Long non-coding RNA H19 promotes glucose metabolism and cell growth in malignant melanoma via miR-106a-5p/E2F3 axis

Abstract

Purpose

lncRNA H19 has been considered as an oncogenic lncRNA in many human tumours. In the present study, we identify the role and molecular mechanism of lncRNA H19 in melanoma.

Method

QRT-PCR was used to detect the expression of lncRNA H19 and E2F3 was detected in melanoma tissues. Cell counting kit-8 (CCK8), representative metabolites analysis was used to explore the biological function of lncRNA H19, miR-106a-5p and E2F3 in melanoma cells. Bioinformatics, luciferase reporter assays, MS2-RIP and RNA pull-down assay was used to demonstrate the molecular mechanism of lncRNA H19 in melanoma. We further test the function of lncRNA H19 in vivo though Xenograft tumour assay.

Results

We found that lncRNA H19 was increased in melanoma tissue, and lncRNA H19 was correlated with poor prognosis of melanoma patients. miR-106a-5p acts as a tumour suppressor in melanoma by targeting E2F3. E2F3 affects the melanoma cell glucose metabolism and growth. We also demonstrated that lncRNA H19 may function as the sponge of miR-106a-5p to up-regulate E2F3 expression, and consequently promote the glucose metabolism and growth of melanoma.

Conclusions

This result elucidates a new mechanism for lncRNA H19 in melanoma development and provides a survival indicator and potential therapeutic target for melanoma patients.

http://ift.tt/2rjJORb

Long non-coding RNA H19 promotes glucose metabolism and cell growth in malignant melanoma via miR-106a-5p/E2F3 axis

Abstract

Purpose

lncRNA H19 has been considered as an oncogenic lncRNA in many human tumours. In the present study, we identify the role and molecular mechanism of lncRNA H19 in melanoma.

Method

QRT-PCR was used to detect the expression of lncRNA H19 and E2F3 was detected in melanoma tissues. Cell counting kit-8 (CCK8), representative metabolites analysis was used to explore the biological function of lncRNA H19, miR-106a-5p and E2F3 in melanoma cells. Bioinformatics, luciferase reporter assays, MS2-RIP and RNA pull-down assay was used to demonstrate the molecular mechanism of lncRNA H19 in melanoma. We further test the function of lncRNA H19 in vivo though Xenograft tumour assay.

Results

We found that lncRNA H19 was increased in melanoma tissue, and lncRNA H19 was correlated with poor prognosis of melanoma patients. miR-106a-5p acts as a tumour suppressor in melanoma by targeting E2F3. E2F3 affects the melanoma cell glucose metabolism and growth. We also demonstrated that lncRNA H19 may function as the sponge of miR-106a-5p to up-regulate E2F3 expression, and consequently promote the glucose metabolism and growth of melanoma.

Conclusions

This result elucidates a new mechanism for lncRNA H19 in melanoma development and provides a survival indicator and potential therapeutic target for melanoma patients.

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Relevant pericardial effusion caused by cytomegalovirus infection in an immunocompetent patient: a case report

Cytomegalovirus infection is known to cause symptomatic disease in immunocompromised patients, while an infection in immunocompetent individuals normally causes few or no symptoms. We present the case of an im...

http://ift.tt/2Be6dyM

Tibolone and risk of gynecological hormone sensitive cancer

Abstract

Risk of ovarian cancer with hormone therapy is associated with use of both unopposed estrogen therapy and combined estrogen-progestin therapy, whereas for endometrial cancer addition of continuous progestin decreases the estrogen induced increased risk. Less is known about risk with use of tibolone; a synthetic steroid with estrogenic, progestagenic, and androgenic properties. We assessed these associations in a prospective cohort study, including all Danish women 50–79 years of age and followed 1995–2009. National Danish Registers captured individually updated exposure information, cancer cases including histology and confounding factors. Poisson regression analyses provided multiple adjusted incidence rate ratio's (IRR).

More than 900,000 women were followed for 9.8 years on average; 4,513 were diagnosed with ovarian cancer and 6,202 with endometrial cancer.

Compared to women never on postmenopausal hormone therapy, current users of tibolone had an increased IRR for ovarian cancer (1.42(95% confidence interval [CI], 1.01-2.00) and serous ovarian tumors (2.21(95%CI 1.48-3.32)). The risk increased with duration of use, particularly for serous ovarian tumors.

Compared to never users, the IRR of endometrial cancer was 3.56(95%CI 2.94-4.32) among current users of tibolone and 3.80(95%CI 3.08–4.69) of Type 1 endometrial cancer. The steepest risk increase with duration of use was for Type I tumors.

In conclusion, tibolone is associated with increased risk for ovarian and endometrial cancer overall; and particular the risk of serous ovarian tumors and Type 1 endometrial cancer. Because the associations are stronger with increasing durations of use - and for hormone sensitive tumors -the results seem indicative of causality. This article is protected by copyright. All rights reserved.

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Progestin-Only and Combined Oral Contraceptives and Receptor-Defined Premenopausal Breast Cancer Risk: The Norwegian Women and Cancer Study

Abstract

Receptor-defined subtypes of breast cancer represent distinct cancer types and have differences in risk factors. Whether the two main hormonal forms of oral contraceptives (OCs); i.e. progestin-only (POC) and combined oral contraceptives (COC), are differentially associated with these subtypes are not well known. The aim of this study was to assess the effect of POC and COC use on hormone receptor-defined breast cancer risk in premenopausal women in a prospective population-based cohort – The Norwegian Women and Cancer study (NOWAC). Information on OC use was collected from 74,862 premenopausal women at baseline. Updated information was applied when follow-up information became available. Multiple imputation was performed to handle missing data, and multivariable Cox regression models were used to calculate hazard ratios (HR) for breast cancer. 1245 incident invasive breast cancer cases occurred. POC use ≥ five years was associated with ER+ (HR = 1.59, 95% CI 1.09 – 2.32, p_trend = 0.03) and ER+/PR+ cancer (HR = 1.63, 95% CI 1.07 – 2.48, p_trend = 0.05), and was not associated with ER- (p_{heterogeneity} = 0.36) or ER-/PR- (p_{heterogeneity} = 0.49) cancer. COC use was associated with ER- and ER-/PR- cancer, but did not increase risk of ER+ and ER+/PR+ cancer. Current COC use gave different estimates for ER/PR-defined subtypes (p_{heterogeneity} = 0.04). This is the first study to show significant associations between POC use and hormone receptor-positive breast cancer. The lack of power to distinguish effects of POC use on subtype development calls for the need of larger studies to confirm our finding. This article is protected by copyright. All rights reserved.

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Quality of life assumptions determine which cervical cancer screening strategies are cost-effective

Abstract

Quality adjusted life years are used in cost-effectiveness analyses (CEAs). To calculate QALYs, a 'utility' (0-1) is used for each health state induced or prevented by the intervention. We aimed to estimate the impact of quality-of-life (QoL) assumptions (utilities and durations of health states) on CEAs of cervical cancer screening. To do so, twelve alternative sets of utility assumptions were retrieved from published cervical cancer screening CEAs. Two additional sets were based on empirical QoL data that were integrally obtained through two different measures (SF-6D and EQ-5D) from eight groups of women (total n= 3,087), from invitation for screening to diagnosis with cervical cancer. Per utility set we calculated the number of quality-adjusted days lost (QADL) for each relevant health state in cervical cancer screening, by multiplying the study-specific assumed disutilities (i.e. 1-utility) with study-specific durations of the loss in QoL, resulting in 14 'QADL-sets'. With microsimulation model MISCAN we calculated cost-effectiveness of 342 alternative screening programs (varying in primary screening test [Human Papillomavirus (HPV) versus cytology], starting ages, and screening interval) for each of the 14 QADL-sets. Utilities used in CEAs appeared to differ largely. We found that ten QADL-sets from the literature resulted in HPV and two in cytology as preferred primary test. The SF-6D empirical QADL-set resulted in cytology and the EQ-5D one in HPV as preferred primary test. In conclusion, assumed utilities and health state durations determine cost-effectiveness of cervical cancer screening. Also, the measure used to empirically assess utilities can be crucial for CEA conclusions. This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/2mUVfKg
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Tibolone and risk of gynecological hormone sensitive cancer

Abstract

Risk of ovarian cancer with hormone therapy is associated with use of both unopposed estrogen therapy and combined estrogen-progestin therapy, whereas for endometrial cancer addition of continuous progestin decreases the estrogen induced increased risk. Less is known about risk with use of tibolone; a synthetic steroid with estrogenic, progestagenic, and androgenic properties. We assessed these associations in a prospective cohort study, including all Danish women 50–79 years of age and followed 1995–2009. National Danish Registers captured individually updated exposure information, cancer cases including histology and confounding factors. Poisson regression analyses provided multiple adjusted incidence rate ratio's (IRR).

More than 900,000 women were followed for 9.8 years on average; 4,513 were diagnosed with ovarian cancer and 6,202 with endometrial cancer.

Compared to women never on postmenopausal hormone therapy, current users of tibolone had an increased IRR for ovarian cancer (1.42(95% confidence interval [CI], 1.01-2.00) and serous ovarian tumors (2.21(95%CI 1.48-3.32)). The risk increased with duration of use, particularly for serous ovarian tumors.

Compared to never users, the IRR of endometrial cancer was 3.56(95%CI 2.94-4.32) among current users of tibolone and 3.80(95%CI 3.08–4.69) of Type 1 endometrial cancer. The steepest risk increase with duration of use was for Type I tumors.

