diploid cancers, while all aneuploid cases showed a gain. The mutation burden was similar in diploid and aneuploid tumors, however, TP53 mutations were not observed in diploid tumors, but in all aneuploid tumors in our collective.

We conclude that quantitative measurements of intratumor heterogeneity by multiplex FISH, detection of MYC amplification and TP53 mutation could augment prognostication in breast cancer patients. This article is protected by copyright. All rights reserved.

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Functions of the multi-interacting protein KIDINS220/ARMS in cancer and other pathologies

Abstract

Development of an organ and subsequently the whole system from an embryo is a highly integrated process. Although there are evidence that different systems are interconnected during developmental stages, the molecular understanding of this relationship is either not known or only to a limited extent. Nervous system development, amongst all, is maybe the most crucial and complex process. It relies on the correct distribution of specific neuronal growth factors and hormones to the specific receptors. Among the plethora of proteins that are involved in downstream signalling of neuronal growth factors, we find the Kinase-D Interacting Substrate of 220 kDa (KIDINS220), also known as Ankyrin-rich Repeat Membrane Spanning (ARMS) protein. KIDINS220 has been shown to play a substantial role in the nervous system and vascular system development as well as in neuronal survival and differentiation. It serves as a downstream regulator for many important neuronal and vascular growth factors such as Vascular Endothelial Growth Factor (VEGF), the neurotrophin family, glutamate receptors and ephrin receptors. Moreover, activation and differentiation of B- and T-cells, as well as tumour cell proliferation has also shown to be related KIDINS220. This review comprehensively summarises the existing research data on this protein, with a particular interest in its role in cancer and in other pathologies. This article is protected by copyright. All rights reserved.

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Measuring childhood cancer late effects: evidence of a healthy survivor effect

Abstract

Introduction

Given considerable focus on health outcomes among childhood cancer survivors, we aimed to explore whether survivor bias is apparent during long-term follow-up of childhood cancer survivors.

Methods

We identified all 1-year survivors of cancer diagnosed before 20 years of age in Denmark, Finland, Iceland, and Sweden. From the general population, we randomly sampled a comparison cohort. Study individuals were followed for hospitalizations for diseases of the gastroenterological tract, endocrine system, cardiovascular system, or urinary tract from the start of the cancer registries to 2010. We estimated cumulative incidence with death as competing risk and used threshold regression to compare the hazards of the diseases of interest at ages 20, 40, 60, and 75 years.

Results

Our study included 27,007 one-year survivors of childhood cancer and 165,620 individuals from the general population. The cumulative incidence of all four outcomes was higher for childhood cancer survivors during early adulthood, but for three outcomes, the cumulative incidence was higher for the general population after age 55 years. The hazard ratios (HRs) decreased for all outcomes with increasing age, and for two of the outcomes, the hazards were higher for the general population at older ages (endocrine diseases: age-specific HRs = 3.0, 1.4, 1.0, 0.87; Cardiovascular diseases: age-specific HRs = 4.1, 1.4, 0.97, 0.84).

Conclusions

Our findings provide empirical evidence that survivor bias attenuates measures of association when comparing survivors with the general population. The design and analysis of studies among childhood cancer survivors, particularly as this population attains older ages, should account for survivor bias to avoid misinterpreting estimates of disease burden.

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Phantom validation of quantitative Y-90 PET/CT-based dosimetry in liver radioembolization

Abstract

Background

PET/CT has recently been shown to be a viable alternative to traditional post-infusion imaging methods providing good quality images of ⁹⁰Y-laden microspheres after selective internal radiation therapy (SIRT). In the present paper, first we assessed the quantitative accuracy of ⁹⁰Y-PET using an anthropomorphic phantom provided with lungs, liver, spine, and a cylindrical homemade lesion located into the hepatic compartment. Then, we explored the accuracy of different computational approaches on dose calculation, including (I) direct Monte Carlo radiation transport using Raydose, (II) Kernel convolution using Philips Stratos, (III) local deposition algorithm, (IV) Monte Carlo technique (MCNP) considering a uniform activity distribution, and (V) MIRD (Medical Internal Radiation Dose) analytical approach. Finally, calculated absorbed doses were compared with those obtained performing measurements with LiF:Mg,Cu,P TLD chips in a liquid environment.

Results

Our results indicate that despite ⁹⁰Y-PET being likely to provide high-resolution images, the ⁹⁰Y low branch ratio, along with other image-degrading factors, may produce non-uniform activity maps, even in the presence of uniform activity. A systematic underestimation of the recovered activity, both for the tumor insert and for the liver background, was found. This is particularly true if no partial volume correction is applied through recovery coefficients. All dose algorithms performed well, the worst case scenario providing an agreement between absorbed dose evaluations within 20%. Average absorbed doses determined with the local deposition method are in excellent agreement with those obtained using the MIRD and the kernel-convolution dose calculation approach.

Finally, absorbed dose assessed with MC codes are in good agreement with those obtained using TLD in liquid solution, thus confirming the soundness of both calculation approaches. This is especially true for Raydose, which provided an absorbed dose value within 3% of the measured dose, well within the stated uncertainties.

Conclusions

Patient-specific dosimetry is possible even in a scenario with low true coincidences and high random fraction, as in ⁹⁰Y–PET imaging, granted that accurate absolute PET calibration is performed and acquisition times are sufficiently long. Despite Monte Carlo calculations seeming to outperform all dose estimation algorithms, our data provide a strong argument for encouraging the use of the local deposition algorithm for routine ⁹⁰Y dosimetry based on PET/CT imaging, due to its simplicity of implementation.

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Phantom validation of quantitative Y-90 PET/CT-based dosimetry in liver radioembolization

Abstract

Background

PET/CT has recently been shown to be a viable alternative to traditional post-infusion imaging methods providing good quality images of ⁹⁰Y-laden microspheres after selective internal radiation therapy (SIRT). In the present paper, first we assessed the quantitative accuracy of ⁹⁰Y-PET using an anthropomorphic phantom provided with lungs, liver, spine, and a cylindrical homemade lesion located into the hepatic compartment. Then, we explored the accuracy of different computational approaches on dose calculation, including (I) direct Monte Carlo radiation transport using Raydose, (II) Kernel convolution using Philips Stratos, (III) local deposition algorithm, (IV) Monte Carlo technique (MCNP) considering a uniform activity distribution, and (V) MIRD (Medical Internal Radiation Dose) analytical approach. Finally, calculated absorbed doses were compared with those obtained performing measurements with LiF:Mg,Cu,P TLD chips in a liquid environment.

Results

Our results indicate that despite ⁹⁰Y-PET being likely to provide high-resolution images, the ⁹⁰Y low branch ratio, along with other image-degrading factors, may produce non-uniform activity maps, even in the presence of uniform activity. A systematic underestimation of the recovered activity, both for the tumor insert and for the liver background, was found. This is particularly true if no partial volume correction is applied through recovery coefficients. All dose algorithms performed well, the worst case scenario providing an agreement between absorbed dose evaluations within 20%. Average absorbed doses determined with the local deposition method are in excellent agreement with those obtained using the MIRD and the kernel-convolution dose calculation approach.

Finally, absorbed dose assessed with MC codes are in good agreement with those obtained using TLD in liquid solution, thus confirming the soundness of both calculation approaches. This is especially true for Raydose, which provided an absorbed dose value within 3% of the measured dose, well within the stated uncertainties.

Conclusions

Patient-specific dosimetry is possible even in a scenario with low true coincidences and high random fraction, as in ⁹⁰Y–PET imaging, granted that accurate absolute PET calibration is performed and acquisition times are sufficiently long. Despite Monte Carlo calculations seeming to outperform all dose estimation algorithms, our data provide a strong argument for encouraging the use of the local deposition algorithm for routine ⁹⁰Y dosimetry based on PET/CT imaging, due to its simplicity of implementation.

http://ift.tt/2jrFmsk

Management of hereditary breast and ovarian cancer

Abstract

Hereditary breast and ovarian cancer (HBOC) syndrome represents 5−10% of all breast cancers. In Japan, the HBOC syndrome is frequently diagnosed in patients with breast cancer. Therefore, a treatment strategy combining a plan for existing breast cancer and for reduction of future breast and ovarian cancer risk is necessary. Breast cancer risk-reducing management involves three options—surveillance, chemoprevention, and risk-reducing mastectomy (RRM). RRM can prevent >90% of new breast cancers. Ovarian cancer risk management options are more limited, and risk-reduction salpingo-oophorectomy is the only option since there is no proven effective early detection method available. The local recurrence rate following breast-conserving surgery in BRCA1/2 mutation-associated breast cancer is not significantly higher than that in sporadic breast cancer. Furthermore, there is no difference in prognosis between surgical methods. Clinicians should inform patients that there are no data on long-term monitoring and fully discuss risks of re-developing breast cancer with patients when choosing the surgical method. In HBOC, BRCA1/2 mutations lead to failure of double-strand DNA break repair, with poly ADP-ribose polymerase (PARP) playing an important role in single-strand DNA nick repair. Use of PARP inhibitors in HBOC prevents DNA repair (synthetic lethality) leading to cell death. This review summarizes management of the HBOC syndrome based on recent evidence.

http://ift.tt/2AhdG1n

Management of hereditary breast and ovarian cancer

Abstract

Hereditary breast and ovarian cancer (HBOC) syndrome represents 5−10% of all breast cancers. In Japan, the HBOC syndrome is frequently diagnosed in patients with breast cancer. Therefore, a treatment strategy combining a plan for existing breast cancer and for reduction of future breast and ovarian cancer risk is necessary. Breast cancer risk-reducing management involves three options—surveillance, chemoprevention, and risk-reducing mastectomy (RRM). RRM can prevent >90% of new breast cancers. Ovarian cancer risk management options are more limited, and risk-reduction salpingo-oophorectomy is the only option since there is no proven effective early detection method available. The local recurrence rate following breast-conserving surgery in BRCA1/2 mutation-associated breast cancer is not significantly higher than that in sporadic breast cancer. Furthermore, there is no difference in prognosis between surgical methods. Clinicians should inform patients that there are no data on long-term monitoring and fully discuss risks of re-developing breast cancer with patients when choosing the surgical method. In HBOC, BRCA1/2 mutations lead to failure of double-strand DNA break repair, with poly ADP-ribose polymerase (PARP) playing an important role in single-strand DNA nick repair. Use of PARP inhibitors in HBOC prevents DNA repair (synthetic lethality) leading to cell death. This review summarizes management of the HBOC syndrome based on recent evidence.

