Timing of radiotherapy (RT) after radical prostatectomy (RP): long-term outcomes in the RADICALS-RT trial (NCT00541047).

BACKGROUND: The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for prostate-specific antigen (PSA) failure. PATIENTS AND METHODS: RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, preoperative PSA≥10 ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT ('Adjuvant-RT') or an observation policy with salvage RT for PSA failure ('Salvage-RT') defined as PSA≥0.1 ng/ml or three consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5 Gy/20 fractions or 66 Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant-metastasis (FFDM), designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10 years with Adjuvant-RT. Secondary outcome measures were biochemical progression-free survival, freedom from non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; hazard ratio (HR)<1 favours Adjuvant-RT. RESULTS: Between October 2007 and December 2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with a median age of 65 years. Ninety-three percent (649/697) Adjuvant-RT reported RT within 6 months after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10-year FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 [95% confidence interval (CI) 0.43-1.07, P=0.095]. Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95% CI 0.667-1.440, P=0.917). Adjuvant-RT reported worse urinary and faecal incontinence 1 year after randomisation (P=0.001); faecal incontinence remained significant after 10 years (P=0.017). CONCLUSION: Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy. TRIAL IDENTIFICATION: RADICALS, RADICALS-RT, ISRCTN40814031, NCT00541047.

A role for androgen receptor variant 7 in sensitivity to therapy: Involvement of IGFBP-2 and FOXA1.

Prostate cancer (PCa) is one of the leading causes of cancer-related deaths in men. Localised PCa can be treated effectively, but most patients relapse/progress to more aggressive disease. One possible mechanism underlying this progression is alternative splicing of the androgen receptor, with AR variant 7(ARV7) considered to play a major role. Using viability assays, we confirmed that ARV7-positive PCa cells were less sensitive to treatment with cabazitaxel and an anti-androgen-enzalutamide. Also, using live-holographic imaging, we showed that PCa cells with ARV7 exhibited an increased rate of cell division, proliferation, and motility, which could potentially contribute to a more aggressive phenotype. Furthermore, protein analysis demonstrated that ARV7 knock-down was associated with a decrease in insulin-like growth factor-2 (IGFBP-2) and forkhead box protein A1(FOXA1). This correlation was confirmed in-vivo using PCa tissue samples. Spearman rank correlation analysis showed significant positive associations between ARV7 and IGFBP-2 or FOXA1 in tissue from patients with PCa. This association was not present with the AR. These data suggest an interplay of FOXA1 and IGFBP-2 with ARV7-mediated acquisition of an aggressive prostate cancer phenotype.

Modified transseptal approach in endoscopic transsphenoidal pituitary surgery.

OBJECTIVE: Transsphenoidal pituitary surgery is commonly performed via a direct transostial approach with a posterior septectomy. However, a technique via an endoscopic transseptal route has been described that avoids a posterior septectomy, but it comes with its own disadvantages. METHODS: This paper describes a modification, and discusses its pros and cons. RESULTS: The initial incision in the mucosa is placed level with the anterior middle turbinate. The mucoperichondrial flap is raised ipsilaterally until the sphenoid sinus ostium. An incision is made at the osseocartilaginous junction, and the contralateral mucoperichondrial flap is raised. The bony septum and posterior aspect of this flap is excised. The size and position of this window can be adapted. At the end of the operation, the lateralised intact mucoperichondrial flap is moved back to the midline. CONCLUSION: Excision or deflection of the cartilaginous septum is not required. It maintains an intact septal mucosa on one side and avoids a septal perforation.

Prospective observational study evaluating acute and delayed treatment related toxicities of prophylactic extended field volumetric modulated arc therapy with concurrent cisplatin in cervical cancer patients with pelvic lymph node metastasis.