In conclusion, tibolone is associated with increased risk for ovarian and endometrial cancer overall; and particular the risk of serous ovarian tumors and Type 1 endometrial cancer. Because the associations are stronger with increasing durations of use - and for hormone sensitive tumors -the results seem indicative of causality. This article is protected by copyright. All rights reserved.

http://ift.tt/2mUf04J

Progestin-Only and Combined Oral Contraceptives and Receptor-Defined Premenopausal Breast Cancer Risk: The Norwegian Women and Cancer Study

Abstract

Receptor-defined subtypes of breast cancer represent distinct cancer types and have differences in risk factors. Whether the two main hormonal forms of oral contraceptives (OCs); i.e. progestin-only (POC) and combined oral contraceptives (COC), are differentially associated with these subtypes are not well known. The aim of this study was to assess the effect of POC and COC use on hormone receptor-defined breast cancer risk in premenopausal women in a prospective population-based cohort – The Norwegian Women and Cancer study (NOWAC). Information on OC use was collected from 74,862 premenopausal women at baseline. Updated information was applied when follow-up information became available. Multiple imputation was performed to handle missing data, and multivariable Cox regression models were used to calculate hazard ratios (HR) for breast cancer. 1245 incident invasive breast cancer cases occurred. POC use ≥ five years was associated with ER+ (HR = 1.59, 95% CI 1.09 – 2.32, p_trend = 0.03) and ER+/PR+ cancer (HR = 1.63, 95% CI 1.07 – 2.48, p_trend = 0.05), and was not associated with ER- (p_{heterogeneity} = 0.36) or ER-/PR- (p_{heterogeneity} = 0.49) cancer. COC use was associated with ER- and ER-/PR- cancer, but did not increase risk of ER+ and ER+/PR+ cancer. Current COC use gave different estimates for ER/PR-defined subtypes (p_{heterogeneity} = 0.04). This is the first study to show significant associations between POC use and hormone receptor-positive breast cancer. The lack of power to distinguish effects of POC use on subtype development calls for the need of larger studies to confirm our finding. This article is protected by copyright. All rights reserved.

http://ift.tt/2Beyu8D

Quality of life assumptions determine which cervical cancer screening strategies are cost-effective

Abstract

Quality adjusted life years are used in cost-effectiveness analyses (CEAs). To calculate QALYs, a 'utility' (0-1) is used for each health state induced or prevented by the intervention. We aimed to estimate the impact of quality-of-life (QoL) assumptions (utilities and durations of health states) on CEAs of cervical cancer screening. To do so, twelve alternative sets of utility assumptions were retrieved from published cervical cancer screening CEAs. Two additional sets were based on empirical QoL data that were integrally obtained through two different measures (SF-6D and EQ-5D) from eight groups of women (total n= 3,087), from invitation for screening to diagnosis with cervical cancer. Per utility set we calculated the number of quality-adjusted days lost (QADL) for each relevant health state in cervical cancer screening, by multiplying the study-specific assumed disutilities (i.e. 1-utility) with study-specific durations of the loss in QoL, resulting in 14 'QADL-sets'. With microsimulation model MISCAN we calculated cost-effectiveness of 342 alternative screening programs (varying in primary screening test [Human Papillomavirus (HPV) versus cytology], starting ages, and screening interval) for each of the 14 QADL-sets. Utilities used in CEAs appeared to differ largely. We found that ten QADL-sets from the literature resulted in HPV and two in cytology as preferred primary test. The SF-6D empirical QADL-set resulted in cytology and the EQ-5D one in HPV as preferred primary test. In conclusion, assumed utilities and health state durations determine cost-effectiveness of cervical cancer screening. Also, the measure used to empirically assess utilities can be crucial for CEA conclusions. This article is protected by copyright. All rights reserved.

http://ift.tt/2mUVfKg

Fertility Preservation in Pediatric Oncology Patients: New Perspectives

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


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Follow-Up Care Provider Preferences of Adolescent and Young Adult Cancer Survivors

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


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Fertility Preservation in Pediatric Oncology Patients: New Perspectives

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


http://ift.tt/2DpFaWL

Follow-Up Care Provider Preferences of Adolescent and Young Adult Cancer Survivors

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


http://ift.tt/2ESS24M

DSP30 and interleukin-2 as a mitotic stimulant in B-cell disorders including those with a low disease burden

Abstract

Chromosome abnormalities detected during cytogenetic investigations for B-cell malignancy offer prognostic information that can have wide ranging clinical impacts on patients. These impacts may include monitoring frequency, treatment type and disease staging level. The use of the synthetic oligonucleotide DSP30 combined with interleukin 2 (IL2) has been described as an effective mitotic stimulant in B-cell disorders, predominantly in chronic lymphocytic leukaemia (CLL) but also a range of other B-cell malignancies. Here we describe the comparison of two B-cell mitogens, lipopolysaccharide (LPS) and DSP30 combined with IL2 as mitogens in a range of common B-cell disorders excluding CLL. The results showed that DSP30/IL2 was an effective mitogen in mature B-cell disorders, revealing abnormal cytogenetic results in a range of B-cell malignancies. The abnormality rate increased when compared to the use of LPS to 64% (DSP30/IL2) from 14% (LPS). In a number of cases the disease burden was proportionally very low, less than 10% of white cells. In 37% of these cases, the DSP30 culture revealed abnormal results. Importantly, we also obtained abnormal conventional cytogenetics results in 3 bone marrow cases in which immunophenotyping showed an absence of an abnormal B-cell clone. In these cases the cytogenetics results correlated with the provisional diagnosis and altered their staging level. The use of DSP30 and IL2 is recommended for use in many B-cell malignancies as an effective mitogen and their use has been shown to enable successful culture of the malignant clone, even at very low levels of disease. This article is protected by copyright. All rights reserved.

http://ift.tt/2mS46MW

DSP30 and interleukin-2 as a mitotic stimulant in B-cell disorders including those with a low disease burden

Abstract

Chromosome abnormalities detected during cytogenetic investigations for B-cell malignancy offer prognostic information that can have wide ranging clinical impacts on patients. These impacts may include monitoring frequency, treatment type and disease staging level. The use of the synthetic oligonucleotide DSP30 combined with interleukin 2 (IL2) has been described as an effective mitotic stimulant in B-cell disorders, predominantly in chronic lymphocytic leukaemia (CLL) but also a range of other B-cell malignancies. Here we describe the comparison of two B-cell mitogens, lipopolysaccharide (LPS) and DSP30 combined with IL2 as mitogens in a range of common B-cell disorders excluding CLL. The results showed that DSP30/IL2 was an effective mitogen in mature B-cell disorders, revealing abnormal cytogenetic results in a range of B-cell malignancies. The abnormality rate increased when compared to the use of LPS to 64% (DSP30/IL2) from 14% (LPS). In a number of cases the disease burden was proportionally very low, less than 10% of white cells. In 37% of these cases, the DSP30 culture revealed abnormal results. Importantly, we also obtained abnormal conventional cytogenetics results in 3 bone marrow cases in which immunophenotyping showed an absence of an abnormal B-cell clone. In these cases the cytogenetics results correlated with the provisional diagnosis and altered their staging level. The use of DSP30 and IL2 is recommended for use in many B-cell malignancies as an effective mitogen and their use has been shown to enable successful culture of the malignant clone, even at very low levels of disease. This article is protected by copyright. All rights reserved.

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The Danish Medical Birth Register

Abstract

The Danish Medical Birth Register was established in 1973. It is a key component of the Danish health information system. The register enables monitoring of the health of pregnant women and their offspring, it provides data for quality assessment of the perinatal care in Denmark, and it is used extensively for research. The register underwent major changes in construction and content in 1997, and new variables have been added during the last 20 years. The aim was to provide an updated description of the register focusing on structure, content, and coverage since 1997. The register includes data on all births in Denmark and comprises primarily of data from the Danish National Patient Registry supplemented with forms on home deliveries and stillbirths. It contains information on maternal age provided by the Civil Registration System. Information on pre-pregnancy body mass index and smoking in first trimester is collected in early pregnancy (first antenatal visit). The individual-level data can be linked to other Danish health registers such as the National Patient Registry and the Danish National Prescription Registry. The register informs several other registers/databases such as the Danish Twin Registry and the Danish Fetal Medicine Database. Aggregated data can be publicly accessed on the Danish Health Data Authority web page (www.esundhed.dk/sundhedsregistre/MFR). Researchers can obtain access to individual-level pseudo-anonymised data via servers at Statistics Denmark and the Danish Health Data Authority.

from Cancer via ola Kala on Inoreader http://ift.tt/2Bc5TRs
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The Danish Medical Birth Register

Abstract

The Danish Medical Birth Register was established in 1973. It is a key component of the Danish health information system. The register enables monitoring of the health of pregnant women and their offspring, it provides data for quality assessment of the perinatal care in Denmark, and it is used extensively for research. The register underwent major changes in construction and content in 1997, and new variables have been added during the last 20 years. The aim was to provide an updated description of the register focusing on structure, content, and coverage since 1997. The register includes data on all births in Denmark and comprises primarily of data from the Danish National Patient Registry supplemented with forms on home deliveries and stillbirths. It contains information on maternal age provided by the Civil Registration System. Information on pre-pregnancy body mass index and smoking in first trimester is collected in early pregnancy (first antenatal visit). The individual-level data can be linked to other Danish health registers such as the National Patient Registry and the Danish National Prescription Registry. The register informs several other registers/databases such as the Danish Twin Registry and the Danish Fetal Medicine Database. Aggregated data can be publicly accessed on the Danish Health Data Authority web page (www.esundhed.dk/sundhedsregistre/MFR). Researchers can obtain access to individual-level pseudo-anonymised data via servers at Statistics Denmark and the Danish Health Data Authority.

http://ift.tt/2Bc5TRs

Moyamoya tipping point: fatal bilateral MCA territory infarction following cocaine abuse

Description  

An adult Caucasian man with a history of polysubstance abuse was found unresponsive by the nursing staff at his rehabilitation centre and intubated by emergency medical services. On examination, he was stuporous, his eyes did not open to stimulation, his pupils were reactive, localised to pain with bilateral upper extremities and demonstrated triple flexion to noxious stimuli in the bilateral lower extremities. Urine toxicology was positive for cocaine metabolites. A CT scan of the head was performed, which showed possible hypodensities in the bilateral temporal lobes. MRI of the brain was performed to further characterise these hypodensities, and it revealed bilateral middle cerebral artery (MCA) infarction and generalised cerebral oedema (figure 1). CT angiogram of the head at this point was performed, which showed narrowing of both MCAs and possible moyamoya pattern on the left (figure 2). This moyamoya-like vascular change was suggested by narrowing of the left MCA and hypervascular lenticulostriate...

http://ift.tt/2DPIyYz

Role of modified Eloesser flap in the treatment of bronchopleural fistula caused by pulmonary coccidioidomycosis

Description

Coccidioidomycosis is a fungal infection by the Coccidioides genus and is usually caused by inhalation of the spores. Patients with diabetes are more likely to present with severe lung disease, especially cavitary lesions.1 2 We depict the case of a 47-year-old man with uncontrolled type 2 diabetes mellitus who presented with a right pulmonary lung abscess due to coccidioidomycosis and underwent a right thoracotomy with partial right upper lobe resection. Intraoperatively the pleura was found to be thickened, and the upper lobe had multiple adhesions and was perforated, creating a purulent bronchopleural fistula. He developed recurrent right-sided empyema due to the fistula and an attempt at a second thoracotomy was unsuccessful. After placement of three failed endobronchial valves, he ultimately had a tunnelled pleural catheter placed. Two weeks later the patient began draining frank pus from the site and a modified Eloesser flap...

http://ift.tt/2DO4hzX

Stent-assisted coil embolization on down-the-barrel view with spring-shaped microcatheter in patient with M1 ultrawide necked circumferential aneurysm