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Clinical consequences of upfront pathology review in the randomised PORTEC-3 trial for high-risk endometrial cancer

Abstract

Background

In the PORTEC-3 trial, women with high-risk endometrial cancer (HR-EC) were randomised to receive pelvic radiotherapy (RT) with or without concurrent and adjuvant chemotherapy (2 cycles of cisplatin 50 mg/m2 in week 1 and 4 of RT, followed by 4 cycles of carboplatin AUC5 and paclitaxel 175 mg/m2). Pathology review was required prior to patient enrolment. The aim of this analysis was to evaluate the role of central pathology review before randomisation.

Patients and methods

A total of 1295 cases underwent pathology review to confirm HR-EC in the Netherlands (n=395) and the United Kingdom (n=900), and for 1226/1295 (95%) matching review and original reports were available. 329 of these patients were enrolled in the PORTEC-3 trial: 145 in the Netherlands and 184 in the United Kingdom, comprising 48% of the total PORTEC-3 cohort of 686 participants. Areas of discrepancies were evaluated, and inter-observer agreement between original and review opinion was evaluated by calculating the kappa value (κ).

Results

In the 1226 pathology reviews, 6356 selected items were evaluable for both original and review pathology. In 43% of cases at least one pathology item changed after review. For 102 patients (8%), this discrepancy led to ineligibility for the PORTEC-3 trial, most frequently due to differences in the assessment of histological type (34%), endocervical stromal involvement (27%) and histological grade (19%). Lowest inter-observer agreement was found for histological type (κ = 0.72), lymph-vascular space invasion (κ = 0.72) and histological grade (κ = 0.70).

Conclusion

Central pathology review by expert gynaeco-pathologists changed histological type, grade or other items in 43% of women with HR-EC, leading to ineligibility for the PORTEC-3 trial in 8%. Upfront pathology review is essential to ensure enrolment of the target trial-population, and to avoid over- or undertreatment, especially when treatment modalities with substantial toxicity are involved.This study is registered with ISRCTN (ISRCTN14387080, http://ift.tt/HkCGY7) and with ClinicalTrials.gov (NCT00411138).

http://ift.tt/2zMrSSQ

Clinical consequences of upfront pathology review in the randomised PORTEC-3 trial for high-risk endometrial cancer

Abstract

Background

In the PORTEC-3 trial, women with high-risk endometrial cancer (HR-EC) were randomised to receive pelvic radiotherapy (RT) with or without concurrent and adjuvant chemotherapy (2 cycles of cisplatin 50 mg/m2 in week 1 and 4 of RT, followed by 4 cycles of carboplatin AUC5 and paclitaxel 175 mg/m2). Pathology review was required prior to patient enrolment. The aim of this analysis was to evaluate the role of central pathology review before randomisation.

Patients and methods

A total of 1295 cases underwent pathology review to confirm HR-EC in the Netherlands (n=395) and the United Kingdom (n=900), and for 1226/1295 (95%) matching review and original reports were available. 329 of these patients were enrolled in the PORTEC-3 trial: 145 in the Netherlands and 184 in the United Kingdom, comprising 48% of the total PORTEC-3 cohort of 686 participants. Areas of discrepancies were evaluated, and inter-observer agreement between original and review opinion was evaluated by calculating the kappa value (κ).

Results

In the 1226 pathology reviews, 6356 selected items were evaluable for both original and review pathology. In 43% of cases at least one pathology item changed after review. For 102 patients (8%), this discrepancy led to ineligibility for the PORTEC-3 trial, most frequently due to differences in the assessment of histological type (34%), endocervical stromal involvement (27%) and histological grade (19%). Lowest inter-observer agreement was found for histological type (κ = 0.72), lymph-vascular space invasion (κ = 0.72) and histological grade (κ = 0.70).

Conclusion

Central pathology review by expert gynaeco-pathologists changed histological type, grade or other items in 43% of women with HR-EC, leading to ineligibility for the PORTEC-3 trial in 8%. Upfront pathology review is essential to ensure enrolment of the target trial-population, and to avoid over- or undertreatment, especially when treatment modalities with substantial toxicity are involved.This study is registered with ISRCTN (ISRCTN14387080, http://ift.tt/HkCGY7) and with ClinicalTrials.gov (NCT00411138).

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Pirfenidone-induced hyponatraemia: insight in mechanism, risk factor and management

Pirfenidone was approved in October 2014 in the USA for the treatment of idiopathic pulmonary fibrosis. Although not included in the adverse events published in the CAPACITY-1 and CAPACITY-2 or ASCEND trials, hyponatraemia was reported in supplementary data with rate of 3.4% in the active therapy arm versus 0.3% in the placebo arm. We performed a retrospective analysis of patients who were initiated on pirfenidone or nintedanib for the treatment of pulmonary fibrosis at our centre. Of the 52 patients who were started on pirfenidone, three (5.8%) developed severe hyponatraemia. Of the 29 patients who were started on nintedanib, none developed hyponatraemia. Laboratory data suggested syndrome of inappropriate antidiuretic hormone secretion (SIADH) induced by pirfenidone and the medication was discontinued. Hyponatraemia is a possible significant adverse effect of pirfenidone, able to induce SIADH in patients taking the medication.

http://ift.tt/2ADFkZl

Puff laddy: a 5-year-old-boy with forehead swelling

Description

A 5-year-old boy presented with forehead swelling in the setting of a recent sinus infection. His initial symptoms were fever and nasal congestion for which he was prescribed a 10-day course of antibiotics, completed 3 days prior to admission. He subsequently developed unsteady gait, photophobia, headache, vomiting and progressive forehead swelling. He was noted to have central forehead oedema and tenderness without overlying erythaema (figure 1). There were no neurological or ophthalmological deficits. Magnetic Resonance Imaging (MRI)/Magnetic Resonance Venography (MRV) of the head demonstrated a 3.5x1.2x3.9 cm subgaleal abscess with communication to the frontal sinuses as well as osteomyelitis of the frontal bone (figure 2). The patient underwent surgical drainage of the abscess with evacuation of purulent fluid (figure 3). Culture from the procedure grew Streptococcus anginosus. He clinically improved following surgery and was transitioned home to complete a 21-day total course of antibiotics.

...

http://ift.tt/2Aaows5

Brief psychotic episode in a patient with chromosome 2q37 microdeletion syndrome

A 21-year-old woman with moderate learning disability secondary to chromosome 2 microdeletion at q37 was admitted to a general adult psychiatric ward following a period of agitation with incessant pressure of speech, nihilistic delusions and worsening of sleep and eating patterns. Her presentation was preceded for a number of weeks by social stressors of an ill family member and another family member moving away. She had also been diagnosed and treated for a respiratory infection several weeks prior to presentation. Her presentation improved with low-dose antipsychotic medication and parallel input from the general adult mental health team and the psychiatry of intellectual disability team.

http://ift.tt/2icwH0x

Treatment of advanced colorectal cancer in a patient with cardiotoxic reactions to 5-fluorouracil and capecitabine using suboptimal doses

A 32-year-old female with stage IV colorectal cancer and metastasis to the liver experienced cardiotoxic reactions after treatment with 5-fluorouracil and its oral prodrug capecitabine even at two-thirds the recommended dose. After careful considerations, the decision was made to attempt capecitabine retrial at a further suboptimal dose with combination chemotherapy where she no longer experienced cardiac events. As a result, the liver tumour shrank and rectal mass stabilised, tumour markers dropped and she underwent surgical resection of both masses. Later there was local recurrence of disease near the previous liver tumour, so the suboptimal capecitabine therapy was restarted without complaint. The patient became a candidate for a NanoKnife procedure, offering a potentially curative therapy. This case report summarises a novel treatment strategy for those patients with advanced colorectal cancer who experience cardiotoxic reactions to fluoropyrimidines, the active agent of gold standard treatment.

http://ift.tt/2k3QBLr

Dying art of a history and physical: pulsatile tinnitus

Modern medicine often leaves the history and physical by the wayside. Physicians instead skip directly to diagnostic modalities like MRI and angiography. In this case report, we discuss a patient who presented with migraine symptoms. Auscultation revealed signs of pulsatile tinnitus. Further imaging concluded that it was secondary to a type I dural arteriovenous fistula. Thanks to a proper and thorough history and physical, the patient was streamlined into an accurate and efficient work-up leading to symptomatic relief and quality of life improvement. Imaging is a powerful adjunctive technique in modern medicine, but physicians must not rely on machines to diagnose their patients. If this trend continues, it will have a tremendous negative impact on the cost and calibre of healthcare. Our hope is that this case will spread awareness in the medical community, urging physicians to use the lost art of a history and physical.

http://ift.tt/2i9XXws

Inverse hypopyon (hyperoleon) at the posterior segment in pathological myopia

Description

A 54-year-old woman presented a year after vitreoretinal surgery with silicone oil injection in the left eye. The left eye showed emulsified silicone oil in the anterior chamber and a posterior chamber intraocular lens. The fundus revealed a posterior staphyloma, attached retina and whitish emulsified silicone bubbles with a horizontal lower border giving rise to inverse hypopyon in the posterior pole (figure 1).

Figure 1

The fundus photo shows chorioretinal atrophy temporal to the optic disc and emulsified silicone oil bubbles with a horizontal lower level suggestive of inverse hypopyon.

Inverted hypopyon at the posterior pole1 is a rare finding which can be seen in patients with posterior staphyloma and long-term silicone oil tamponade.2 The emulsified silicone oil being lighter than fluid floats superiorly giving rise to this appearance mostly in the anterior segment (hyperoleon).

http://ift.tt/2k3Qwr7

Rare and unusual case of perforated appendicitis in a Spigelian hernia

Background

Amyand hernia is a rare phenomenon, defined as an inguinal hernia containing the vermiform appendix. It is seen in less than 1% of inguinal hernias. Claudius Amyand first reported this interesting finding in 1735.

De Garengeot hernia: this is the clinical finding of the vermiform appendix within a femoral hernia sac; it occurs in less than 1% of all femoral hernias and is named after the French surgeon, Rene Jacques Croissant de Garengeot.

Unnamed: The clinical entity we describe in this case report is the last of the 'appendix in a hernia—yet to be eponymously named'. It is an interesting and intriguing clinical finding, yet without a referenced name it does not immediately come to mind as a potential differential diagnosis. Medical historians may well commence the search for the first description of the condition.