PURPOSE: To evaluate the treatment related acute and delayed toxicities of extended field Volumetric modulated arc therapy (VMAT) with concurrent chemotherapy in patients of locally advanced cervical cancer with pelvic lymph nodes. MATERIAL AND METHODS: From 2014 to 2016, 15 patients of locally advanced cervical cancer with Fluoro-deoxyglucose positron emission tomography (FDG-PET) positive pelvic lymph nodes were treated with extended field Simultaneous integrated boost (SIB)-VMAT 45 Gy/55 Gy/25#/5weeks and concurrent cisplatin. Acute toxicities were documented according to common terminology criteria for adverse events version 4 (CTCAE v.4). Dose volume parameters and patient characteristics were analyzed for association with toxicities. RESULTS: Median age of patients at diagnosis was 48 years. 40% (6 patients) were stage IIB & 60% (9 patients) were stage IIIB. Median number of involved pelvic lymph nodes was 2 (range, 1-4), commonest location was external iliac lymph node region (86%). Median number of concurrent chemotherapy cycles received was five. Treatment was well tolerated and there were no grade ≥ 3 acute toxicities. Commonest acute toxicities observed were vomiting (≥grade2 -13.3%) followed by & nausea (grade ≥ 2 in 6%) and were associated with volume of bowel bag receiving 45 Gy. Constitutional symptoms (≥grade 2) were observed in 6% patients and had no dosimetric associations. At a median follow up of 43 months, delayed ≥ grade1, 2, 3 toxicity were observed in 80%, 0%, and 0% respectively with diarrhea being the commonest. CONCLUSION: Prophylactic para aortic extended field VMAT with concurrent chemotherapy for locally advanced cervical cancer is well tolerated with acceptable acute toxicity profile. Significant grade 3 acute/delayed toxicities were not observed in this cohort of patients.

Spine and Non-spine Bone Metastases - Current Controversies and Future Direction.

Bone is a common site of metastases in advanced cancers. The main symptom is pain, which increases morbidity and reduces quality of life. The treatment of bone metastases needs a multidisciplinary approach, with the main aim of relieving pain and improving quality of life. Apart from systemic anticancer therapy (hormonal therapy, chemotherapy or immunotherapy), there are several therapeutic options available to achieve palliation, including analgesics, surgery, local radiotherapy, bone-seeking radioisotopes and bone-modifying agents. Long-term use of non-steroidal analgesics and opiates is associated with significant side-effects, and tachyphylaxis. Radiotherapy is effective mainly in localised disease sites. Bone-targeting radionuclides are useful in patients with multiple metastatic lesions. Bone-modifying agents are beneficial in reducing skeletal-related events. This overview focuses on the role of surgery, including minimally invasive treatments, conventional radiotherapy in spinal and non-spinal bone metastases, bone-targeting radionuclides and bone-modifying agents in achieving palliation. We present the clinical data and their associated toxicity. Recent advances are also discussed.

Importance and vulnerability of the world's water towers.

Mountains are the water towers of the world, supplying a substantial part of both natural and anthropogenic water demands1,2. They are highly sensitive and prone to climate change3,4, yet their importance and vulnerability have not been quantified at the global scale. Here we present a global water tower index (WTI), which ranks all water towers in terms of their water-supplying role and the downstream dependence of ecosystems and society. For each water tower, we assess its vulnerability related to water stress, governance, hydropolitical tension and future climatic and socio-economic changes. We conclude that the most important (highest WTI) water towers are also among the most vulnerable, and that climatic and socio-economic changes will affect them profoundly. This could negatively impact 1.9 billion people living in (0.3 billion) or directly downstream of (1.6 billion) mountainous areas. Immediate action is required to safeguard the future of the world's most important and vulnerable water towers.

Practical consensus recommendations regarding the management of HER2 neu positive early breast cancer.

Over-expression of HER2 is generally considered to be a negative prognostic feature because it accompanies an increase in breast cancer mortality. However, the development of agents that specifically target HER2 has improved the management of patients with these tumours. This expert group used data from published literature, practical experience and opinion of a large group of academic oncologists to arrive at these practical consensus recommendations with regards to the use of these agents and the management of HER2 neu early breast cancer for the benefit of community oncologists.

Bound-Electron Nonlinearity Beyond the Ionization Threshold.