Herein, we describe a technique for stent-assisted coil embolization with a spring-shaped microcatheter in a patient with an M1 ultrawide-necked circumferential aneurysm in the middle cerebral artery (MCA). A 49-year-old man was referred for treatment of an incidentally detected M1 large-circumference aneurysm on magnetic resonance angiography. Subsequent digital subtraction angiography revealed an 18.2x16.5 mm ultrawide-necked circumferential aneurysm on the distal M1 portion of the left MCA, and we planned stent-assisted coil embolization using a spring-shaped microcatheter. After we deployed the stent, we performed coil embolization under the down-the-barrel view by pulling out the microcatheter little by little. Using this technique, we could fill the coil mass evenly into the aneurysmal sac around the stent. And there were no immediate or delayed complications after the procedure. Stent-assisted coiling using a spring-shaped microcatheter is a useful and safe technique for treating ultrawide-necked circumferential aneurysm or fusiform aneurysms.

http://ift.tt/2Djz3zQ

Megaduodenum in a 59-year-old man: a very late postoperative complication after duodenal atresia

Intestinal malformations are common defects of the newborn, treated in experienced centres. Reports on long-term follow-up and associated complications are scarce, possibly leading to misinterpretation of clinical signs and symptoms in adulthood. To prevent treatment errors, it is important that physicians are aware of long-term complications of intestinal malformations.

http://ift.tt/2Di1azw

Retroperitoneal bile leak after laparoscopic cholecystectomy

Bile duct injury (BDI) is a well-recognised complication of laparoscopic cholecystectomy (LC). Following a BDI, bile usually leaks into the peritoneal space and causes biliary peritonitis. This manifests as non-specific abdominal pain and fever occurring several days after the surgery. It can be managed by laparoscopic washout with or without bile duct repair. We present a rare case of retroperitoneal bile leak post-LC. The mechanism of injury here was likely partial avulsion from excessive traction of the cystic duct during intraoperative cholangiogram. Diagnosing retroperitoneal bile leak can be difficult because it is extremely rare and the presenting symptoms can be similar to an intraperitoneal bile leak. A high index of clinical suspicion is required. In cases of suspected bile leak, any mismatch between the exploratory laparoscopic findings and imaging findings should alert surgeons to consider the rare possibility of a retroperitoneal bile leak.

http://ift.tt/2DP09zN

Vanadium allergy following total knee arthroplasty

Allergic reactions to metals following joint arthroplasty represent a rare and poorly understood phenomenon. Much is still unknown regarding the natural history of this complication, and how it can best be prevented and managed. We present a case of a 68-year-old woman who underwent a left total knee arthroplasty for treatment of osteoarthritis. After an initial uneventful postoperative course, she developed a troublesome erythematous rash both around the incision site and over her trunk. Blood testing revealed no evidence of infection and clinically her prosthesis was functioning well. Skin patch testing revealed positive results for vanadium (+) and palladium (+). Her cutaneous symptoms are currently being managed conservatively and have shown a partial response to topical steroids. Revision surgery remains a long-term treatment option should conservative therapy fail; however, it would require a custom-made prosthesis as no standard tibial component is free from vanadium.

http://ift.tt/2Dm69yQ

Continuous subcutaneous levetiracetam in end-of-life care

Seizures constitute a determining aspect in quality of life and are frequently challenging in palliative care—a field where treatment has yet to be standardised. Levetiracetam—a new generation anticonvulsant—has proved efficacy both through oral, as well as intravenous administration in the general population. This case reports on the use of continuous subcutaneous levetiracetam to effectively control seizures in a terminally ill patient without patent oral route.

http://ift.tt/2DhCHdt

Unusual skin mass (primary cutaneous mucinous carcinoma)

Primary mucinous carcinoma of the skin is a rare malignant tumour of sweat gland origin. Diagnostic concerns include its deceptively benign appearance in some cases and the difficulty in differentiating it from secondary mucinous carcinoma of skin metastasising from a primary source elsewhere. A case of a 75-year-old man is reported who presented with a slowly growing painless mass near the lateral canthus of the right eye for about 2 years. Clinically, a diagnosis of basal cell carcinoma was made whereas histopathology revealed mucinous carcinoma of the skin. The primary source of the tumour could not be found on detailed physical examination and laboratory investigations. Immunohistochemistry, performed later, was consistent with primary cutaneous mucinous carcinoma.

http://ift.tt/2DPfWia

An adult case with shigellosis-associated encephalopathy

A 45-year-old man was presented at the emergency department with altered neurological status and a 1-day history of diarrhoea and fever. The patient's sexual history revealed multiple male partners. As bacterial meningitis or viral encephalitis was suspected, treatment was started accordingly. Cerebrospinal fluid investigations only showed a slight increase of leucocytes, and microbiological studies remained negative. Stool culture revealed Shigella flexneri, after which Shigella-associated encephalopathy was suspected. The patient recovered quickly with antibiotic treatment. The incidence of Shigella infections in the Western world is rising due to sexual transmission among men who have sex with men. Shigella-induced encephalopathy is a notorious complication among children with a severe form known as the Ekiri syndrome, though rarely seen in adults. This is the second report of encephalopathy in an adult with S. flexneri enteric infection.

http://ift.tt/2DkESgf

Angiodysplastic Sturge Weber syndrome

Description

A 3-year-old boy presented with global developmental delay, abnormal craniofacial growth and left focal seizures since infancy. He was the first child of a non-consanguineous couple with unremarkable perinatal period. Family history was non-contributory. On examination, he had macrocephaly (head circumference 55 cm, >3 z-score), extensive port-wine stain distributed bilaterally over the face and the trunk, cloverleaf-shaped skull with facial distortion (figure 1A), marked gingival hyperplasia with dental malocclusion (figure 1B), bilateral blue sclera with tortuous engorged veins, brisk muscle stretch reflexes, left hemiparesis and bilateral Babinski's sign. The rest of the systemic examination was unremarkable. A clinical diagnosis of angiodysplastic variant of Sturge Weber syndrome (SWS) with extensive bilateral facial and truncal port-wine stain, glaucoma and focal epilepsy was considered. CT of the brain revealed right-sided subcortical tram-track calcification and concordant parenchymal volume loss (figure 1C). MRI of the brain showed right-sided...

http://ift.tt/2DL5oQZ

Intravitreal bevacizumab for postviral fever retinitis: a novel approach for early resolution of macular oedema

Severe macular oedema causing marked loss of vision is seen in cases of retinitis developing postviral fever. The use of antivascular endothelial growth factor agents for macular oedema and submacular fluid secondary to viral retinitis has not been studied or well established in the past. We report a case series of two patients of postviral retinitis with severe macular oedema resistant to steroid therapy, treated with intravitreal bevacizumab. The patients showed significant symptomatic improvement in the visual acuity. The retinitis lesions resolved slowly and macular oedema regressed. Bevacizumab appears to be a safe and useful agent to manage macular oedema subsequent to postviral retinitis. An early resolution of macular oedema helps in the preservation of visual acuity which left untreated can cause severe visual loss.

http://ift.tt/2DhCDdJ

Abnormal deep dorsal vein resulting in veno-occlusive erectile dysfunction

A 59-year-old man with a 6-year history of erectile dysfunction presented to the andrology outpatient clinic. Multimodality assessment with ultrasound, MRI venography and fluoroscopic venography demonstrated an aberrant emissary vein arising from the corporal bodies causing venogenic erectile dysfunction. Selective coil embolisation of the collateral vein resulted in an almost immediate and sustained improvement in his erections.

http://ift.tt/2DP04ft

Anterior choroidal artery infarction

Description 

A 38-year-old male patient with a history of hypertension presented with left hemiplegia, hemianaesthesia and hemianopia. MRI of the brain showed anterior choroidal artery (AchA) territory infarct (figure 1). MRI brain angiography and 2D echo were normal. Serum fasting lipid profile, sugar levels, thyroid studies, serum homocysteine levels and antinuclear antibody (ANA), double-stranded deoxyribonucleic acid (DsDNA) and antiphospholipid antibody (APLA) were negative. Trans-oesophageal echocardiography and Holter monitoring were normal. Workup for sickle cell anaemia was negative.

Figure 1

Axial diffusion weighted MRI shows restricted diffusion in (A,B) right lateral thalamus, posterior limb of internal capsule; hippocampal gyrus and uncus and (C) paraventricular corona radiata and uncus. (D) Coronal T2 image showing involvement of same areas.

The territory of AchA is shown in figure 2.1

Figure 2

(A) Anterior choroidal artery originates from internal carotid artery...

http://ift.tt/2DjruJi

Sacral bone cyst treatment resulting in paraplegia

Description

A 50-year-old man with a stage 1 solitary right sacral plasmacytoma complained of a sharp, burning lower back pain with radiation into his right lower extremity which worsened with movement. He had initially undergone localised radiation therapy, but the pain did not resolve. Postradiation CT-guided biopsy showed persistence of malignant plasma cells, and he then underwent seven cycles of VRD (dexamethasone, lenalidomide and bortezomib) chemotherapy. After chemotherapy, an 18-fluorodeoxyglucose-positron emission tomography/CT scan showed a new area of uptake in the right sacral ala near the initial plasmacytoma. A subsequent CT-guided biopsy was non-diagnostic, and repeat imaging at the time of presentation showed no interval growth. The lesion was believed to be a residual cyst with inflammatory changes from radiotherapy. Examination revealed no neurological deficits. The patient's pain was thought to be secondary to the cyst (figure 1) and was not relieved with physical therapy, duloxetine...

http://ift.tt/2DPfC2W

Risk stratification for febrile neutropenia in patients with testicular germ cell tumors

Abstract

The aim of this study was to detect risk factors for febrile neutropenia (FN) in patients with testicular germ cell tumors (TGCT). In this retrospective cohort study at the Medical University of Graz, we included 413 consecutive TGCT patients who received adjuvant or curative treatment with cisplatin-based chemotherapy. FN occurred in 70 (16.9%) of 413 patients. In univariable logistic regression, higher age (odds ratio (OR) per 5 years = 1.17, 95% CI: 1.02–1.35, P = 0.022), reduced performance status (PS) (OR = 2.73, 1.47–5.06, P = 0.001), seminomatous histology (OR = 2.19, 1.26–3.78, P = 0.005), poor IGCCCG risk class (OR = 4.20, 1.71–10.33, P = 0.002), and prior radiotherapy (pRTX) (OR = 8.98, 2.09–38.61, P = 0.003) were associated with a higher risk of FN. In multivariable analysis adjusting for age and risk classification, only poor PS (OR = 2.06, 1.05–4.03, P = 0.035), seminomatous histology (OR = 2.08, 1.01–4.26, P = 0.047), and pRTX (OR = 7.31, 1.61–33.17, P = 0.010) prevailed. In the subgroup of seminoma patients (n = 104), only pRTX predicted for FN risk (OR = 5.60, 1.24–25.34, P = 0.025). Five of eight seminoma patients with pRTX developed FN (63%), as compared to 22 FN cases (23%) in the 96 seminoma patients without pRTX (P = 0.027). The eight seminoma patients who received pRTX had significantly lower pre-chemo white blood counts (4.7 vs. 6.5 G/L), neutrophil counts (3.2 vs. 4.3 G/L), and platelet counts (185 vs. 272 G/L) than patients without pRTX (all P < 0.0001). TGCT patients with a reduced performance status or who had been previously treated with radiotherapy have an increased risk for neutropenic fever during chemotherapy.