Case presentation

An 83-year-old woman was admitted to the...

http://ift.tt/2ibG5Bw

Fish hook injury: an easy removal using the string yank technique

Description

An embedded fish hook injury is a tough condition for clinical decision-making, as it needs to be determined whether to advance the hook or to pull it out. Patients or their friends usually attempt to remove a fish hook, causing more soft tissue trauma. There are many different sizes and types of fish hooks, and the four main techniques for their removal are (1) retrograde technique for barbless and superficially embedded hooks, (2) needle cover technique for large hooks with a single barb, (3) advance and cut technique for large fish hooks with potential additional trauma and (4) string yank technique for superficially embedded, small-sized to medium-sized fish hooks.1 The technique of removal should be selected based on the size and shape of a fish hook and the anatomical condition of the injury. Here, we report a useful technique for primary care physicians, accompanied by an instructional video given in the online...

http://ift.tt/2k3ZZyS

Paediatric Salter-Harris type IV injury of distal tibia with talus fracture

Fracture of talus with Salter-Harris injury of the distal end of tibia is a rare injury in paediatric age group. The authors report a case of a 13-year-old male child who sustained type IV Salter-Harris injury to the medial malleolus with coronal spilt along with spilt and depressed fracture of the neck of talus and fracture of the lateral process of talus with stable compression fracture of spine sustained due to fall from 6 meters height. CT scan delineated the morphology of fracture pattern and helped in preoperative planning. Talar articular fracture was reduced and fixed arthroscopically while distal tibial fracture was fixed under image intensifier. We observed favourable outcome following arthroscopic reduction at 4-year follow-up.

http://ift.tt/2ia7zY5

Lesion in the external auditory canal: an unusual site for basal cell carcinoma

Description

An 85-year-old woman presented to the ear, nose and throat clinic with a 2-week history of left-sided otorrhoea and pruritus of the ear. Examination of the left external auditory canal (EAC) revealed a polypoidal lesion and purulent discharge (figure 1). The tympanic membrane was intact. The suspicious lesion prompted imaging, including CT neck and thorax (figure 2). An ultrasound scan of the parotid and neck showed no metastatic disease. A biopsy was undertaken and histology demonstrated a basal cell carcinoma (BCC). The patient was managed with a staged procedure. Stage 1 consisted of a wide local excision of the BCC, with a 4 mm margin. Frozen section was not available; therefore, a second stage was needed to achieve clear margins using a sleeve resection. Fortunately, the disease was limited to the cartilaginous ear canal, hence did not require further resection or reconstruction. This management...

http://ift.tt/2k3ZMM6

Puzzling thyroid function test

A 13-1/2-year-old boy was referred to the Department of Endocrinology as a case of thyrotoxicosis for initiation of antithyroid medication. His chief complaint was a swelling in front of the neck, which was incidentally noted by his mother 2 weeks prior to presentation. He denied any history of symptoms suggestive of hyperthyroidism or ophthalmological involvement. His physical examination was unremarkable except for a grade 2 goitre. Thyroid function test revealed elevated free triiodothyronine and tetraiodothyronine in the face of an unsuppressed thyroid-stimulating hormone level. Technetium-99 uptake scan showed increased uptake indicating enhanced thyroid activity. However, he was clinically euthyroid. This raised the possibility of resistance to thyroid hormones, which was confirmed by documenting similar thyroid function test abnormalities in other members of his family and genetic testing. The family was reassured of the benign nature of the condition.

http://ift.tt/2i9XFpm

Cancer-related microangiopathic haemolytic anaemia

Description

A 71-year-old woman with widely metastatic breast cancer to liver and bone marrow presented with 2 weeks of fatigue. Examination revealed a severely ill-appearing woman in moderate distress with icterus and jaundice. Laboratory investigations revealed profound anaemia (haemoglobin 5.2 g/dL) with appropriate reticulocyte response (14.4%) and a normal platelet count (207x 10⁹/L). Additional tests revealed a lactate dehydrogenase of 2997 IU/L (normal: 140–297 IU/L), negative direct Coombs antiglobulin, an undetectable haptoglobin level, elevated total bilirubin, newly elevated prothrombin time (19.7 s, normal: <14.1 s), elevated fibrin split products and D-dimer (14.36 µg/dL, normal: <0.53 µg/dL) but normal fibrinogen level (322 mg/dL, normal: 193–488 mg/dL). Peripheral blood smear revealed marked schistocytosis (figure 1) with normal platelet count. The patient was diagnosed with cancer-associated microangiopathic haemolytic anaemia1 2 with laboratory evidence of disseminated intravascular coagulation, and she passed away on comfort measures 24 hours after admission.

Figure 1

Arrows showing marked schistocytes.

...

http://ift.tt/2k3ZHbg

Delayed presentation of iatrogenic bladder perforation

Description 

A 41-year-old lady presented to a district general hospital with a 24-hour history of abdominal pain, shoulder tip pain and anuria. No other symptoms were reported, and observations were stable. Her medical history included endometriosis, one normal vaginal delivery in 1998 and three caesarean sections dated 2003, 2010 and 2012. On examination, there was tenderness in the suprapubic region and left loin; the bladder was not palpable, and she did not elicit any signs of peritonitis. A Foley catheter was inserted. Urinalysis showed 4+ blood and 2+ ketones. She had raised inflammatory markers and a raised creatinine of 200 µmol/L.

The following day, creatinine had normalised, but there was no improvement in symptoms, despite antibiotics. A CT of her kidneys, ureters and bladder was reported as showing locules of free gas in the bladder consistent with recent catheterisation. There was free fluid in the pelvis, and a faecolith...

http://ift.tt/2icfjIY

Rhabdomyolysis, lactic acidosis, and multiple organ failure during telbivudine treatment for hepatitis B: a case report and review of the literature

Telbivudine can cause severe side effects, including myositis, neuritis, rhabdomyolysis, and lactic acidosis. However, reported cases of telbivudine leading to multiple organ failure are rare. Here, we report ...

http://ift.tt/2zLcYMI

Effect of dendritic cell-cytokine-induced killer cells in patients with advanced colorectal cancer combined with first-line treatment

Abstract

Background

Surgical resection combined with adjuvant chemotherapy is considered as the gold-standard treatment for advanced colorectal cancer patients. These patients have a poor 5-year survival rate of 5% or less. Furthermore, a large dose of chemotherapy can produce adverse side effects and severe toxicity. Therefore, this retrospective study aimed to evaluate the efficacy of dendritic cell-cytokine-induced killer (DC-CIK) cell infusion as an adjuvant therapy in patients with advanced colorectal cancer combined with first-line treatment.

Methods

A total of 142 patients with stage III/IV colorectal carcinoma who had been treated with first-line therapy were included in this study. Among these patients, 71 patients received first-line treatment only (non-DC-CIK group), while the other 71 patients who had similar demographic and clinical characteristics received a DC-CIK cell infusion combined with first-line treatment (DC-CIK group). These patients were followed up until August 2014. Data were analyzed by Kaplan-Meier and Cox regression.

Results

Our results showed that the 5-year overall survival (OS) rate for the DC-CIK group versus the non-DC-CIK group was 41.3 versus 19.4% (p = 0.001) and the 5-year progression-free survival (PFS) rate for the DC-CIK group versus the non-DC-CIK group was 57.4 versus 33.6% (p = 0.022).

Conclusions

Our results showed that patients with advanced colorectal cancer might benefit from DC-CIK immunotherapy combined with first-line therapy by significantly prolonging 5-year OS and PFS.

http://ift.tt/2Aczvl7

Effect of dendritic cell-cytokine-induced killer cells in patients with advanced colorectal cancer combined with first-line treatment

Abstract

Background

Surgical resection combined with adjuvant chemotherapy is considered as the gold-standard treatment for advanced colorectal cancer patients. These patients have a poor 5-year survival rate of 5% or less. Furthermore, a large dose of chemotherapy can produce adverse side effects and severe toxicity. Therefore, this retrospective study aimed to evaluate the efficacy of dendritic cell-cytokine-induced killer (DC-CIK) cell infusion as an adjuvant therapy in patients with advanced colorectal cancer combined with first-line treatment.

Methods

A total of 142 patients with stage III/IV colorectal carcinoma who had been treated with first-line therapy were included in this study. Among these patients, 71 patients received first-line treatment only (non-DC-CIK group), while the other 71 patients who had similar demographic and clinical characteristics received a DC-CIK cell infusion combined with first-line treatment (DC-CIK group). These patients were followed up until August 2014. Data were analyzed by Kaplan-Meier and Cox regression.

Results

Our results showed that the 5-year overall survival (OS) rate for the DC-CIK group versus the non-DC-CIK group was 41.3 versus 19.4% (p = 0.001) and the 5-year progression-free survival (PFS) rate for the DC-CIK group versus the non-DC-CIK group was 57.4 versus 33.6% (p = 0.022).

Conclusions

Our results showed that patients with advanced colorectal cancer might benefit from DC-CIK immunotherapy combined with first-line therapy by significantly prolonging 5-year OS and PFS.

from Cancer via ola Kala on Inoreader http://ift.tt/2Aczvl7
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Life course evolution of body size and breast cancer survival in the E3N cohort

Abstract

Although adult obesity has been associated with poor breast cancer survival, data on adiposity at different periods in life and its lifelong evolution are scarce. Our aims were to assess the associations between breast cancer survival and body size during childhood, puberty, and early adulthood and body size trajectories from childhood to adulthood.

Self-assessed body size at age 8, at puberty, at age 20-25, and at age 35-40 and trajectories of body size of 4 662 breast cancer survivors from the prospective E3N cohort were studied in relation to risk of death from any cause, death from breast cancer and second invasive cancer event using multivariate Cox regression models.

Four trajectories of body size were identified (T1 "moderate increase", T2 "stable/low increase", T3 "increase at puberty", T4 "constantly high"). Compared with stable body size, an increase in body size during adult life was associated with an increased risk of death from any cause (HR T1 versus T2=1.27; 95% CI=1.01-1.60), and an increased risk of second invasive cancer event (HR T1 versus T2=1.25; 95% CI=1.06-1.47). Silhouettes at various ages were not associated with survival.

Our results suggest that the evolution of body size from childhood to adulthood has a long-term influence on breast cancer survival. Although these results need to be confirmed, this work sheds light on the need to combine lifelong approaches to current BMI to better identify breast cancer survivors who are at higher risk of recurrence or second primary cancer, or of death. This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/2naSFCH
via IFTTT

Life course evolution of body size and breast cancer survival in the E3N cohort

Abstract

Although adult obesity has been associated with poor breast cancer survival, data on adiposity at different periods in life and its lifelong evolution are scarce. Our aims were to assess the associations between breast cancer survival and body size during childhood, puberty, and early adulthood and body size trajectories from childhood to adulthood.