We present absolute space- and time-resolved measurements of the ultrafast laser-driven nonlinear polarizability in argon, krypton, xenon, nitrogen, and oxygen up to ionization fractions of a few percent. These measurements enable determination of the strongly nonperturbative bound-electron nonlinear polarizability well beyond the ionization threshold, where it is found to remain approximately quadratic in the laser field, a result normally expected at much lower intensities where perturbation theory applies.

Ability of computed tomography to predict right heart strain on an echocardiogram in patients with acute pulmonary embolus.

Patients with submassive pulmonary embolism (PE) resulting in right heart strain (RHS) have an increased risk of mortality compared to those with a preserved right ventricular function. This study aimed to investigate the predictive value of computed tomography pulmonary angiogram (CTPA) findings of right heart strain in patients with computed tomography (CT)-proven PE for the diagnosis of right heart strain by echocardiogram (ECHO). The institutional review board (IRB) approved retrospective chart review of the adult emergency department patients diagnosed with an acute PE between 2012 and 2016. A total of 128 patients diagnosed with RHS by CT who had received an ECHO during their hospitalization were included in the study. Descriptive statistics were run for the variables of interest. The majority of patients (101 patients) with reported findings of RHS on CT had similar findings on ECHO. In our cohort, a finding of enlarged right atrium (RA) on CT was 100% predictive of RHS diagnosis on ECHO, whereas having interventricular septal bowing alone on CT was the least predictive of RHS on subsequent ECHO (61%). The 2 remaining subgroups: right ventricle (RV) enlargement alone and RV enlargement with either interventricular septal bowing/hepatic vein blood reflux or both lies somewhere in between, with 80% of these patients showing strain on ECHO. We found that signs of RHS on CT are predictive of strain on an ECHO (78%) and RA enlargement in any combination was the most predictive finding of RHS on ECHO (100%). Future prospective randomized investigations are needed to confirm such findings.

Inhibition of FASN and ERα signalling during hyperglycaemia-induced matrix-specific EMT promotes breast cancer cell invasion via a caveolin-1-dependent mechanism.

Since disturbed metabolic conditions such as obesity and diabetes can be critical determinants of breast cancer progression and therapeutic failure, we aimed to determine the mechanism responsible for their pro-oncogenic effects. Using non-invasive, epithelial-like ERα-positive MCF-7 and T47D human breast cancer cells we found that hyperglycaemia induced epithelial to mesenchymal transition (EMT), a key programme responsible for the development of metastatic disease. This was demonstrated by loss of the epithelial marker E-cadherin together with increases in mesenchymal markers such as vimentin, fibronectin and the transcription factor SLUG, together with an enhancement of cell growth and invasion. These phenotypic changes were only observed with cells grown on fibronectin and not with those plated on collagen. Analyzing metabolic parameters, we found that hyperglycaemia-induced, matrix-specific EMT promoted the Warburg effect by upregulating glucose uptake, lactate release and specific glycolytic enzymes and transporters. We showed that silencing of fatty acid synthase (FASN) and the downstream ERα, which we showed previously to mediate hyperglycaemia-induced chemoresistance in these cells, resulted in suppression of cell growth: however, this also resulted in a dramatic enhancement of cell invasion and SLUG mRNA levels via a novel caveolin-1-dependent mechanism.

Health resource utilisation associated with skeletal-related events in patients with bone metastases secondary to solid tumours: regional comparisons in an observational study.