The aim of this study was to detect prognostic factors for febrile neutropenia (FN) in patients with testicular germ cell tumors. We identified (1) higher age, (2) poor performance status, (3) poor IGCCCG risk classification, and (4) prior radiotherapy in the seminoma subpopulation as risk factors for FN in patients with testicular cancer.

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Phase Ib study evaluating safety and clinical activity of the anti-HER3 antibody lumretuzumab combined with the anti-HER2 antibody pertuzumab and paclitaxel in HER3-positive, HER2-low metastatic breast cancer

Summary

Purpose To investigate the safety and clinical activity of comprehensive human epidermal growth factor receptor (HER) family receptor inhibition using lumretuzumab (anti-HER3) and pertuzumab (anti-HER2) in combination with paclitaxel in patients with metastatic breast cancer (MBC). Methods This phase Ib study enrolled 35 MBC patients (first line or higher) with HER3-positive and HER2-low (immunohistochemistry 1+ to 2+ and in-situ hybridization negative) tumors. Patients received lumretuzumab (1000 mg in Cohort 1; 500 mg in Cohorts 2 and 3) plus pertuzumab (840 mg loading dose [LD] followed by 420 mg in Cohorts 1 and 2; 420 mg without LD in Cohort 3) every 3 weeks, plus paclitaxel (80 mg/m² weekly in all cohorts). Patients in Cohort 3 received prophylactic loperamide treatment. Results Diarrhea grade 3 was a dose-limiting toxicity of Cohort 1 defining the maximum tolerated dose of lumretuzumab when given in combination with pertuzumab and paclitaxel at 500 mg every three weeks. Grade 3 diarrhea decreased from 50% (Cohort 2) to 30.8% (Cohort 3) with prophylactic loperamide administration and omission of the pertuzumab LD, nonetheless, all patients still experienced diarrhea. In first-line MBC patients, the objective response rate in Cohorts 2 and 3 was 55% and 38.5%, respectively. No relationship between HER2 and HER3 expression or somatic mutations and clinical response was observed. Conclusions Combination treatment with lumretuzumab, pertuzumab and paclitaxel was associated with a high incidence of diarrhea. Despite the efforts to alter dosing, the therapeutic window remained too narrow to warrant further clinical development. Trial registration: on ClinicalTrials.gov with the identifier NCT01918254 first registered on 3rd July 2013.

http://ift.tt/2FSPXXB

Well-Differentiated Liposarcoma (Atypical Lipomatous Tumor) Presenting as an Esophageal Polyp

http://ift.tt/2DPClMl

Risk stratification for febrile neutropenia in patients with testicular germ cell tumors

Abstract

The aim of this study was to detect risk factors for febrile neutropenia (FN) in patients with testicular germ cell tumors (TGCT). In this retrospective cohort study at the Medical University of Graz, we included 413 consecutive TGCT patients who received adjuvant or curative treatment with cisplatin-based chemotherapy. FN occurred in 70 (16.9%) of 413 patients. In univariable logistic regression, higher age (odds ratio (OR) per 5 years = 1.17, 95% CI: 1.02–1.35, P = 0.022), reduced performance status (PS) (OR = 2.73, 1.47–5.06, P = 0.001), seminomatous histology (OR = 2.19, 1.26–3.78, P = 0.005), poor IGCCCG risk class (OR = 4.20, 1.71–10.33, P = 0.002), and prior radiotherapy (pRTX) (OR = 8.98, 2.09–38.61, P = 0.003) were associated with a higher risk of FN. In multivariable analysis adjusting for age and risk classification, only poor PS (OR = 2.06, 1.05–4.03, P = 0.035), seminomatous histology (OR = 2.08, 1.01–4.26, P = 0.047), and pRTX (OR = 7.31, 1.61–33.17, P = 0.010) prevailed. In the subgroup of seminoma patients (n = 104), only pRTX predicted for FN risk (OR = 5.60, 1.24–25.34, P = 0.025). Five of eight seminoma patients with pRTX developed FN (63%), as compared to 22 FN cases (23%) in the 96 seminoma patients without pRTX (P = 0.027). The eight seminoma patients who received pRTX had significantly lower pre-chemo white blood counts (4.7 vs. 6.5 G/L), neutrophil counts (3.2 vs. 4.3 G/L), and platelet counts (185 vs. 272 G/L) than patients without pRTX (all P < 0.0001). TGCT patients with a reduced performance status or who had been previously treated with radiotherapy have an increased risk for neutropenic fever during chemotherapy.

The aim of this study was to detect prognostic factors for febrile neutropenia (FN) in patients with testicular germ cell tumors. We identified (1) higher age, (2) poor performance status, (3) poor IGCCCG risk classification, and (4) prior radiotherapy in the seminoma subpopulation as risk factors for FN in patients with testicular cancer.

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Phase Ib study evaluating safety and clinical activity of the anti-HER3 antibody lumretuzumab combined with the anti-HER2 antibody pertuzumab and paclitaxel in HER3-positive, HER2-low metastatic breast cancer

Summary

Purpose To investigate the safety and clinical activity of comprehensive human epidermal growth factor receptor (HER) family receptor inhibition using lumretuzumab (anti-HER3) and pertuzumab (anti-HER2) in combination with paclitaxel in patients with metastatic breast cancer (MBC). Methods This phase Ib study enrolled 35 MBC patients (first line or higher) with HER3-positive and HER2-low (immunohistochemistry 1+ to 2+ and in-situ hybridization negative) tumors. Patients received lumretuzumab (1000 mg in Cohort 1; 500 mg in Cohorts 2 and 3) plus pertuzumab (840 mg loading dose [LD] followed by 420 mg in Cohorts 1 and 2; 420 mg without LD in Cohort 3) every 3 weeks, plus paclitaxel (80 mg/m² weekly in all cohorts). Patients in Cohort 3 received prophylactic loperamide treatment. Results Diarrhea grade 3 was a dose-limiting toxicity of Cohort 1 defining the maximum tolerated dose of lumretuzumab when given in combination with pertuzumab and paclitaxel at 500 mg every three weeks. Grade 3 diarrhea decreased from 50% (Cohort 2) to 30.8% (Cohort 3) with prophylactic loperamide administration and omission of the pertuzumab LD, nonetheless, all patients still experienced diarrhea. In first-line MBC patients, the objective response rate in Cohorts 2 and 3 was 55% and 38.5%, respectively. No relationship between HER2 and HER3 expression or somatic mutations and clinical response was observed. Conclusions Combination treatment with lumretuzumab, pertuzumab and paclitaxel was associated with a high incidence of diarrhea. Despite the efforts to alter dosing, the therapeutic window remained too narrow to warrant further clinical development. Trial registration: on ClinicalTrials.gov with the identifier NCT01918254 first registered on 3rd July 2013.

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Well-Differentiated Liposarcoma (Atypical Lipomatous Tumor) Presenting as an Esophageal Polyp

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The Danish Medical Birth Register

Abstract

The Danish Medical Birth Register was established in 1973. It is a key component of the Danish health information system. The register enables monitoring of the health of pregnant women and their offspring, it provides data for quality assessment of the perinatal care in Denmark, and it is used extensively for research. The register underwent major changes in construction and content in 1997, and new variables have been added during the last 20 years. The aim was to provide an updated description of the register focusing on structure, content, and coverage since 1997. The register includes data on all births in Denmark and comprises primarily of data from the Danish National Patient Registry supplemented with forms on home deliveries and stillbirths. It contains information on maternal age provided by the Civil Registration System. Information on pre-pregnancy body mass index and smoking in first trimester is collected in early pregnancy (first antenatal visit). The individual-level data can be linked to other Danish health registers such as the National Patient Registry and the Danish National Prescription Registry. The register informs several other registers/databases such as the Danish Twin Registry and the Danish Fetal Medicine Database. Aggregated data can be publicly accessed on the Danish Health Data Authority web page (www.esundhed.dk/sundhedsregistre/MFR). Researchers can obtain access to individual-level pseudo-anonymised data via servers at Statistics Denmark and the Danish Health Data Authority.

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Medical management of brain metastases and leptomeningeal disease in patients with breast carcinoma

Future Oncology, Ahead of Print.


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Inherited forms of bladder cancer: a review of lynch syndrome and other inherited conditions

Future Oncology, Ahead of Print.


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Minimally invasive adrenal surgery: virtue or vice?

Future Oncology, Ahead of Print.


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Ovarian tissue cryopreservation in young females through the Oncofertility Consortium's National Physicians Cooperative

Future Oncology, Ahead of Print.


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Medical management of brain metastases and leptomeningeal disease in patients with breast carcinoma

Future Oncology, Ahead of Print.


http://ift.tt/2EWh5Ut

Inherited forms of bladder cancer: a review of lynch syndrome and other inherited conditions

Future Oncology, Ahead of Print.


http://ift.tt/2DuwwWE

Minimally invasive adrenal surgery: virtue or vice?