Self-assessed body size at age 8, at puberty, at age 20-25, and at age 35-40 and trajectories of body size of 4 662 breast cancer survivors from the prospective E3N cohort were studied in relation to risk of death from any cause, death from breast cancer and second invasive cancer event using multivariate Cox regression models.

Four trajectories of body size were identified (T1 "moderate increase", T2 "stable/low increase", T3 "increase at puberty", T4 "constantly high"). Compared with stable body size, an increase in body size during adult life was associated with an increased risk of death from any cause (HR T1 versus T2=1.27; 95% CI=1.01-1.60), and an increased risk of second invasive cancer event (HR T1 versus T2=1.25; 95% CI=1.06-1.47). Silhouettes at various ages were not associated with survival.

Our results suggest that the evolution of body size from childhood to adulthood has a long-term influence on breast cancer survival. Although these results need to be confirmed, this work sheds light on the need to combine lifelong approaches to current BMI to better identify breast cancer survivors who are at higher risk of recurrence or second primary cancer, or of death. This article is protected by copyright. All rights reserved.

http://ift.tt/2naSFCH

miR-221/222 cluster expression improves clinical stratification of non-muscle invasive bladder cancer (TaT1) patients' risk for short-term relapse and progression

Abstract

Clinical heterogeneity of bladder cancer prognosis requires the identification of bladder tumors' molecular profile to improve the prediction value of the established and clinically used markers. In the present study, we have analyzed miR-221/222 cluster expression in bladder tumors and its clinical significance for patients' prognosis and disease outcome. The study included 387 tissue specimens. Following extraction, total RNA was polyadenylated at 3΄-end and reversed transcribed. SYBR-Green based qPCR assays were performed for the quantification of miR-221/222 expression. Extensive statistical analysis was completed for the evaluation of miR-221/222 cluster's clinical significance. The expression of miR-221/222 is significantly downregulated in tumors compared to normal urothelium, while ROC curve and logistic regression analysis highlighted cluster's discriminatory ability. However, miR-222 levels were increased in muscle-invasive (T2-T4) compared to superficial tumors (TaT1), and in high compared to low-grade tumors. Kaplan-Meier survival curves and Cox regression analysis revealed the stronger risk of TaT1 patients overexpressing miR-222 for disease short-term relapse and progression following treatment. Moreover, multivariate Cox models highlighted the independent prognostic value of miR-222 overexpression for TaT1 patients' poor prognosis. Finally, the analysis of miR-222 expression improved significantly the positive prediction strength of the clinically used prognostic markers of tumor stage, grade, EORTC risk-stratification and recurrence at the first follow-up cystoscopy for TaT1 patients' outcome, and resulted to higher clinical net benefit following decision curve analysis. In conclusion, the expression of miR-221/222 cluster is deregulated in bladder tumors and miR-222 overexpression results to a superior positive prediction of TaT1 patients' short-term relapse and progression. This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/2BidOwL
via IFTTT

miR-221/222 cluster expression improves clinical stratification of non-muscle invasive bladder cancer (TaT1) patients' risk for short-term relapse and progression

Abstract

Clinical heterogeneity of bladder cancer prognosis requires the identification of bladder tumors' molecular profile to improve the prediction value of the established and clinically used markers. In the present study, we have analyzed miR-221/222 cluster expression in bladder tumors and its clinical significance for patients' prognosis and disease outcome. The study included 387 tissue specimens. Following extraction, total RNA was polyadenylated at 3΄-end and reversed transcribed. SYBR-Green based qPCR assays were performed for the quantification of miR-221/222 expression. Extensive statistical analysis was completed for the evaluation of miR-221/222 cluster's clinical significance. The expression of miR-221/222 is significantly downregulated in tumors compared to normal urothelium, while ROC curve and logistic regression analysis highlighted cluster's discriminatory ability. However, miR-222 levels were increased in muscle-invasive (T2-T4) compared to superficial tumors (TaT1), and in high compared to low-grade tumors. Kaplan-Meier survival curves and Cox regression analysis revealed the stronger risk of TaT1 patients overexpressing miR-222 for disease short-term relapse and progression following treatment. Moreover, multivariate Cox models highlighted the independent prognostic value of miR-222 overexpression for TaT1 patients' poor prognosis. Finally, the analysis of miR-222 expression improved significantly the positive prediction strength of the clinically used prognostic markers of tumor stage, grade, EORTC risk-stratification and recurrence at the first follow-up cystoscopy for TaT1 patients' outcome, and resulted to higher clinical net benefit following decision curve analysis. In conclusion, the expression of miR-221/222 cluster is deregulated in bladder tumors and miR-222 overexpression results to a superior positive prediction of TaT1 patients' short-term relapse and progression. This article is protected by copyright. All rights reserved.

http://ift.tt/2BidOwL

Perioperative, spatiotemporally coordinated activation of T and NK cells prevents recurrence of pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal and disseminating cancer resistant to therapy, including checkpoint immunotherapies, and early tumor resection and (neo)adjuvant chemotherapy fails to improve a poor prognosis. In a transgenic mouse model of resectable PDAC, we investigated the coordinated activation of T and NK cells in addition to gemcitabine chemotherapy to prevent tumor recurrence. Only neoadjuvant, but not adjuvant treatment with a PD-1 antagonist effectively supported chemotherapy and suppressed local tumor recurrence and improved survival involving both NK and T cells. Local T cell activation was confirmed by increased tumor infiltration with CD103+CD8+ T cells and neoantigen-specific CD8 T lymphocytes against the marker neoepitope LAMA4-G1254V. To achieve effective prevention of distant metastases in a complementary approach, we blocked the NK cell checkpoint CD96, an inhibitory NK cell receptor that binds CD155, which was abundantly expressed in primary PDAC and metastases of human patients. In gemcitabine-treated mice, neoadjuvant PD-1 blockade followed by adjuvant inhibition of CD96 significantly prevented relapse of PDAC, allowing for long-term survival. In summary, our results show in an aggressively growing transgenic mouse model of PDAC that the coordinated activation of both innate and adaptive immunity can effectively reduce the risk of tumor recurrence after surgery, facilitating long-term remission of this lethal disease.

http://ift.tt/2ib0B5f

miR-139-5p modulates radiotherapy resistance in breast cancer by repressing multiple gene networks of DNA repair and ROS defense

Radiotherapy (RT) is essential to the treatment of most solid tumors and acquired or innate resistance to this therapeutic modality is a major clinical problem. Here we show that miR-139-5p is a potent modulator of radiotherapy response in breast cancer (BC) via its regulation of genes involved in multiple DNA repair and reactive oxygen species defense pathways. Treatment of breast cancer cells with a miR-139-5p mimic strongly synergized with radiation both in vitro and in vivo, resulting in significantly increased oxidative stress, accumulation of unrepaired DNA damage and induction of apoptosis. Several miR-139-5p target genes were also strongly predictive of outcome, specifically in RT-treated patients across multiple independent breast cancer cohorts. These prognostically relevant miR-139-5p target genes were used as companion biomarkers to identify radioresistant BC xenografts highly amenable to sensitization by co-treatment with a miR-139-5p mimetic.

http://ift.tt/2AayWYV

A potent, metabolically stable tubulin inhibitor targets the colchicine binding site and overcomes taxane resistance

Antimitotics that target tubulin are among the most useful chemotherapeutic drugs, but their clinical activity is often limited by the development of multidrug resistance. We recently discovered the novel small molecule DJ101 as a potent and metabolically stable tubulin inhibitor that can circumvent the drug efflux pumps responsible for multidrug resistance of existing tubulin inhibitors. In this study, we determined the mechanism of action of this drug. The basis for its activity was illuminated by solving the crystal structure of DJ101 in complex with tubulin at a resolution of 2.8Å. Investigations of the potency of DJ101 in a panel of human metastatic melanoma cell lines harboring major clinically relevant mutations defined IC50 values of 7-10 nM. In cells, DJ101 disrupted microtubule networks, suppressed anchorage-dependent melanoma colony formation and impaired cancer cell migration. In melanoma-bearing mice, DJ101 administration inhibited tumor growth and reduced lung metastasis in the absence of observable toxicity. DJ101 also completely inhibited tumor growth in a paclitaxel-resistant xenograft mouse model of human prostate cancer (PC-3/TxR), where paclitaxel was minimally effective. Our findings offer preclinical proof of concept for the continued development of DJ101 as a next-generation tubulin inhibitor for cancer therapy.

http://ift.tt/2ibVt0s

Distinct TP63 isoform-driven transcriptional signatures predict tumor progression and clinical outcomes

TP63 is required to maintain stem cell pluripotency and suppresses the metastatic potential of cancer cells through multiple mechanisms. These functions are differentially regulated by individual isoforms, necessitating a deeper understanding of how the distinct transcriptional programs controlled by these isoforms affect cancer progression and outcomes. In this study, we conducted a pan-cancer analysis of The Cancer Genome Atlas (TCGA) to identify transcriptional networks regulated by TAp63 and ΔNp63 using transcriptomes derived from epidermal cells of TAp63-/- and ΔNp63-/- mice. Analysis of 17 cancer developmental and 27 cancer progression signatures revealed a consistent tumor suppressive pattern for TAp63. In contrast, we identified pleiotropic roles for ΔNp63 in tumor development and found that its regulation of Lef1 was crucial for its oncogenic role. ΔNp63 performed a distinctive role as suppressor of tumor progression by cooperating with TAp63 to modulate key biological pathways, principally cell cycle regulation, extra cellular matrix remodeling, epithelial-to-mesenchymal transition, and the enrichment of pluripotent stem cells. Importantly, these TAp63 and ΔNp63 signatures prognosticated progression and survival, even within specific stages, in bladder and renal carcinomas as well as low-grade gliomas. These data describe a novel approach for understanding transcriptional activities of TP63 isoforms across a large number of cancer types, potentially enabling identification of patient subsets most likely to benefit from therapies predicated on manipulating specific TP63 isoforms.

http://ift.tt/2AayRV7

New mechanisms of resistance to MEK inhibitors in melanoma revealed by intravital imaging