Skeletal-related events (SREs) including spinal cord compression, pathologic fracture, and radiation or surgery to bone, occur frequently due to bone metastases in advanced cancer. This analysis of a multicentre, observational study was designed to describe cross-regional differences in health resource utilisation (HRU) of SREs in Western Europe and the US. Patients with bone metastases due to breast, lung or prostate cancer, or multiple myeloma who had experienced a SRE within the past 97 days were enrolled. Investigators recorded HRU associated with SREs, including hospitalisation and length of stay (LOS), outpatient visits, procedures and bisphosphonate use. This subanalysis includes 668 patients with solid tumours (US, n = 190 with 354 SREs; EU, n = 478 with 893 SREs). The rate of SREs associated with hospitalisation(s) was higher in the EU vs. the US (30% vs. 15%, P < 0.001) and LOS was longer in the EU [mean (SD) days/SRE: 19.87 (17.31) vs. 10.61 (9.39)]. However, the US was associated with higher rate of SREs with outpatient visits than the EU (88% vs. 74%, P < 0.0001) and more procedures [mean (SD)/SRE: 11.26 (7.94) vs. 6.91 (6.48)]. Bisphosphonates were less often used in the EU (65% vs. 76% of US, P = 0.0033). In patients experiencing SREs due to bone metastases, HRU patterns reflect regional diversity with a substantial burden in both regions.

Hyperglycaemia-induced resistance to Docetaxel is negated by metformin: a role for IGFBP-2.

The incidence of many common cancers varies between different populations and appears to be affected by a Western lifestyle. Highly proliferative malignant cells require sufficient levels of nutrients for their anabolic activity. Therefore, targeting genes and pathways involved in metabolic pathways could yield future therapeutics. A common pathway implicated in energetic and nutritional requirements of a cell is the LKB1/AMPK pathway. Metformin is a widely studied anti-diabetic drug, which improves glycaemia in patients with type 2 diabetes by targeting this pathway. We investigated the effect of metformin on prostate cancer cell lines and evaluated its mechanism of action using DU145, LNCaP, PC3 and VCaP prostate cancer cell lines. Trypan blue dye-exclusion assay was used to assess levels of cell death. Western immunoblotting was used to determine the abundance of proteins. Insulin-like growth factor-binding protein-2 (IGFBP-2) and AMPK genes were silenced using siRNA. Effects on cell morphology were visualised using microscopy. IGFBP-2 gene expression was assessed using real-time RT-PCR. With DU145 and LNCaP cells metformin alone induced cell death, but this was reduced in hyperglycaemic conditions. Hyperglycaemia also reduced the sensitivity to Docetaxel, but this was countered by co-treatment with metformin. LKB1 was required for the activation of AMPK but was not essential to mediate the induction of cell death. An alternative pathway by which metformin exerted its action was through downregulation of IGFBP-2 in DU145 and LNCaP cells, independently of AMPK. This finding could have important implications in relation to therapeutic strategies in prostate cancer patients presenting with diabetes.

Treatment patterns and clinical outcomes in patients with renal cell carcinoma in the UK: insights from the RECCORD registry.

BACKGROUND: The aim of the RECCORD registry was to gather real-world UK data on the use of targeted therapies in renal cell carcinoma (RCC) and assess clinical outcomes. Here, demographic and outcome data are presented with the treatment patterns and demographic profile of patients on the registry. PATIENTS AND METHODS: Patients were retrospectively identified at seven UK hospitals with large cancer centres in England (5), Scotland (1) and Wales (1). Anonymised data were collected through an online registry covering demographics, treatments and outcomes. Five hundred and fourteen UK adult patients with metastatic RCC were included in the study for analysis. Patients were included if they were treated for metastatic RCC at one of the seven centres, and started systemic anti-cancer treatment from March 2009 to November 2012 inclusive. In addition to demographic factors, the principal outcome measures were overall survival (OS), time to disease progression and toxicity. RESULTS: The majority of first-line treatment was with sunitinib; first-line use of pazopanib increased as the study progressed. 15.8% of patients received second-line treatment, half of whom were prescribed everolimus. Median OS (from initiation of first-line treatment) was 23.9 months (95% confidence interval [CI] 18.6-29.1 months), similar to that reported for clinical trials of targeted RCC therapies [Ljungberg B, Campbell SC, Choi HY et al. The epidemiology of renal cell carcinoma. Eur Urol 2011; 60: 615-621; Abe H, Kamai T. Recent advances in the treatment of metastatic renal cell carcinoma. Int J Urol 2013; 20: 944-955; Motzer RJ, Hutson TE, Tomczak P et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009; 27: 3584-3590]. OS was significantly longer for those who received second-line treatment after disease progression (33.0 months; 95% CI 30.8-35.2 months) than those who did not (20.9 months; 95% CI 16.4-25.3 months; P = 0.008). CONCLUSIONS: RECCORD is a large 'real-world' database assessing metastatic RCC treatment patterns and outcomes. Treatment patterns changed over time as targeted therapies were approved and became widely available; survival data in RECCORD are consistent with those reported for systemic treatments in clinical trials. Kaplan-Meier analysis of results demonstrated that receiving second-line therapy was a major prognostic factor for longer OS.