Future Oncology, Ahead of Print.


http://ift.tt/2EWgX7r

Ovarian tissue cryopreservation in young females through the Oncofertility Consortium's National Physicians Cooperative

Future Oncology, Ahead of Print.


http://ift.tt/2DrEU9w

Phase I dose-escalation study of copanlisib in combination with gemcitabine or cisplatin plus gemcitabine in patients with advanced cancer

Phase I dose-escalation study of copanlisib in combination with gemcitabine or cisplatin plus gemcitabine in patients with advanced cancer

Phase I dose-escalation study of copanlisib in combination with gemcitabine or cisplatin plus gemcitabine in patients with advanced cancer, Published online: 18 January 2018; doi:10.1038/bjc.2017.428

Phase I dose-escalation study of copanlisib in combination with gemcitabine or cisplatin plus gemcitabine in patients with advanced cancer

http://ift.tt/2Dp9tNh

H1/pHGFK1 nanoparticles exert anti-tumoural and radiosensitising effects by inhibition of MET in glioblastoma

H1/pHGFK1 nanoparticles exert anti-tumoural and radiosensitising effects by inhibition of MET in glioblastoma

H1/pHGFK1 nanoparticles exert anti-tumoural and radiosensitising effects by inhibition of MET in glioblastoma, Published online: 18 January 2018; doi:10.1038/bjc.2017.461

H1/pHGFK1 nanoparticles exert anti-tumoural and radiosensitising effects by inhibition of MET in glioblastoma

http://ift.tt/2DubEPi

Interferon-alpha enhances the antitumour activity of EGFR-targeted therapies by upregulating RIG-I in head and neck squamous cell carcinoma

Interferon-alpha enhances the antitumour activity of EGFR-targeted therapies by upregulating RIG-I in head and neck squamous cell carcinoma

Interferon-alpha enhances the antitumour activity of EGFR-targeted therapies by upregulating RIG-I in head and neck squamous cell carcinoma, Published online: 18 January 2018; doi:10.1038/bjc.2017.442

Interferon-alpha enhances the antitumour activity of EGFR-targeted therapies by upregulating RIG-I in head and neck squamous cell carcinoma

http://ift.tt/2EUheYo

Which patients are not included in the English Cancer Waiting Times monitoring dataset, 2009–2013? Implications for use of the data in research

Which patients are not included in the English Cancer Waiting Times monitoring dataset, 2009–2013? Implications for use of the data in research

Which patients are not included in the English Cancer Waiting Times monitoring dataset, 2009–2013? Implications for use of the data in research, Published online: 18 January 2018; doi:10.1038/bjc.2017.452

Which patients are not included in the English Cancer Waiting Times monitoring dataset, 2009–2013? Implications for use of the data in research

http://ift.tt/2DubKGE

Robot-assisted radical prostatectomy vs laparoscopic and open retropubic radical prostatectomy: functional outcomes 18 months after diagnosis from a national cohort study in England

Robot-assisted radical prostatectomy vs laparoscopic and open retropubic radical prostatectomy: functional outcomes 18 months after diagnosis from a national cohort study in England

Robot-assisted radical prostatectomy <i>vs</i> laparoscopic and open retropubic radical prostatectomy: functional outcomes 18 months after diagnosis from a national cohort study in England, Published online: 18 January 2018; doi:10.1038/bjc.2017.454

Robot-assisted radical prostatectomy vs laparoscopic and open retropubic radical prostatectomy: functional outcomes 18 months after diagnosis from a national cohort study in England

http://ift.tt/2EWquLH

Phase I dose-escalation study of copanlisib in combination with gemcitabine or cisplatin plus gemcitabine in patients with advanced cancer

Phase I dose-escalation study of copanlisib in combination with gemcitabine or cisplatin plus gemcitabine in patients with advanced cancer

Phase I dose-escalation study of copanlisib in combination with gemcitabine or cisplatin plus gemcitabine in patients with advanced cancer, Published online: 18 January 2018; doi:10.1038/bjc.2017.428

Phase I dose-escalation study of copanlisib in combination with gemcitabine or cisplatin plus gemcitabine in patients with advanced cancer

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H1/pHGFK1 nanoparticles exert anti-tumoural and radiosensitising effects by inhibition of MET in glioblastoma

H1/pHGFK1 nanoparticles exert anti-tumoural and radiosensitising effects by inhibition of MET in glioblastoma

H1/pHGFK1 nanoparticles exert anti-tumoural and radiosensitising effects by inhibition of MET in glioblastoma, Published online: 18 January 2018; doi:10.1038/bjc.2017.461

H1/pHGFK1 nanoparticles exert anti-tumoural and radiosensitising effects by inhibition of MET in glioblastoma

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Interferon-alpha enhances the antitumour activity of EGFR-targeted therapies by upregulating RIG-I in head and neck squamous cell carcinoma

Interferon-alpha enhances the antitumour activity of EGFR-targeted therapies by upregulating RIG-I in head and neck squamous cell carcinoma

Interferon-alpha enhances the antitumour activity of EGFR-targeted therapies by upregulating RIG-I in head and neck squamous cell carcinoma, Published online: 18 January 2018; doi:10.1038/bjc.2017.442

Interferon-alpha enhances the antitumour activity of EGFR-targeted therapies by upregulating RIG-I in head and neck squamous cell carcinoma

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Which patients are not included in the English Cancer Waiting Times monitoring dataset, 2009–2013? Implications for use of the data in research

Which patients are not included in the English Cancer Waiting Times monitoring dataset, 2009–2013? Implications for use of the data in research

Which patients are not included in the English Cancer Waiting Times monitoring dataset, 2009–2013? Implications for use of the data in research, Published online: 18 January 2018; doi:10.1038/bjc.2017.452

Which patients are not included in the English Cancer Waiting Times monitoring dataset, 2009–2013? Implications for use of the data in research

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Robot-assisted radical prostatectomy vs laparoscopic and open retropubic radical prostatectomy: functional outcomes 18 months after diagnosis from a national cohort study in England

Robot-assisted radical prostatectomy vs laparoscopic and open retropubic radical prostatectomy: functional outcomes 18 months after diagnosis from a national cohort study in England

Robot-assisted radical prostatectomy <i>vs</i> laparoscopic and open retropubic radical prostatectomy: functional outcomes 18 months after diagnosis from a national cohort study in England, Published online: 18 January 2018; doi:10.1038/bjc.2017.454

Robot-assisted radical prostatectomy vs laparoscopic and open retropubic radical prostatectomy: functional outcomes 18 months after diagnosis from a national cohort study in England

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CART targeting of solid tumors: More pieces to the puzzle

CART-based targeting of solid tumors remains a considerable and worthwhile challenge in the field of immunotherapy. The role of chemotherapy to target stroma and enhance CAR cell anti-tumor function, expansion and persistence is still unresolved

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CNS Metastases Needn't Rule Out Trial Inclusion [News in Brief]

Guidelines aim to open more drug studies to patients with central nervous system tumors, increase efficacy data.

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Mutation Burden Predicts Anti-PD-1 Response [News in Brief]

Study of multiple cancer types finds correlation between response and mutation number.

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CART targeting of solid tumors: More pieces to the puzzle

CART-based targeting of solid tumors remains a considerable and worthwhile challenge in the field of immunotherapy. The role of chemotherapy to target stroma and enhance CAR cell anti-tumor function, expansion and persistence is still unresolved

http://ift.tt/2Be3Fkq

Intratumoral Payload Concentration Correlates with the Activity of Antibody- Drug Conjugates

Antibody-drug conjugates (ADCs) have become important scaffolds for targeted cancer therapies. However, ADC exposure - response correlation is not well characterized. We demonstrated that intratumor payload exposures correlated well with the corresponding efficacies of several disulfide-linked ADCs bearing an DNA alkylating agent, pyrrolo[2,1-c][1,4]benzodiazepine-dimer (PBD), in HER2-expressing xenograft models. The correlation suggests that a threshold concentration of intratumor payload is required to support sustained efficacy and an ADC can deliver an excessive level of payload to tumors that does not enhance efficacy ('Plateau' effect). In contrast to tumor PBD concentrations, related assessments of systemic exposures, plasma stability, and drug-to-antibody ratio (DAR) changes of related ADCs did not consistently rationalize the observed ADC efficacies. A minimal efficacious dose could be determined by ADC dose-fractionation studies in the xenograft models. Mechanistic investigations revealed that both linker immolation and linker disulfide stability are the key factors that determine intratumor PBD concentrations. Overall, this study demonstrates how a linker design can impact ADC efficacy and that the intratumor exposure of a payload drug as the molecular mechanism quantitatively correlate with and predict the anti-tumor efficacy of ADCs.

http://ift.tt/2FVq5dV

Intratumoral Payload Concentration Correlates with the Activity of Antibody- Drug Conjugates

Antibody-drug conjugates (ADCs) have become important scaffolds for targeted cancer therapies. However, ADC exposure - response correlation is not well characterized. We demonstrated that intratumor payload exposures correlated well with the corresponding efficacies of several disulfide-linked ADCs bearing an DNA alkylating agent, pyrrolo[2,1-c][1,4]benzodiazepine-dimer (PBD), in HER2-expressing xenograft models. The correlation suggests that a threshold concentration of intratumor payload is required to support sustained efficacy and an ADC can deliver an excessive level of payload to tumors that does not enhance efficacy ('Plateau' effect). In contrast to tumor PBD concentrations, related assessments of systemic exposures, plasma stability, and drug-to-antibody ratio (DAR) changes of related ADCs did not consistently rationalize the observed ADC efficacies. A minimal efficacious dose could be determined by ADC dose-fractionation studies in the xenograft models. Mechanistic investigations revealed that both linker immolation and linker disulfide stability are the key factors that determine intratumor PBD concentrations. Overall, this study demonstrates how a linker design can impact ADC efficacy and that the intratumor exposure of a payload drug as the molecular mechanism quantitatively correlate with and predict the anti-tumor efficacy of ADCs.

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Updated efficacy of avelumab in patients with previously treated metastatic Merkel cell carcinoma after ≥1 year of follow-up: JAVELIN Merkel 200, a phase 2 clinical trial

Abstract

Background

Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer associated with poor survival outcomes in patients with distant metastatic disease (mMCC). In an initial analysis from JAVELIN Merkel 200, a phase 2, prospective, open-label, single-arm trial in mMCC, avelumab—a human anti–programmed death-ligand 1 (PD-L1) monoclonal antibody—showed promising efficacy and a safety profile that was generally manageable and tolerable. Here, we report the efficacy of avelumab after ≥1 year of follow-up in patients with distant mMCC that had progressed following prior chemotherapy for metastatic disease.

Patients and methods

Patients received avelumab 10 mg/kg by 1-h intravenous infusion every 2 weeks until confirmed disease progression, unacceptable toxicity, or withdrawal. The primary endpoint was best overall response. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

Results

Patients (N = 88) were followed for a minimum of 12 months. The confirmed objective response rate was 33.0% (95% CI, 23.3%-43.8%; complete response: 11.4%). An estimated 74% of responses lasted ≥1 year, and 72.4% of responses were ongoing at data cutoff. Responses were durable, with the median DOR not yet reached (95% CI, 18.0 months-not estimable), and PFS was prolonged; 1-year PFS and OS rates were 30% (95% CI, 21%-41%) and 52% (95% CI, 41%-62%), respectively. Median OS was 12.9 months (95% CI, 7.5-not estimable). Subgroup analyses suggested a higher probability of response in patients receiving fewer prior lines of systemic therapy, with a lower baseline disease burden, and with PD-L1–positive tumors; however, durable responses occurred irrespective of baseline factors, including tumor Merkel cell polyomavirus status.

Conclusions

With longer follow-up, avelumab continues to show durable responses and promising survival outcomes in patients with distant mMCC whose disease had progressed after chemotherapy.

Trial registration

Clinicaltrials.gov identifier: NCT02155647.