Targeted therapeutics that are initially effective in cancer patients nearly invariably engender resistance at some stage, an inherent challenge in the use of any molecular targeted drug in cancer settings. In this study, we evaluated resistance mechanisms arising in metastatic melanoma to MAPK pathway kinase inhibitors, as a strategy to identify candidate strategies to limit risks of resistance. To investigate longitudinal responses, we developed an intravital serial imaging approach that can directly visualize drug response in an inducible RAF-driven, autochthonous murine model of melanoma incorporating a fluorescent reporter allele (tdTomatoLSL). Using this system, we visualized formation and progression of tumors in situ starting from the single cell level longitudinally over time. Reliable reporting of the status of primary murine tumors treated with the selective MEK1/2 inhibitor (MEKi) trametinib illustrated a time-course of initial drug response and persistence followed by the development of drug resistance. We found that tumor cells adjacent to bundled collagen had a preferential persistence in response to MEKi. Unbiased transcriptional and kinome reprogramming analyses from selected treatment time points suggested increased c-Kit and PI3K/AKT pathway activation in resistant tumors, along with enhanced expression of epithelial genes and EMT downregulation signatures with development of MEKi resistance. Similar trends were observed following simultaneous treatment with BRAF and MEK inhibitors aligned to standard of care combination therapy, suggesting these re-programming events were not specific to MEKi alone. Overall, our results illuminate the integration of tumor-stroma dynamics with tissue plasticity in melanoma progression and provide new insights into the basis for drug response, persistence and resistance.

http://ift.tt/2icbjIM

Vitamin C sensitizes melanoma to BET inhibitors

Bromodomain and extra-terminal inhibitors (BETi) are promising cancer therapies, yet prominent side effects of BETi at effective doses have been reported in Phase I clinical trials. Here we screened a panel of small molecules targeting epigenetic modulators against human metastatic melanoma cells. Cells were pretreated with or without ascorbate (vitamin C), which promotes DNA demethylation and subsequently changes the sensitivity to drugs. Top hits were structurally unrelated BETi including JQ1, I-BET151, CPI-203, and BI-2536. Ascorbate enhanced the efficacy of BETi by decreasing acetylation of histone H4, but not H3, while exerting no effect on the expression of BRD proteins. Histone acetyltransferase 1 (HAT1), which catalyzes H4K5ac and H4K12ac, was downregulated by ascorbate mainly via the TET-mediated DNA hydroxymethylation pathway. Loss of H4ac, especially H4K5ac and H4K12ac, disrupted the interaction between BRD4 and H4 by which ascorbate and BETi blocked the binding of BRD4 to acetylated histones. Co-treatment with ascorbate and JQ1 induced apoptosis and inhibited proliferation of cultured melanoma cells. Ascorbate deficiency as modeled in Gulo-/- mice diminished the treatment outcome of JQ1 for melanoma tumorgraft. In contrast, ascorbate supplementation lowered the effective dose of JQ1 needed to successfully inhibit melanoma tumors in mice. Based on our findings, future clinical trials with BETi should consider ascorbate levels in patients. Furthermore, ascorbate supplementation might help reduce the severe side effects that arise from BETi therapy by reducing the dosage necessary for treatment.

http://ift.tt/2AayJVD

Utility of single cell genomics in diagnostic evaluation of prostate cancer

A distinction between indolent and aggressive disease is a major challenge in diagnostics of prostate cancer. As genetic heterogeneity and complexity may influence clinical outcome, we have initiated studies on single tumor cell genomics. In this study, we demonstrate that sparse DNA sequencing of single cell nuclei from prostate core biopsies is a rich source of quantitative parameters for evaluating neoplastic growth and aggressiveness. These include the presence of clonal populations, the phylogenetic structure of those populations, the degree of the complexity of copy number changes in those populations, and measures of the proportion of cells with clonal copy number signatures. The parameters all showed good correlation to the measure of prostatic malignancy, the Gleason score, derived from individual prostate biopsy tissue cores. Remarkably, a more accurate histopathological measure of malignancy, the surgical Gleason score, agrees better with these genomic parameters of diagnostic biopsy than it does with the diagnostic Gleason score and related measures of diagnostic histopathology. This is highly relevant since primary treatment decisions are dependent upon the biopsy and not the surgical specimen. Thus, single cell analysis has the potential to augment traditional core histopathology, improving both the objectivity and accuracy of risk assessment and inform treatment decisions.

http://ift.tt/2Ag1EVX

SHMT2 desuccinylation by SIRT5 drives cancer cell proliferation

The mitochondrial serine hydroxymethyltransferase SHMT2 which catalyzes the rate-limiting step in serine catabolism drives cancer cell proliferation, but how this role is regulated is undefined. Here we report that the sirtuin SIRT5 desuccinylates SHMT2 to increase its activity and drive serine catabolism in tumor cells. SIRT5 interaction directly mediated desuccinylation of lysine 280 on SHMT2 which was crucial for activating its enzymatic activity. Conversely hypersuccinylation of SHMT2 at lysine 280 was sufficient to inhibit its enzymatic activity and downregulate tumor cell growth in vitro and in vivo. Notably, SIRT5 inactivation led to SHMT2 enzymatic downregulation and abrogated cell growth under metabolic stress. Our results reveal that SHMT2 desuccinylation is a pivotal signal in cancer cells to adapt serine metabolic processes for rapid growth, and they highlight SIRT5 as a candidate target for suppressing serine catabolism as a strategy to block tumor growth.

http://ift.tt/2ztVlgu

MYC targeted long non-coding RNA DANCR promotes cancer in part by reducing p21 levels

The MYC oncogene broadly promotes transcription mediated by all nuclear RNA polymerases, thereby acting as a positive modifier of global gene expression. Here we report that MYC stimulates the transcription of DANCR, a long non-coding RNA (lncRNA) that is widely overexpressed in human cancer. We identified DANCR through its overexpression in a transgenic model of MYC-induced lymphoma, but found that it was broadly upregulated in many human cancer cell lines and cancers, including most notably in prostate and ovarian cancers. Mechanistic investigations indicated that DANCR limited the expression of cell cycle inhibitor p21 (CDKN1A), and that the inhibitory effects of DANCR loss on cell proliferation could be partially rescued by p21 silencing. In a xenograft model of human ovarian cancer, a nanoparticle-mediated siRNA strategy to target DANCR in vivo was sufficient to strongly inhibit tumor growth. Our observations expand knowledge of how MYC drives cancer cell proliferation by identifying DANCR as a critical lncRNA widely overexpressed in human cancers.

http://ift.tt/2Ag2bXX

ER alpha binding by transcription factors NFIB and YBX1 enables FGFR2 signalling to modulate estrogen responsiveness in breast cancer

Two opposing clusters of transcription factors (TF) have been associated with the differential risks of estrogen receptor positive or negative breast cancers, but the mechanisms underlying the opposing functions of the two clusters are undefined. In this study, we identified NFIB and YBX1 as novel interactors of the estrogen receptor alpha (ESR1). NFIB and YBX1 are both risk TF associated with progression of ESR1-negative disease. Notably, they both interacted with the ESR1-FOXA1 complex and inhibited the transactivational potential of ESR1. Moreover, signaling through FGFR2, a known risk factor in breast cancer development, augmented these interactions and further repressed ESR1 target gene expression. We therefore show that members of two opposing clusters of risk associated with ESR1 positive and negative breast cancer can physically interact. We postulate that this interaction forms a toggle between two developmental pathways affected by FGFR2 signaling, possibly offering a junction to exploit therapeutically.

http://ift.tt/2zxLarb

Small molecule inhibition of Axl targets tumor immune suppression and enhances chemotherapy in pancreatic cancer

Activation of the receptor tyrosine kinase Axl is associated with poor outcomes in pancreatic cancer (PDA), where it coordinately mediates immune evasion and drug resistance. Here we demonstrate that the selective Axl kinase inhibitor BGB324 targets the tumor-immune interface to blunt the aggressive traits of PDA cells in vitro and enhance gemcitibine efficacy in vivo. Axl signaling stimulates the TBK1-NFκB pathway and innate immune suppression in the tumor microenvironment. In tumor cells, BGB324 treatment drove epithelial differentiation, expression of nucleoside transporters affecting gemcitabine response and an immune stimulatory microenvironment. Our results establish a preclinical mechanistic rationale for the clinical development of Axl inhibitors to improve the treatment of PDA patients.

http://ift.tt/2Ag1BJL

YAP1 and COX2 coordinately regulate urothelial cancer stem-like cells

Overcoming acquired drug resistance remains a core challenge in the clinical management of human cancer, including in urothelial carcinoma of the bladder (UCB). Cancer stem-like cells (CSC) have been implicated in the emergence of drug resistance but mechanisms and intervention points are not completely understood. Here we report that the pro-inflammatory COX2/PGE2 pathway and the YAP1 growth regulatory pathway cooperate to recruit the stem cell factor SOX2 in expanding and sustaining the accumulation of urothelial CSC. Mechanistically, COX2/PGE2 signaling induced promoter methylation of let-7, resulting in its downregulation and subsequent SOX2 upregulation. YAP1 induced SOX2 expression more directly by binding its enhancer region. In UCB clinical specimens, positive correlations in the expression of SOX2, COX2, and YAP1 were observed, with co-expression COX2 and YAP1 particularly commonly observed. Additional investigations suggested that activation of the COX2/PGE2 and YAP1 pathways also promoted acquired resistance to EGFR inhibitors in basal-type UCB. In a mouse xenograft model of UCB, dual inhibition of COX2 and YAP1 elicited a long-lasting therapeutic response by limiting CSC expansion after chemotherapy and EGFR inhibition. Our findings provide a preclinical rationale to target these pathways concurrently with systemic chemotherapy as a strategy to improve the clinical management of UCB.

http://ift.tt/2ztCOk9

Synthetic lethality of PARP inhibitors in combination with MYC blockade is independent of BRCA status in triple negative breast cancer

PARP inhibitors (PARPi) benefit only a fraction of breast cancer patients. Several of those patients exhibit intrinsic/acquired resistance mechanisms that limit efficacy of PARPi monotherapy. Here we show how the efficacy of PARPi in triple-negative breast cancers (TNBC) can be expanded by targeting MYC-induced oncogenic addiction. In BRCA-mutant/sporadic TNBC patients, amplification of the MYC gene is correlated with increased expression of the homologous DNA recombination enzyme RAD51 and tumors overexpressing both genes are associated with worse overall survival. Combining MYC blockade with PARPi yielded synthetic lethality in MYC-driven TNBC cells. Using the cyclin-dependent kinase inhibitor dinaciclib, which downregulates MYC expression, we found that combination with the PARPi niraparib increased DNA damage and downregulated homologous recombination, leading to subsequent downregulation of the epithelial-mesenchymal transition (EMT) and cancer stem-like cell phenotypes. Notably, dinaciclib re-sensitized TBNC cells, which had acquired resistance to niraparib. We found that the synthetic lethal strategy employing dinaciclib and niraparib was also highly efficacious in ovarian, prostate, pancreatic, colon and lung cancer cells. Taken together, our results show how blunting MYC oncogene addiction can leverage cancer cell sensitivity to PARPi, facilitating the clinical use of c-myc as a predictive biomarker for this treatment.