Hyperglycaemia-induced chemoresistance in breast cancer cells: role of the estrogen receptor.

Breast cancer patients with diabetes respond less well to chemotherapy; in keeping with this we determined previously that hyperglycaemia-induced chemoresistance in estrogen receptor (ERα) positive breast cancer cells and showed that this was mediated by fatty acid synthase (FASN). More recent evidence suggests that the effect of metabolic syndrome and diabetes is not the same for all subtypes of breast cancer with inferior disease-free survival and worse overall survival only found in women with ERα positive breast cancer and not for other subtypes. Here we examined the impact of hyperglycaemia on ERα negative breast cancer cells and further investigated the mechanism underlying chemoresistance in ERα with a view to identifying strategies to alleviate hyperglycaemia-induced chemoresistance. We found that hyperglycaemia-induced chemoresistance was only observed in ERα breast cancer cells and was dependent upon the expression of ERα as chemoresistance was negated when the ERα was silenced. Hyperglycaemia-induced an increase in activation and nuclear localisation of the ERα that was downstream of FASN and dependent on the activation of MAPK. We found that fulvestrant successfully negated the hyperglycaemia-induced chemoresistance, whereas tamoxifen had no effect. In summary our data suggests that the ERα may be a predictive marker of poor response to chemotherapy in breast cancer patients with diabetes. It further indicates that anti-estrogens could be an effective adjuvant to chemotherapy in such patients and indicates the importance for the personalised management of breast cancer patients with diabetes highlighting the need for clinical trials of tailored chemotherapy for diabetic patients diagnosed with ERα positive breast cancers.

Assessment of the metastable electronic state approach as a microscopically self-consistent description for the nonlinear response of atoms.

This Letter presents the first quantitative assessment of the recently proposed metastable electronic state approach (MESA) for calculation of the nonlinear optical response of noble gas atoms. Based on the single active electron potentials for several atomic species, Stark resonant states are used to extract the nonlinear polarization and ionization rates free of any additional fitting parameters. It is shown that even the simplest version of the method provides a viable, first-principle-based, and self-consistent alternative to the standard model commonly used for simulations in the field of extreme nonlinear optics.

BRCA1/2 Mutation-associated Breast Cancer, Wide Local Excision and Radiotherapy or Unilateral Mastectomy: A Systematic Review.

AIMS: BRCA1/2 mutation carriers show reduced apoptotic response to ionising radiation leading to recent debate about the safety of wide local excision and radiotherapy. The aim of the current study was to determine if BRCA1/2 mutation carriers with breast cancer undergoing wide local excision and radiotherapy show increased ipsilateral and contralateral breast tumour recurrence and reduced survival compared with unilateral mastectomy. MATERIALS AND METHODS: Following a detailed literature search, the methodology, populations, biases and outcomes of ipsilateral breast tumour recurrence, contralateral breast tumour recurrence and survival were evaluated for 25 articles. RESULTS: No differences in outcomes were found between wide local excision and mastectomy. BRCA1/2 mutation status was predictive of contralateral breast cancer only. Radiotherapy reduces the risk of ipsilateral recurrence and confers no increase in contralateral recurrence. CONCLUSION: BRCA1/2 mutation status does not preclude treatment with wide local excision and radiotherapy. Given the retrospective studies with inherent flaws and small patient numbers, further large prospective trials are required.