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Updated efficacy of avelumab in patients with previously treated metastatic Merkel cell carcinoma after ≥1 year of follow-up: JAVELIN Merkel 200, a phase 2 clinical trial

Abstract

Background

Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer associated with poor survival outcomes in patients with distant metastatic disease (mMCC). In an initial analysis from JAVELIN Merkel 200, a phase 2, prospective, open-label, single-arm trial in mMCC, avelumab—a human anti–programmed death-ligand 1 (PD-L1) monoclonal antibody—showed promising efficacy and a safety profile that was generally manageable and tolerable. Here, we report the efficacy of avelumab after ≥1 year of follow-up in patients with distant mMCC that had progressed following prior chemotherapy for metastatic disease.

Patients and methods

Patients received avelumab 10 mg/kg by 1-h intravenous infusion every 2 weeks until confirmed disease progression, unacceptable toxicity, or withdrawal. The primary endpoint was best overall response. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

Results

Patients (N = 88) were followed for a minimum of 12 months. The confirmed objective response rate was 33.0% (95% CI, 23.3%-43.8%; complete response: 11.4%). An estimated 74% of responses lasted ≥1 year, and 72.4% of responses were ongoing at data cutoff. Responses were durable, with the median DOR not yet reached (95% CI, 18.0 months-not estimable), and PFS was prolonged; 1-year PFS and OS rates were 30% (95% CI, 21%-41%) and 52% (95% CI, 41%-62%), respectively. Median OS was 12.9 months (95% CI, 7.5-not estimable). Subgroup analyses suggested a higher probability of response in patients receiving fewer prior lines of systemic therapy, with a lower baseline disease burden, and with PD-L1–positive tumors; however, durable responses occurred irrespective of baseline factors, including tumor Merkel cell polyomavirus status.

Conclusions

With longer follow-up, avelumab continues to show durable responses and promising survival outcomes in patients with distant mMCC whose disease had progressed after chemotherapy.

Trial registration

Clinicaltrials.gov identifier: NCT02155647.

http://ift.tt/2mPD3Rt

Current Trends in the Rate of Rectal Cancer Restorative Operations in the Era of Neoadjuvant Chemoradiation

Abstract

Purpose of Review

The following review addresses the relationship between neoadjuvant chemoradiotherapy and the rate of restorative operations in patients with rectal cancer.

Recent Findings

The rate of restorative operations performed for rectal cancer has improved over the past several decades. The relationship between this increase and the addition of neoadjuvant chemoradiotherapy to the treatment regimen for locally advanced rectal cancer is still being defined. Improved rates of sphincter-sparing procedures between patients who receive preoperative chemoradiation compared to those who receive treatment postoperatively have not been supported in the literature. The patients who seem to benefit from neoadjuvant therapy in terms of sphincter preservation are those with distal tumors. Better tumor response to neoadjuvant chemotherapy and longer interval to surgical intervention appear to have little if any benefit to preserving the sphincter.

Summary

Increased rates of restorative operations for rectal cancer seem to be most significant among distal tumors. The reasons for the increase are likely multifactorial and include improvements in patient selection, surgical technique, imaging modalities, and patient care. The role of neoadjuvant chemoradiotherapy in this setting remains equivocal.

http://ift.tt/2Dp6zsw

Is Timing Important? The Role of Diet and Lifestyle During Early Life on Colorectal Neoplasia

Abstract

Purpose of the Review

To summarize the current evidence on the most important dietary and lifestyle factors in colorectal carcinogenesis during different stages of a lifetime with special emphasis on studies investigating exposure during childhood, adolescence, and young adulthood.

Recent Findings

A number of studies showed that independent of adult obesity, higher body fatness during childhood, adolescence, and young adulthood is associated with risk of colorectal cancer later in life. In one large cohort study, the Nurses' Health Study II, adherence to a western pattern diet was associated with higher risk of advanced adenoma. The current evidence relating consumption of individual foods and nutrients as well as physical activity during early life to colorectal cancer is sparse and less consistent, at least in part due to limitations in study design, such as sample size, limited data on potential confounders or lack of a validated dietary assessment instrument.

Summary

As colorectal carcinogenesis is a long process and can take up to several decades to develop, early life risk factors may also be etiologically relevant. The recent rise in early-onset colorectal cancer incidence and mortality in the USA, i.e., in individuals younger than 55 years at diagnosis, strongly supports that early life risk factors may influence colorectal carcinogenesis. Considering that the majority of colorectal cancers are preventable, there is an urgent need for well-designed investigations on the role of diet and lifestyle factors throughout the life course and risk of colorectal cancers.

http://ift.tt/2mQTFIT

The Changing Face of Noncardia Gastric Cancer Incidence Among US Non-Hispanic Whites

Abstract

Background

The initial step for noncardia gastric carcinogenesis is atrophic gastritis, driven by either Helicobacter pylori infection or autoimmunity. In recent decades, the prevalence rates of these two major causes declined and increased, respectively, with changes in Western lifestyles. We therefore assessed gastric cancer incidence trends for US race/ethnic groups, 1995–2013.

Methods

Age-standardized rates (ASRs) from 45 North American Association of Central Cancer Tumor Registries were summarized by estimated annual percentage change (EAPC) and 95% confidence intervals (CIs). Age period cohort models supplemented standard descriptive techniques and projected future trends.

Results

There were 137 447 noncardia cancers in 4.4 billion person-years of observation. Among non-Hispanic whites, the ASR was 2.2 per 100 000 person-years, with an EAPC of –2.3% (95% CI = –2.0% to –2.6%). Notwithstanding this overall decline, EAPCs rose 1.3% (95% CI = 0.6% to 2.1%) for persons younger than age 50 years and fell –2.6% (95% CI = –2.4% to –2.9%) for older individuals. These converging trends manifested a birth cohort effect more pronounced among women than men, with incidence among women born in 1983 twofold (95% CI = 1.1-fold to 3.6-fold) greater than those born in 1951. Age interaction was also statistically significant among Hispanic whites, with slightly increasing vs decreasing EAPCs for younger and older individuals, respectively. Incidence declined regardless of age for other races. Current trends foreshadow expected reversals in both falling incidence and male predominance among non-Hispanic whites.

Conclusions

Dysbiosis of the gastric microbiome associated with modern living conditions may be increasing risk of autoimmune gastritis and consequent noncardia cancer. The changing face by age and sex of gastric cancer warrants analytical studies to identify potential causal mechanisms.

http://ift.tt/2DfbpnZ

A New Gastric Cancer Among Us

In 1900, gastric cancer was the leading cause of cancer death in the United States and in many countries (1). This cancer, nearly all of which is attributable to decades-long gastric colonization by Helicobacter pylori (2), has been declining with the progressive disappearance of these bacteria (3). This has been very good news, indeed a triumph (1), and the trends began long before H. pylori was discovered in 1983, with cohorts born in the late 19th century (1).

http://ift.tt/2DOQU2u

Two-Year Trends of Taxane-Induced Neuropathy in Women Enrolled in a Randomized Trial of Acetyl-L-Carnitine (SWOG S0715)

Abstract

Background

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and disabling side effect of taxanes. Acetyl-L-carnitine (ALC) was unexpectedly found to increase CIPN in a randomized trial. We investigated the long-term patterns of CIPN among patients in this trial.

Methods

S0715 was a randomized, double-blind, multicenter trial comparing ALC (1000 mg three times a day) with placebo for 24 weeks in women undergoing adjuvant taxane-based chemotherapy for breast cancer. CIPN was measured by the 11-item neurotoxicity (NTX) component of the FACT-Taxane scale at weeks 12, 24, 36, 52, and 104. We examined NTX scores over two years using linear mixed models for longitudinal data. Individual time points were examined using linear regression. Regression analyses included stratification factors and the baseline score as covariates. All statistical tests were two-sided.

Results

Four-hundred nine subjects were eligible for evaluation. Patients receiving ALC had a statistically significantly (P = .01) greater reduction in NTX scores (worse CIPN) of –1.39 points (95% confidence interval [CI] = –2.48 to –0.30) than the placebo group. These differences were particularly evident at weeks 24 (–1.68, 95% CI = –3.02 to –0.33), 36 (–1.37, 95% CI = –2.69 to –0.04), and 52 (–1.83, 95% CI = –3.35 to –0.32). At 104 weeks, 39.5% on the ALC arm and 34.4% on the placebo arm reported a five-point (10%) decrease from baseline. For both treatment groups, 104-week NTX scores were statistically significantly different compared with baseline (P < .001).

Conclusions

For both groups, NTX scores were reduced from baseline and remained persistently low. Twenty-four weeks of ALC therapy resulted in statistically significantly worse CIPN over two years. Understanding the mechanism of this persistent effect may inform prevention and treatment strategies. Until then, the potential efficacy and harms of commonly used supplements should be rigorously studied.

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Supplements to Help Prevent Neuropathy During Chemotherapy? A Cautionary Tale

Chemotherapy-induced peripheral neuropathy (CIPN) remains a common and challenging treatment-related toxicity of many anticancer therapies. Sensory neuropathy involving the hands and/or feet has been observed in more than 70% of women with localized breast cancer receiving a taxane (1,2). Some of these neuropathies have a profound and disabling impact on an individual's quality of life, with the majority of those affected experiencing persistent symptoms at 12 months (3). Developing CIPN also can lead to dose reductions, delays, or discontinuation of chemotherapy, which may impair the effectiveness of cancer treatments (4). Numerous clinical trials have been performed to attempt to protect against neuropathy in this setting, but no agent has been well proven to prevent CIPN (5).

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Long-term outcome of definitive radiotherapy for cervical esophageal squamous cell carcinoma

The aim of this study was to identify the long-term clinical outcome of definitive radiotherapy using three-dimensional conformal radiotherapy (3DCRT) for cervical esophageal squamous cell carcinoma (CESCC).

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Correction to expert consensus on re-irradiation for recurrent glioma

In the original publication [1] two author names were missing the middle names. The corrected versions can be found in this Erratum.

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Incidence of Cancers of the Lower Stomach Increasing among Younger Americans

A type of cancer that occurs in the lower stomach has been increasing among some Americans under the age of 50, even though in the general population the incidence of all stomach cancers has been declining for decades, according to a new study.

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Long-term outcome of definitive radiotherapy for cervical esophageal squamous cell carcinoma

The aim of this study was to identify the long-term clinical outcome of definitive radiotherapy using three-dimensional conformal radiotherapy (3DCRT) for cervical esophageal squamous cell carcinoma (CESCC).

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Correction to expert consensus on re-irradiation for recurrent glioma

In the original publication [1] two author names were missing the middle names. The corrected versions can be found in this Erratum.

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Incidence of Cancers of the Lower Stomach Increasing among Younger Americans

A type of cancer that occurs in the lower stomach has been increasing among some Americans under the age of 50, even though in the general population the incidence of all stomach cancers has been declining for decades, according to a new study.