http://ift.tt/2Ag27aF

Utility of single cell genomics in diagnostic evaluation of prostate cancer

A distinction between indolent and aggressive disease is a major challenge in diagnostics of prostate cancer. As genetic heterogeneity and complexity may influence clinical outcome, we have initiated studies on single tumor cell genomics. In this study, we demonstrate that sparse DNA sequencing of single cell nuclei from prostate core biopsies is a rich source of quantitative parameters for evaluating neoplastic growth and aggressiveness. These include the presence of clonal populations, the phylogenetic structure of those populations, the degree of the complexity of copy number changes in those populations, and measures of the proportion of cells with clonal copy number signatures. The parameters all showed good correlation to the measure of prostatic malignancy, the Gleason score, derived from individual prostate biopsy tissue cores. Remarkably, a more accurate histopathological measure of malignancy, the surgical Gleason score, agrees better with these genomic parameters of diagnostic biopsy than it does with the diagnostic Gleason score and related measures of diagnostic histopathology. This is highly relevant since primary treatment decisions are dependent upon the biopsy and not the surgical specimen. Thus, single cell analysis has the potential to augment traditional core histopathology, improving both the objectivity and accuracy of risk assessment and inform treatment decisions.

from Cancer via ola Kala on Inoreader http://ift.tt/2Ag1EVX
via IFTTT

Perioperative, spatiotemporally coordinated activation of T and NK cells prevents recurrence of pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal and disseminating cancer resistant to therapy, including checkpoint immunotherapies, and early tumor resection and (neo)adjuvant chemotherapy fails to improve a poor prognosis. In a transgenic mouse model of resectable PDAC, we investigated the coordinated activation of T and NK cells in addition to gemcitabine chemotherapy to prevent tumor recurrence. Only neoadjuvant, but not adjuvant treatment with a PD-1 antagonist effectively supported chemotherapy and suppressed local tumor recurrence and improved survival involving both NK and T cells. Local T cell activation was confirmed by increased tumor infiltration with CD103+CD8+ T cells and neoantigen-specific CD8 T lymphocytes against the marker neoepitope LAMA4-G1254V. To achieve effective prevention of distant metastases in a complementary approach, we blocked the NK cell checkpoint CD96, an inhibitory NK cell receptor that binds CD155, which was abundantly expressed in primary PDAC and metastases of human patients. In gemcitabine-treated mice, neoadjuvant PD-1 blockade followed by adjuvant inhibition of CD96 significantly prevented relapse of PDAC, allowing for long-term survival. In summary, our results show in an aggressively growing transgenic mouse model of PDAC that the coordinated activation of both innate and adaptive immunity can effectively reduce the risk of tumor recurrence after surgery, facilitating long-term remission of this lethal disease.

from Cancer via ola Kala on Inoreader http://ift.tt/2ib0B5f
via IFTTT

miR-139-5p modulates radiotherapy resistance in breast cancer by repressing multiple gene networks of DNA repair and ROS defense

Radiotherapy (RT) is essential to the treatment of most solid tumors and acquired or innate resistance to this therapeutic modality is a major clinical problem. Here we show that miR-139-5p is a potent modulator of radiotherapy response in breast cancer (BC) via its regulation of genes involved in multiple DNA repair and reactive oxygen species defense pathways. Treatment of breast cancer cells with a miR-139-5p mimic strongly synergized with radiation both in vitro and in vivo, resulting in significantly increased oxidative stress, accumulation of unrepaired DNA damage and induction of apoptosis. Several miR-139-5p target genes were also strongly predictive of outcome, specifically in RT-treated patients across multiple independent breast cancer cohorts. These prognostically relevant miR-139-5p target genes were used as companion biomarkers to identify radioresistant BC xenografts highly amenable to sensitization by co-treatment with a miR-139-5p mimetic.

from Cancer via ola Kala on Inoreader http://ift.tt/2AayWYV
via IFTTT

A potent, metabolically stable tubulin inhibitor targets the colchicine binding site and overcomes taxane resistance

Antimitotics that target tubulin are among the most useful chemotherapeutic drugs, but their clinical activity is often limited by the development of multidrug resistance. We recently discovered the novel small molecule DJ101 as a potent and metabolically stable tubulin inhibitor that can circumvent the drug efflux pumps responsible for multidrug resistance of existing tubulin inhibitors. In this study, we determined the mechanism of action of this drug. The basis for its activity was illuminated by solving the crystal structure of DJ101 in complex with tubulin at a resolution of 2.8Å. Investigations of the potency of DJ101 in a panel of human metastatic melanoma cell lines harboring major clinically relevant mutations defined IC50 values of 7-10 nM. In cells, DJ101 disrupted microtubule networks, suppressed anchorage-dependent melanoma colony formation and impaired cancer cell migration. In melanoma-bearing mice, DJ101 administration inhibited tumor growth and reduced lung metastasis in the absence of observable toxicity. DJ101 also completely inhibited tumor growth in a paclitaxel-resistant xenograft mouse model of human prostate cancer (PC-3/TxR), where paclitaxel was minimally effective. Our findings offer preclinical proof of concept for the continued development of DJ101 as a next-generation tubulin inhibitor for cancer therapy.

from Cancer via ola Kala on Inoreader http://ift.tt/2ibVt0s
via IFTTT

Distinct TP63 isoform-driven transcriptional signatures predict tumor progression and clinical outcomes

TP63 is required to maintain stem cell pluripotency and suppresses the metastatic potential of cancer cells through multiple mechanisms. These functions are differentially regulated by individual isoforms, necessitating a deeper understanding of how the distinct transcriptional programs controlled by these isoforms affect cancer progression and outcomes. In this study, we conducted a pan-cancer analysis of The Cancer Genome Atlas (TCGA) to identify transcriptional networks regulated by TAp63 and ΔNp63 using transcriptomes derived from epidermal cells of TAp63-/- and ΔNp63-/- mice. Analysis of 17 cancer developmental and 27 cancer progression signatures revealed a consistent tumor suppressive pattern for TAp63. In contrast, we identified pleiotropic roles for ΔNp63 in tumor development and found that its regulation of Lef1 was crucial for its oncogenic role. ΔNp63 performed a distinctive role as suppressor of tumor progression by cooperating with TAp63 to modulate key biological pathways, principally cell cycle regulation, extra cellular matrix remodeling, epithelial-to-mesenchymal transition, and the enrichment of pluripotent stem cells. Importantly, these TAp63 and ΔNp63 signatures prognosticated progression and survival, even within specific stages, in bladder and renal carcinomas as well as low-grade gliomas. These data describe a novel approach for understanding transcriptional activities of TP63 isoforms across a large number of cancer types, potentially enabling identification of patient subsets most likely to benefit from therapies predicated on manipulating specific TP63 isoforms.

from Cancer via ola Kala on Inoreader http://ift.tt/2AayRV7
via IFTTT

New mechanisms of resistance to MEK inhibitors in melanoma revealed by intravital imaging

Targeted therapeutics that are initially effective in cancer patients nearly invariably engender resistance at some stage, an inherent challenge in the use of any molecular targeted drug in cancer settings. In this study, we evaluated resistance mechanisms arising in metastatic melanoma to MAPK pathway kinase inhibitors, as a strategy to identify candidate strategies to limit risks of resistance. To investigate longitudinal responses, we developed an intravital serial imaging approach that can directly visualize drug response in an inducible RAF-driven, autochthonous murine model of melanoma incorporating a fluorescent reporter allele (tdTomatoLSL). Using this system, we visualized formation and progression of tumors in situ starting from the single cell level longitudinally over time. Reliable reporting of the status of primary murine tumors treated with the selective MEK1/2 inhibitor (MEKi) trametinib illustrated a time-course of initial drug response and persistence followed by the development of drug resistance. We found that tumor cells adjacent to bundled collagen had a preferential persistence in response to MEKi. Unbiased transcriptional and kinome reprogramming analyses from selected treatment time points suggested increased c-Kit and PI3K/AKT pathway activation in resistant tumors, along with enhanced expression of epithelial genes and EMT downregulation signatures with development of MEKi resistance. Similar trends were observed following simultaneous treatment with BRAF and MEK inhibitors aligned to standard of care combination therapy, suggesting these re-programming events were not specific to MEKi alone. Overall, our results illuminate the integration of tumor-stroma dynamics with tissue plasticity in melanoma progression and provide new insights into the basis for drug response, persistence and resistance.

from Cancer via ola Kala on Inoreader http://ift.tt/2icbjIM
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Vitamin C sensitizes melanoma to BET inhibitors

Bromodomain and extra-terminal inhibitors (BETi) are promising cancer therapies, yet prominent side effects of BETi at effective doses have been reported in Phase I clinical trials. Here we screened a panel of small molecules targeting epigenetic modulators against human metastatic melanoma cells. Cells were pretreated with or without ascorbate (vitamin C), which promotes DNA demethylation and subsequently changes the sensitivity to drugs. Top hits were structurally unrelated BETi including JQ1, I-BET151, CPI-203, and BI-2536. Ascorbate enhanced the efficacy of BETi by decreasing acetylation of histone H4, but not H3, while exerting no effect on the expression of BRD proteins. Histone acetyltransferase 1 (HAT1), which catalyzes H4K5ac and H4K12ac, was downregulated by ascorbate mainly via the TET-mediated DNA hydroxymethylation pathway. Loss of H4ac, especially H4K5ac and H4K12ac, disrupted the interaction between BRD4 and H4 by which ascorbate and BETi blocked the binding of BRD4 to acetylated histones. Co-treatment with ascorbate and JQ1 induced apoptosis and inhibited proliferation of cultured melanoma cells. Ascorbate deficiency as modeled in Gulo-/- mice diminished the treatment outcome of JQ1 for melanoma tumorgraft. In contrast, ascorbate supplementation lowered the effective dose of JQ1 needed to successfully inhibit melanoma tumors in mice. Based on our findings, future clinical trials with BETi should consider ascorbate levels in patients. Furthermore, ascorbate supplementation might help reduce the severe side effects that arise from BETi therapy by reducing the dosage necessary for treatment.