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Which patients are not included in the English Cancer Waiting Times monitoring dataset, 2009–2013? Implications for use of the data in research

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Robot-assisted radical prostatectomy vs laparoscopic and open retropubic radical prostatectomy: functional outcomes 18 months after diagnosis from a national cohort study in England

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Interferon-alpha enhances the antitumour activity of EGFR-targeted therapies by upregulating RIG-I in head and neck squamous cell carcinoma

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Phase I dose-escalation study of copanlisib in combination with gemcitabine or cisplatin plus gemcitabine in patients with advanced cancer

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H1/pHGFK1 nanoparticles exert anti-tumoural and radiosensitising effects by inhibition of MET in glioblastoma

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Robot-assisted radical prostatectomy vs laparoscopic and open retropubic radical prostatectomy: functional outcomes 18 months after diagnosis from a national cohort study in England

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Interferon-alpha enhances the antitumour activity of EGFR-targeted therapies by upregulating RIG-I in head and neck squamous cell carcinoma

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Which patients are not included in the English Cancer Waiting Times monitoring dataset, 2009–2013? Implications for use of the data in research

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Phase I dose-escalation study of copanlisib in combination with gemcitabine or cisplatin plus gemcitabine in patients with advanced cancer

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H1/pHGFK1 nanoparticles exert anti-tumoural and radiosensitising effects by inhibition of MET in glioblastoma

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Toxicological profile and safety pharmacology of a single dose of fibroblast activation protein-[alpha]-based doxorubicin prodrug: in-vitro and in-vivo evaluation.

Fibroblast activation protein-[alpha] (FAP[alpha]) is a promising tumor-associated target expressed by reactive stromal fibroblasts in tumor tissue. FAP[alpha] has a postprolyl peptidase activity and can specifically cleave N-terminal benzyloxycarbonyl (Z)-blocked peptides, such as the substrate Z-Gly-Pro-AMC. Doxorubicin (DOX) is an effective antitumor drug, but its application is greatly limited by toxic adverse effects owing to poor tumor selectivity. Based on these facts, we previously designed a FAP[alpha]-targeting prodrug of doxorubicin (FTPD) which can be selectively hydrolyzed by FAP[alpha]. FTPD can retain potent antitumor efficacy and has favorable tumor targeting. The present study aimed to further evaluate the toxicological profile and the safety pharmacological property of FTPD in vitro and in vivo. The cytotoxicity assay showed that FTPD displayed markedly lower cytotoxicity to 3T3 cells and HEK-293 cells compared with DOX. In the short-term toxicity study, mice treated with 25 mg/kg of FTPD showed no obvious change in the appearance and general behavior, and no case of mortality was observed within 14 days. Unlike DOX, FTPD exhibited reduced toxicity to heart, liver, kidney, spleen as well as peripheral white blood cells in mice. Moreover, open file test and general pharmacology study were also conducted correspondingly in mice and beagle dogs. It was found that FTPD may not produce significant pharmacological effects on spontaneous locomotor activity and cardiovascular-respiratory system except for a transient decreasing in systolic blood pressure. Taken together, the results of this work suggest that FTPD has more favorable toxicological profile and better drug safety compared with its parent drug DOX. Copyright (C) 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Refractory Pain Management in Amyloid-Associated Peripheral Neuropathy.

Objective: Systemic amyloidosis is a disease that often involves multiple organ systems, including the peripheral nervous system. Patients may present with severe, refractory neuropathic pain; however, the optimal treatment approach for pain for these patients remains unclear. Case Report: A man with severe, refractory neuropathic pain in his bilateral upper and lower extremities and the trunk secondary to amyloid neuropathy is presented. Multiple medication trials, including neuropathic and opioid agents, produced considerable adverse effects and minimal relief. Scrambler therapy, a novel electrical stimulation modality, was used and was associated with substantial short-term but nonsustained benefit. Spinal cord stimulation was considered, but given his diffuse symptoms, it was deemed a less-than-optimal approach. Ultimately, an intrathecal drug delivery system was placed with infusion of hydromorphone, resulting in substantial pain reduction in all involved areas and with an improved adverse effect profile. This intervention resulted in immense improvement in the patient's quality of life, despite progression of his systemic amyloidosis. Conclusions: Severe pain in the setting of amyloid neuropathy is often difficult to treat. To our knowledge, this represents the first report of Scrambler therapy or an implanted intrathecal drug delivery system used for a patient with refractory amyloidosis-related neuropathic pain, resulting in substantial analgesic benefit and improved quality of life. Copyright (C) 2018 by American Society of Regional Anesthesia and Pain Medicine.

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Analgesia of Combined Femoral Triangle and Obturator Nerve Blockade Is Superior to Local Infiltration Analgesia After Total Knee Arthroplasty With High-Dose Intravenous Dexamethasone.

Background and Objectives: High-dose intravenous dexamethasone reduces the postoperative opioid requirement and is often included in the multimodal analgesia strategy after total knee arthroplasty (TKA). Combined obturator nerve and femoral triangle blockade (OFB) reduces the opioid consumption and pain after TKA better than local infiltration analgesia (LIA). The question is whether preoperative high-dose intravenous dexamethasone would cancel out the superior analgesic effect of OFB compared with LIA. The aim was to evaluate the analgesic effect of OFB versus LIA after TKA when all patients received high-dose intravenous dexamethasone. Methods: Eighty-two patients were randomly assigned either to OFB or LIA after primary unilateral TKA. All patients received 16 mg dexamethasone. Primary outcome was morphine consumption via patient-controlled analgesia during the first 20 postoperative hours. Secondary outcomes were pain, nausea, dizziness, and length of hospital stay. Results: Seventy-four patients were included in the analysis. Median total intravenous morphine consumption during the first 20 postoperative hours was 6 mg (interquartile range [IQR], 2-18 mg) in the OFB group and 20 mg (IQR, 12-28 mg) in the LIA group. The 14-mg difference (95% confidence interval, 6.4-18.0 mg) was significant (P

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Anatomical Variations of the Vertebral Artery in the Upper Cervical Spine: Clinical Relevance for Procedures Targeting the C1/C2 and C2/C3 Joints.

Background and Objectives: Accidental breach of the vertebral artery (VA) during the performance of cervical pain blocks can result in significant morbidity. Whereas anatomical variations have been described for the foraminal (V2) segment of the VA, those involving its V3 portion (between the C2 transverse process and dura) have not been investigated and may be of importance for procedures targeting the third occipital nerve or the lateral atlantoaxial joint. Methods: Five hundred computed tomography angiograms of the neck performed in patients older than 50 years for the management of cerebrovascular accident or cervical trauma (between January 2010 and May 2016) were retrospectively and independently reviewed by 2 neuroradiologists. Courses of the VA in relation to the lateral aspect of the C2/C3 joint and the posterior surface of the C1/C2 joint were examined. For the latter, any medial encroachment of the VA (or one of its branches) was noted. The presence of a VA loop between C1 and C2 and its distance from the upper border of the superior articular process (SAP) of C3 were also recorded. If the VA loop coursed posteriorly, its position in relation to 6 fields found on the lateral aspects of the articular pillars of C2 and C3 was tabulated. Results: At the C1/C2 level, the VA coursed medially over the lateral quarter of the dorsal joint surface in 1% of subjects (0.6% and 0.4% on the left and right sides, respectively; P = 0.998). A VA loop originating between C1 and C2 was found to travel posteroinferiorly over the anterolateral aspect of the inferior articular pillar of C2 in 55.5% of patients on the left and 41.9% on the right side (P

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Toxicological profile and safety pharmacology of a single dose of fibroblast activation protein-[alpha]-based doxorubicin prodrug: in-vitro and in-vivo evaluation.

Fibroblast activation protein-[alpha] (FAP[alpha]) is a promising tumor-associated target expressed by reactive stromal fibroblasts in tumor tissue. FAP[alpha] has a postprolyl peptidase activity and can specifically cleave N-terminal benzyloxycarbonyl (Z)-blocked peptides, such as the substrate Z-Gly-Pro-AMC. Doxorubicin (DOX) is an effective antitumor drug, but its application is greatly limited by toxic adverse effects owing to poor tumor selectivity. Based on these facts, we previously designed a FAP[alpha]-targeting prodrug of doxorubicin (FTPD) which can be selectively hydrolyzed by FAP[alpha]. FTPD can retain potent antitumor efficacy and has favorable tumor targeting. The present study aimed to further evaluate the toxicological profile and the safety pharmacological property of FTPD in vitro and in vivo. The cytotoxicity assay showed that FTPD displayed markedly lower cytotoxicity to 3T3 cells and HEK-293 cells compared with DOX. In the short-term toxicity study, mice treated with 25 mg/kg of FTPD showed no obvious change in the appearance and general behavior, and no case of mortality was observed within 14 days. Unlike DOX, FTPD exhibited reduced toxicity to heart, liver, kidney, spleen as well as peripheral white blood cells in mice. Moreover, open file test and general pharmacology study were also conducted correspondingly in mice and beagle dogs. It was found that FTPD may not produce significant pharmacological effects on spontaneous locomotor activity and cardiovascular-respiratory system except for a transient decreasing in systolic blood pressure. Taken together, the results of this work suggest that FTPD has more favorable toxicological profile and better drug safety compared with its parent drug DOX. Copyright (C) 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Role of the anesthesiologist-intensivist outside the ICU: opportunity to add value for the hospital or an unnecessary distraction?.

Purpose of review: Given the extremely expensive nature of critical care medicine, it seems logical that intensivists should play an active role in designing efficient systems of care. The true value of intensivists, however, is not well defined. Recent findings: Anesthesiologists have taken key roles in improving patient safety in the operating room. Anesthesia-related mortality rates have decreased from 20 deaths per 100 000 anesthetics in the early 1980s to less than one death per 100 000 currently. Anesthesiologist-intensivists remain rare (less than 5% of certified anesthesiologists), but increasingly play multiple roles within multidisciplinary teams. This review outlines the roles of intensivists in performance improvement, perioperative assessment; sedation services, extracorporeal and mechanical support, and code/rapid response teams. Critical-care physicians, by definition, work in collaborative multispecialty and multidisciplinary teams that make it difficult to isolate each team member's precise contribution to healthcare value. Summary: Anesthesiologist-intensivists working outside their usual environment provide leadership and clinical guidance towards improving patient outcomes. Copyright (C) 2018 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Withdrawal of life-sustaining therapy.

Purpose of review: The aim of this review is to examine literature relating to the withdrawal of life-sustaining therapy (WLST). Recent findings: Discussions regarding end-of-life issues in adults and children are not occurring comprehensively. Discussions relating to the WLST in the pediatric population varies by institution and may vary by race, age, health insurance, diagnosis, and severity of illness. Completing advance directives prior to placement of life-sustaining treatments is not consistent practice. With the WLST, differences in perspectives exist between medical specialties, within one specialty at different levels of training, and in physicians' ethical and psychological responses to the WLST. The timing of WLST appears to be influenced by ICU strain and communication issues. Study outcomes differ regarding the functionally favorable survival of patients who have had WLST. Universal guidelines for the WLST may not address individual patient circumstances. Summary: Discussions of end-of-life issues early in the course of a patient's health care will contribute to the healthcare team's understanding and respect of the patient's wishes. This article addresses the withdrawal of left ventricular assist devices; attending physicians and physicians-in-training perspectives of WLST; do physicians distinguish between withholding and WLST; the timing of WLST; guidelines for the process of WLST; and pediatrics and end-of-life decisions. Copyright (C) 2018 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Positive Correlation between Matrix Metalloproteinases and Epithelial-to-Mesenchymal Transition and its Association with Clinical Outcome in Bladder Cancer Patients

Abstract

Involvement of matrix metalloproteinases (MMPs) in the pathogenesis of urothelial carcinoma elects them to be sensitive marker for clinical and prognostic implications. MMPs regulate tumor growth and invasion by inducing epithelial-to-mesenchymal transition (EMT) which is characterized by the complex reprogramming of epithelial cells and ultimately bring about major changes in the structural organization of bladder urothelium. The present study has been undertaken to evaluate the clinical relevance of MMPs in two distinct types of bladder cancer disease. Expression analysis of MMPs namely MMP-2, MMP-7, MMP-9 and EMT markers including epithelial marker, E-cadherin; mesenchymal markers, N-cadherin and Vimentin; and EMT-activating transcriptional factors (EMT-ATFs), Snail, Slug, Twist and Zeb was done in 64 cases of bladder tumor tissues [{Non-muscle invasive bladder cancer (NMIBC): 35 cases} and {Muscle invasive bladder cancer (MIBC): 29 cases}] by real-time quantitative polymerase chain reaction (RT-qPCR). Immunohistochemistry (IHC) staining was done in matched bladder tumor tissues to evaluate the protein expression and localization of E-cadherin, N-cadherin, Vimentin, Snail, and Slug. Our data showed overexpression of MMP-2, MMP-7 and MMP-9 at transcriptome level in 32.8%, 25% and 37.5% bladder tumor cases respectively. These tumor tissues were examined for higher expression of mesenchymal markers (N-cadherin and Vimentin) at mRNA and protein level and exhibited statistical association with tumor stage and tumor grade (p = 0.02, p = 0.04, Mann-Whitney test). Significant statistical correlation in tumor tissues with overexpressed MMPs has also been observed between gain of transcriptional factors and weak expression of E-cadherin with tumor stage, grade, gender, presence of hematuria and smoking history of the patients. Gene expression patterns of EMT markers in bladder tumors with overexpressed MMPs and their significant association with clinical profile validate the important role of MMPs in the pathogenesis of urothelial carcinoma of bladder (UCB). Increased expression of specific MMPs may affect several downstream EMT programs and thus may improve its diagnostic and prognostic utility in clinical setting.

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Positive Correlation between Matrix Metalloproteinases and Epithelial-to-Mesenchymal Transition and its Association with Clinical Outcome in Bladder Cancer Patients

Abstract

Involvement of matrix metalloproteinases (MMPs) in the pathogenesis of urothelial carcinoma elects them to be sensitive marker for clinical and prognostic implications. MMPs regulate tumor growth and invasion by inducing epithelial-to-mesenchymal transition (EMT) which is characterized by the complex reprogramming of epithelial cells and ultimately bring about major changes in the structural organization of bladder urothelium. The present study has been undertaken to evaluate the clinical relevance of MMPs in two distinct types of bladder cancer disease. Expression analysis of MMPs namely MMP-2, MMP-7, MMP-9 and EMT markers including epithelial marker, E-cadherin; mesenchymal markers, N-cadherin and Vimentin; and EMT-activating transcriptional factors (EMT-ATFs), Snail, Slug, Twist and Zeb was done in 64 cases of bladder tumor tissues [{Non-muscle invasive bladder cancer (NMIBC): 35 cases} and {Muscle invasive bladder cancer (MIBC): 29 cases}] by real-time quantitative polymerase chain reaction (RT-qPCR). Immunohistochemistry (IHC) staining was done in matched bladder tumor tissues to evaluate the protein expression and localization of E-cadherin, N-cadherin, Vimentin, Snail, and Slug. Our data showed overexpression of MMP-2, MMP-7 and MMP-9 at transcriptome level in 32.8%, 25% and 37.5% bladder tumor cases respectively. These tumor tissues were examined for higher expression of mesenchymal markers (N-cadherin and Vimentin) at mRNA and protein level and exhibited statistical association with tumor stage and tumor grade (p = 0.02, p = 0.04, Mann-Whitney test). Significant statistical correlation in tumor tissues with overexpressed MMPs has also been observed between gain of transcriptional factors and weak expression of E-cadherin with tumor stage, grade, gender, presence of hematuria and smoking history of the patients. Gene expression patterns of EMT markers in bladder tumors with overexpressed MMPs and their significant association with clinical profile validate the important role of MMPs in the pathogenesis of urothelial carcinoma of bladder (UCB). Increased expression of specific MMPs may affect several downstream EMT programs and thus may improve its diagnostic and prognostic utility in clinical setting.

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Remarkable response with pembrolizumab plus albumin-bound paclitaxel in 2 cases of HER2-positive metastatic breast cancer who have failed to multi-anti-HER2 targeted therapy

.


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Improved effectiveness of stereotactic radiosurgery in large brain metastases by individualized isotoxic dose prescription: an in silico study

Abstract

Introduction

In large brain metastases (BM) with a diameter of more than 2 cm there is an increased risk of radionecrosis (RN) with standard stereotactic radiosurgery (SRS) dose prescription, while the normal tissue constraint is exceeded. The tumor control probability (TCP) with a single dose of 15 Gy is only 42%. This in silico study tests the hypothesis that isotoxic dose prescription (IDP) can increase the therapeutic ratio (TCP/Risk of RN) of SRS in large BM.

Materials and methods

A treatment-planning study with 8 perfectly spherical and 46 clinically realistic gross tumor volumes (GTV) was conducted. The effects of GTV size (0.5–4 cm diameter), set-up margins (0, 1, and 2 mm), and beam arrangements (coplanar vs non-coplanar) on the predicted TCP using IDP were assessed. For single-, three-, and five-fraction IDP dose–volume constraints of V_12Gy = 10 cm³, V_19.2 Gy = 10 cm³, and a V_20Gy = 20 cm³, respectively, were used to maintain a low risk of radionecrosis.

Results

In BM of 4 cm in diameter, the maximum achievable single-fraction IDP dose was 14 Gy compared to 15 Gy for standard SRS dose prescription, with respective TCPs of 32 and 42%. Fractionated SRS with IDP was needed to improve the TCP. For three- and five-fraction IDP, a maximum predicted TCP of 55 and 68% was achieved respectively (non-coplanar beams and a 1 mm GTV-PTV margin).

Conclusions

Using three-fraction or five-fraction IDP the predicted TCP can be increased safely to 55 and 68%, respectively, in large BM with a diameter of 4 cm with a low risk of RN. Using IDP, the therapeutic ratio of SRS in large BM can be increased compared to current SRS dose prescription.

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Quality of training in radiation oncology in Germany: where do we stand?

Abstract

Purpose

To evaluate the current situation of young radiation oncologists in Germany with regard to the contents and quality of training and level of knowledge, as well as their working conditions and professional satisfaction.

Methods

From June 2016 to February 2017, a survey was conducted by the young DEGRO (yDEGRO) using an online platform. The questionnaire consisted of 28 items examining a broad range of aspects influencing residency. There were 96 completed questionnaires

Results

83% of participants stated to be very or mostly pleased with their residency training. Moderate working hours and a good colleagueship contribute to a comfortable working environment. Level of knowledge regarding the most common tumor sites (i.e. palliative indications, lung, head and neck, brain, breast, prostate) was pleasing. Radiochemotherapy embodies a cornerstone in training. Modern techniques such as intensity-modulated radiotherapy (IMRT) and stereotactic procedures are now in widespread use. Education for rare indications and center-based procedures offers room for improvement.

Conclusion

Radiation oncology remains an attractive and versatile specialty with favorable working conditions. Continuing surveys in future years will be a valuable measuring tool to set further priorities in order to preserve and improve quality of training.

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Remarkable response with pembrolizumab plus albumin-bound paclitaxel in 2 cases of HER2-positive metastatic breast cancer who have failed to multi-anti-HER2 targeted therapy

.


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Expression of UGP2 and CFL1 expression levels in benign and malignant pancreatic lesions and their clinicopathological significance

Abstract

Background

This study investigated UGP2 (uridine diphosphate-glucose pyrophosphorylase-2) and CFL1 (cofilin-1) expression in pancreatic ductal carcinoma (PDC), paracancerous tissue (PT), benign lesions (BL), and normal tissue (NT) and their clinicopathological significance.

Methods

Surgical specimens, which were collected from 106 cases of pancreatic ductal carcinoma, 35 cases of paracancerous tissues, 55 cases of benign lesions and 13 cases of normal pancreatic tissues, were fixed with 4% formaldehyde to prepare conventional paraffin-embedded sections. EnVision immunohistochemical was used to stain for UGP2 and CFL1. Kaplan-Meier survival analysis was performed to assess the correlation of expression pattern with survival.

Results

We found that positive UGP2 and CFL1 expression in PDC were significantly higher than those in PT, BL, and NT. In PT and BL with positive UGP2 and CFL1 expression, mild to severe atypical hyperplasia or intraepithelial neoplasia of grades II–III was observed in ductal epithelium. Positive UGP2 and CFL1 expression in cases with high differentiation, no lymph node metastasis, no surrounding invasion, and TNM (tumor-node-metastasis) staging I or/and II were significantly lower than those in cases with poor differentiation, lymph node metastasis, surrounding invasion, and TNM stage III and/or IV. Positive UGP2 expression in male patients was significantly lower than that in female patients. UGP2 and CFL1 expression in PDC were positively correlated. Kaplan-Meier survival analysis showed the degree of differentiation, tumor maximal diameter, TNM stage, lymph node metastasis, and surrounding invasion, and UGP2 and CFL1 expression were closely related to the average survival time of patients with PDC. The survival time of patients with positive UGP2 and CFL1 expression was significantly shorter than that of patients with negative expression. Cox multivariate analysis showed that poor differentiation, tumor maximal diameter ≥ 3 cm, TNM stage III or IV, lymph node metastasis, surrounding invasion, and positive UGP2 and CFL1 expression was negatively correlated with the postoperative survival rate and positively correlated with the mortality of patients with PDC.

Conclusion

Positive expression of UGP2 and CFL1 can serve a valuable prognostic factor in pancreatic cancer.

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