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SHMT2 desuccinylation by SIRT5 drives cancer cell proliferation

The mitochondrial serine hydroxymethyltransferase SHMT2 which catalyzes the rate-limiting step in serine catabolism drives cancer cell proliferation, but how this role is regulated is undefined. Here we report that the sirtuin SIRT5 desuccinylates SHMT2 to increase its activity and drive serine catabolism in tumor cells. SIRT5 interaction directly mediated desuccinylation of lysine 280 on SHMT2 which was crucial for activating its enzymatic activity. Conversely hypersuccinylation of SHMT2 at lysine 280 was sufficient to inhibit its enzymatic activity and downregulate tumor cell growth in vitro and in vivo. Notably, SIRT5 inactivation led to SHMT2 enzymatic downregulation and abrogated cell growth under metabolic stress. Our results reveal that SHMT2 desuccinylation is a pivotal signal in cancer cells to adapt serine metabolic processes for rapid growth, and they highlight SIRT5 as a candidate target for suppressing serine catabolism as a strategy to block tumor growth.

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MYC targeted long non-coding RNA DANCR promotes cancer in part by reducing p21 levels

The MYC oncogene broadly promotes transcription mediated by all nuclear RNA polymerases, thereby acting as a positive modifier of global gene expression. Here we report that MYC stimulates the transcription of DANCR, a long non-coding RNA (lncRNA) that is widely overexpressed in human cancer. We identified DANCR through its overexpression in a transgenic model of MYC-induced lymphoma, but found that it was broadly upregulated in many human cancer cell lines and cancers, including most notably in prostate and ovarian cancers. Mechanistic investigations indicated that DANCR limited the expression of cell cycle inhibitor p21 (CDKN1A), and that the inhibitory effects of DANCR loss on cell proliferation could be partially rescued by p21 silencing. In a xenograft model of human ovarian cancer, a nanoparticle-mediated siRNA strategy to target DANCR in vivo was sufficient to strongly inhibit tumor growth. Our observations expand knowledge of how MYC drives cancer cell proliferation by identifying DANCR as a critical lncRNA widely overexpressed in human cancers.

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ER alpha binding by transcription factors NFIB and YBX1 enables FGFR2 signalling to modulate estrogen responsiveness in breast cancer

Two opposing clusters of transcription factors (TF) have been associated with the differential risks of estrogen receptor positive or negative breast cancers, but the mechanisms underlying the opposing functions of the two clusters are undefined. In this study, we identified NFIB and YBX1 as novel interactors of the estrogen receptor alpha (ESR1). NFIB and YBX1 are both risk TF associated with progression of ESR1-negative disease. Notably, they both interacted with the ESR1-FOXA1 complex and inhibited the transactivational potential of ESR1. Moreover, signaling through FGFR2, a known risk factor in breast cancer development, augmented these interactions and further repressed ESR1 target gene expression. We therefore show that members of two opposing clusters of risk associated with ESR1 positive and negative breast cancer can physically interact. We postulate that this interaction forms a toggle between two developmental pathways affected by FGFR2 signaling, possibly offering a junction to exploit therapeutically.

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Small molecule inhibition of Axl targets tumor immune suppression and enhances chemotherapy in pancreatic cancer

Activation of the receptor tyrosine kinase Axl is associated with poor outcomes in pancreatic cancer (PDA), where it coordinately mediates immune evasion and drug resistance. Here we demonstrate that the selective Axl kinase inhibitor BGB324 targets the tumor-immune interface to blunt the aggressive traits of PDA cells in vitro and enhance gemcitibine efficacy in vivo. Axl signaling stimulates the TBK1-NFκB pathway and innate immune suppression in the tumor microenvironment. In tumor cells, BGB324 treatment drove epithelial differentiation, expression of nucleoside transporters affecting gemcitabine response and an immune stimulatory microenvironment. Our results establish a preclinical mechanistic rationale for the clinical development of Axl inhibitors to improve the treatment of PDA patients.

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YAP1 and COX2 coordinately regulate urothelial cancer stem-like cells

Overcoming acquired drug resistance remains a core challenge in the clinical management of human cancer, including in urothelial carcinoma of the bladder (UCB). Cancer stem-like cells (CSC) have been implicated in the emergence of drug resistance but mechanisms and intervention points are not completely understood. Here we report that the pro-inflammatory COX2/PGE2 pathway and the YAP1 growth regulatory pathway cooperate to recruit the stem cell factor SOX2 in expanding and sustaining the accumulation of urothelial CSC. Mechanistically, COX2/PGE2 signaling induced promoter methylation of let-7, resulting in its downregulation and subsequent SOX2 upregulation. YAP1 induced SOX2 expression more directly by binding its enhancer region. In UCB clinical specimens, positive correlations in the expression of SOX2, COX2, and YAP1 were observed, with co-expression COX2 and YAP1 particularly commonly observed. Additional investigations suggested that activation of the COX2/PGE2 and YAP1 pathways also promoted acquired resistance to EGFR inhibitors in basal-type UCB. In a mouse xenograft model of UCB, dual inhibition of COX2 and YAP1 elicited a long-lasting therapeutic response by limiting CSC expansion after chemotherapy and EGFR inhibition. Our findings provide a preclinical rationale to target these pathways concurrently with systemic chemotherapy as a strategy to improve the clinical management of UCB.

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Synthetic lethality of PARP inhibitors in combination with MYC blockade is independent of BRCA status in triple negative breast cancer

PARP inhibitors (PARPi) benefit only a fraction of breast cancer patients. Several of those patients exhibit intrinsic/acquired resistance mechanisms that limit efficacy of PARPi monotherapy. Here we show how the efficacy of PARPi in triple-negative breast cancers (TNBC) can be expanded by targeting MYC-induced oncogenic addiction. In BRCA-mutant/sporadic TNBC patients, amplification of the MYC gene is correlated with increased expression of the homologous DNA recombination enzyme RAD51 and tumors overexpressing both genes are associated with worse overall survival. Combining MYC blockade with PARPi yielded synthetic lethality in MYC-driven TNBC cells. Using the cyclin-dependent kinase inhibitor dinaciclib, which downregulates MYC expression, we found that combination with the PARPi niraparib increased DNA damage and downregulated homologous recombination, leading to subsequent downregulation of the epithelial-mesenchymal transition (EMT) and cancer stem-like cell phenotypes. Notably, dinaciclib re-sensitized TBNC cells, which had acquired resistance to niraparib. We found that the synthetic lethal strategy employing dinaciclib and niraparib was also highly efficacious in ovarian, prostate, pancreatic, colon and lung cancer cells. Taken together, our results show how blunting MYC oncogene addiction can leverage cancer cell sensitivity to PARPi, facilitating the clinical use of c-myc as a predictive biomarker for this treatment.

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The influence of family adaptability and cohesion on anxiety and depression of terminally ill cancer patients

Abstract

Purpose

This study investigated the effect of family members on terminally ill cancer patients by measuring the relationship of the presence of the family caregivers, visiting time by family and friends, and family adaptability and cohesion with patient's anxiety and depression.

Methods

From June, 2016 to March, 2017, 100 terminally ill cancer patients who were admitted to a palliative care unit in Seoul, South Korea, were surveyed, and their medical records were reviewed. The Korean version of the Family Adaptability and Cohesion Evaluation Scales III and Hospital Anxiety-Depression Scale was used. Chi-square and multiple logistic regression analyses were used.

Results

The results of the chi-square analysis showed that the presence of family caregivers and family visit times did not have statistically significant effects on anxiety and depression in terminally ill cancer patients. In multiple logistic regression, when adjusted for age, sex, ECOG PS, and the monthly average income, the odds ratios (ORs) of the low family adaptability to anxiety and depression were 2.4 (1.03–5.83) and 5.4 (1.10–26.87), respectively. The OR of low family cohesion for depression was 5.4 (1.10–27.20) when adjusted for age, sex, ECOG PS, and monthly average household income.

Conclusions

A higher family adaptability resulted in a lower degree of anxiety and depression in terminally ill cancer patients. The higher the family cohesion, the lower the degree of depression in the patient. The presence of the family caregiver and the visiting time by family and friends did not affect the patient's anxiety and depression.

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Management of bone health in postmenopausal women on aromatase inhibitors (AIs): a single health care system experience

Abstract

Introduction

Aromatase inhibitors (AIs) are the preferred therapy for postmenopausal women with early-stage estrogen receptor-positive breast cancers. However, their use causes bone loss and increased risks of osteoporosis and fractures.

Methods

This is a retrospective review of all postmenopausal women with breast cancer diagnosed and treated with AI between 2010 and 2015. Of the 564 women identified, 319 were eligible.

Results

The median age at AI initiation was 65 years (range 51–85 years), and the median duration of AI therapy was 28 months (1–72 months). The median number of DEXA scans per woman was 1 (0–4), performed at a median frequency of 24 months (1–48 months). Recommendations for calcium and vitamin D were in 66 and 59% of women, respectively. There were 52 (16%) women who received antiresorptive treatments with bisphosphonates (69%), denosumab (25%), or both drugs (6%). Based on guideline recommendations from six societies, starting antiresorptive treatment was unnecessary in 15–54% of women.

Conclusions

In this single health system experience, women start antiresorptive drugs that are unnecessary in 15–52%. These results highlight the nonuniformity in guideline recommendations, and this has implications for quality of care, cost-effectiveness, and value-of-care analyses for preventing fractures.

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Automatic referral to standardize palliative care access: an international Delphi survey

Abstract

Purpose

Palliative care referral is primarily based on clinician judgment, contributing to highly variable access. Standardized criteria to trigger automatic referral have been proposed, but it remains unclear how best to apply them in practice. We conducted a Delphi study of international experts to identify a consensus for the use of standardized criteria to trigger automatic referral.

Methods

Sixty international experts stated their level of agreement for 14 statements regarding the use of clinician-based referral and automatic referral over two Delphi rounds. A consensus was defined as an agreement of ≥70% a priori.

Results

The response rate was 59/60 (98%) for the first round and 56/60 (93%) for the second round. Twenty-six (43%), 19 (32%), and 11 (18%) respondents were from North America, Asia/Australia, and Europe, respectively. The panel reached consensus that outpatient palliative care referral should be based on both automatic referral and clinician-based referral (agreement = 86%). Only 18% felt that referral should be clinician-based alone, and only 7% agreed that referral should be based on automatic referral only. There was consensus that automatic referral criteria may increase the number of referrals (agreement = 98%), facilitate earlier palliative care access, and help administrators to set benchmarks for quality improvement (agreement = 86%).

Conclusions

Our panelists favored the combination of automatic referral to augment clinician-based referral. This integrated referral framework may inform policy and program development.

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Totally implantable venous access ports: a prospective long-term study of early and late complications in adult patients with cancer

Abstract

Purpose

Totally implantable venous access ports (TIVAP) have been widely used for many years in the management of patients suffering from cancer. The implantation and long-term use of TIVAPs are associated with mechanical, thrombotic, and infectious complications. This is the first exhaustive prospective study of all complications occurring in a whole population on long-term follow-up and therefore allows an objective assessment to be made of the safety of TIVAPs.

Methods

We carried out a prospective single-center observational study. All adult patients with cancer who had a TIVAP implanted between January 1 and December 31, 2006 were registered. Early and late complications were recorded until the removal of the device, the patient's death, or until December 31, 2013. Exhaustive data concerning patients and TIVAP was recorded at time of implantation.

Results

Four hundred and ninety-three TIVAPs were implanted in 483 adult cancer patients and were followed during a period from 1 to 94 months (median = 18 months) representing a global quantity of 367,359 catheter-days. Eighty-seven complications were recorded (0.237/1000 catheter-days), including 37 infections (0.101/1000 catheter-days), 17 thrombotic events (0.046/1000 catheter-days), and 9 extravasations. Out of the 87 events, 62 (71.3%) occurred during the first year after implantation. Events were therefore extremely rare after 1 year. Thromboembolic and infectious complications were rare and no risk factors for these were found.

Conclusions

This study demonstrates excellent tolerability, with only occasional complications. Most of these occurred during the year following implantation. A TIVAP may also be left in place for an extremely long time.

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Clinical equivalence with G-CSF biosimilars: methodologic approach in a (neo)adjuvant setting in non-metastatic breast cancer

Abstract

Biosimilars are biological medicines that have been shown to be similar to a reference biological medicine that has already been approved for use. Development of biosimilars is based on a "totality of evidence" approach that involves a series of steps by which biosimilars must demonstrate similarity to a reference product in all aspects of the drug and eliminate any remaining uncertainties. Clinical studies are then considered confirmatory and are performed to show that there are no clinically meaningful differences compared with the reference product in a sensitive patient population. The recombinant human granulocyte colony-stimulating factor (G-CSF) biosimilar EP2006/Zarxio® (filgrastim-sdnz) became the first FDA-approved biosimilar in 2015. This review evaluates how clinical equivalence can be demonstrated with G-CSF biosimilars through the identification of "sensitive" study populations and endpoints. Patients with non-metastatic breast cancer treated in the (neo)adjuvant setting represent a potentially homogenous population, making this a suitable sensitive indication for assessing filgrastim and pegfilgrastim biosimilars compared with reference products. This review includes clinical trials of G-CSF biosimilars in breast cancer, focusing on key aspects of the trials that were necessary to accurately demonstrate clinical equivalence and enable extrapolation to relevant indications, based on guidelines and biostatistical principles.

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Amisulpride in the prevention of nausea and vomiting induced by cisplatin-based chemotherapy: a dose-escalation study

Abstract

Purpose

The purpose of this study was to investigate the antiemetic effect of the dopamine D₂- and dopamine D₃-receptor antagonist, amisulpride, in patients receiving cisplatin-based chemotherapy.

Methods

This dose-finding, non-comparative study investigated the antiemetic effect and safety of increasing doses (2.5, 7.5 and 20 mg) of amisulpride against acute nausea and vomiting in the period 0–24 h after initiation of cisplatin-based chemotherapy. The 20 mg dose was also investigated in combination with the 5-HT₃-receptor antagonist, ondansetron. The primary parameter was complete response (0–24 h), defined as no emesis and no need for rescue antiemetics. Secondary parameters were number of emetic episodes, severity of nausea and time to first emetic episode and start of nausea.

Results

A total of 51 patients were enrolled and evaluable. None of the 10 patients in the 2.5 and 7.5 mg groups obtained a CR. In the 20 mg monotherapy cohort, two of the 18 subjects (11%) had a CR, 3/18 (17%) had no emesis and 12/18 (67%) had no significant nausea. Seven subjects (39%) had no nausea at all (a VAS score < 5 mm). In the combination (ondansetron plus amisulpride) cohort, 19/23 (83%; 90% confidence interval: 65–94%) had a CR and 14/23 (61%) had no nausea at all.

Conclusions

Amisulpride has antiemetic effect against cisplatin-induced acute nausea and vomiting. The effect against nausea is of particular interest. Randomised studies are warranted to further explore the effect and safety of amisulpride.

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Impact of emotional competence on supportive care needs, anxiety and depression symptoms of cancer patients: a multiple mediation model

Abstract

Purpose

The aim of this study was to test the effect of intrapersonal and interpersonal emotional competence on cancer patients' supportive care needs, as mediated by anxiety and depression symptoms.

Methods

Cross-sectional design: 137 cancer patients (42% breast or ovarian cancer, 58% gastrointestinal cancer) in 4 French hospitals completed the Profile of Emotional Competence (PEC), the Hospital Anxiety and Depression Scale (HADS), and the Supportive Care Needs Survey Short Form (SCNS-SF). Bootstrap methods with PROCESS Macro were used to test multiple mediation models.

Results

Emotional competence presented a direct or indirect beneficial effect on the satisfaction of supportive care needs, anxiety and depression symptoms. As expected, anxiety and depression symptoms had also strong positive correlations with unmet needs. All multiple mediation models were significant, except for physical needs: intrapersonal and interpersonal emotional competence impacted anxiety and depression symptoms, which in turn impacted psychological, sexual, care/support, and information needs.

Conclusions

These innovative results show the important effect of patients' emotional competence on their supportive care need satisfaction, as mediated by anxiety and depression. Consequently, patients with high emotional competence may require less psychosocial input from medical clinicians. Thus, emotional competence may be integrated into health models and psychosocial interventions to improve patient adjustment. Further investigation is, however, needed to know which are the most beneficial specific emotional competences and at what point of the cancer pathway.

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A randomized phase II trial of geriatric assessment and management for older cancer patients

Abstract

Purpose

Geriatric assessment and management (GAM) can identify current health issues and recommend interventions to optimize well-being of older adults, but no randomized trial has yet been completed in oncology. Therefore, a randomized phase 2 trial was conducted.

Methods

A two-group parallel single-blinded randomized phase II trial (ClinicalTrials.gov Identifier: NCT02222259) enrolled patients aged ≥70 years, diagnosed with stage 2–4 gastrointestinal, genitourinary, or breast cancer within 6 weeks of commencing chemotherapy at Princess Margaret Cancer Centre. The coprimary feasibility outcomes were the proportion of eligible patients enrolled and retained. The coprimary clinical outcomes were quality of life (QOL) (EORTC QLQ C30) and modification of cancer treatment. Descriptive and regression analyses using intent-to-treat analysis were conducted.

Results

Sixty-one persons (64%) agreed to participate (31 allocated to intervention arm and 30 to control group). In the control group, more participants died and refused follow-up. The benefit of intervention over control on QOL at 3 months was greater for those who survived 6 months (difference 9.28; 95% CI −10.35 to 28.91) versus those who survived only 3 months (difference 6.55; 95% CI −9.63 to 22.73).

Conclusions

This trial showed that it was feasible to recruit and retain older adults for a GAM study. Those who survived at least 6 months seemed to receive a greater QOL benefit than those who died or withdrew.

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Predictive model of complexity in early palliative care: a cohort of advanced cancer patients (PALCOM study)

Abstract

Proposal

Model of early palliative care (PC) integrated in oncology is based on shared care from the diagnosis to the end of life and is mainly focused on patients with greater complexity. However, there is no definition or tools to evaluate PC complexity. The objectives of the study were to identify the factors influencing level determination of complexity, propose predictive models, and build a complexity scale of PC.

Patients and method

We performed a prospective, observational, multicenter study in a cohort of advanced cancer patients with an estimated prognosis ≤ 6 months. An ad hoc structured evaluation including socio-demographic and clinical data, symptom burden, functional and cognitive status, psychosocial problems, and existential-ethic dilemmas was recorded systematically. According to this multidimensional evaluation, investigator classified patients as high, medium, or low palliative complexity, associated to need of basic or specialized PC. Logistic regression was used to identify the variables influencing determination of level of PC complexity and explore predictive models.

Results

We included 324 patients; 41% were classified as having high PC complexity and 42.9% as medium, both levels being associated with specialized PC. Variables influencing determination of PC complexity were as follows: high symptom burden (OR 3.19 95%CI: 1.72–6.17), difficult pain (OR 2.81 95%CI:1.64–4.9), functional status (OR 0.99 95%CI:0.98–0.9), and social-ethical existential risk factors (OR 3.11 95%CI:1.73–5.77). Logistic analysis of variables allowed construct a complexity model and structured scales (PALCOM 1 and 2) with high predictive value (AUC ROC 76%).

Conclusion

This study provides a new model and tools to assess complexity in palliative care, which may be very useful to manage referral to specialized PC services, and agree intensity of their intervention in a model of early-shared care integrated in oncology.

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Making an informed decision of Korean cancer patients: the discrepancy between a patient’s recall of information and the information needed for acquisition of radiotherapy informed consent

Abstract

Introduction

To give informed consent, a patient needs to sufficiently understand the information provided by a physician to decide among treatment options. Although shared decision-making is becoming an important aspect of patient-centered care, little is known about decision-making by cancer patients in Korea.

Objectives

This study assessed Korean cancer patients' understanding of treatment goals and the need to obtain further information after a physician obtained informed consent for radiotherapy.

Methods

In this prospective study, doctors and patients completed questionnaires independently after informed consent for radiotherapy had been obtained. The questionnaires for the doctors and patients were comprised of matched items regarding treatment aims and the need for further information.

Results

The study enrolled 103 cancer patients scheduled for radiotherapy. The proportion of respondents who stated that the intent of treatment was to bring about a cure was 80.6% among the patients (83 of 103 patients) and 53.4% (55 of 103 patients) among the doctors (p = 0.000). The proportion of respondents who believed that the aim was prolongation of life was 16.5 and 1.9%, respectively (p = 0.000). Regarding the need for further information, 42.7% (44/103) of the patients did not want further information because they had faith in the physicians' medical expertise.

Conclusion

Many Korean cancer patients misunderstand the aims of treatment and half of participants do not want further information. Physicians should address whether specific interventions can solve these barriers so that Korean cancer patients can make truly autonomous treatment decisions.

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