Iron-induced Hypophosphatemic Osteomalacia-An Atypical Case of Bilateral Femoral Stress Fractures.

We present a case of a 61-year-old healthy man who had bilateral femoral neck insufficiency fractures attributed to repeated iron transfusions, causing iron-induced hypophosphatemic rickets, requiring surgical intervention. Atraumatic insufficiency fractures present a diagnostic dilemma in orthopaedics. Chronic fractures with no acute precipitating trigger can often go unrecognized until complete fracturing or displacement occurs. Early identification of the risk factors in conjunction with a comprehensive history, clinical examination, and imaging can potentially avoid these serious complications. Atraumatic femoral neck insufficiency fractures have been sporadically reported in the literature, often unilateral and attributed to the use of long-term bisphosphonates. Through this case, we elaborate on the relatively unknown link between iron transfusions and insufficiency fractures. This case highlights the importance of early detection and imaging of such fractures from an orthopaedic perspective.

Involvement of single nucleotide polymorphisms of junction adhesion molecule with small vessel vascular dementia.

Objectives: It is now recognized that blood brain barrier (BBB) leakage occurs in cerebral small vascular disease (CSVD) and plays a significant role in the pathophysiology of vascular dementia. We hypothesized that genetic polymorphisms of junctional adhesion molecule-A (JAM-A) (which may result in compromised structure of tight junction proteins that form the BBB) in combination with cerebrovascular risk factors hypertension, lipid disorders, and type 2 diabetes may result in BBB leakage and increase the individual's risk of CSVD-related dementia. Methods: In this case-control study, 97 controls with a mean Mini-Mental State Exam (MMSE) score of 29 and 38 CSVD-related vascular dementia participants (mean MMSE score of 19) were recruited. Bloods were collected for the analysis of two common single nucleotide polymorphisms (SNPs) of the JAM-A genotypes rs790056 and rs2481084 using real-time polymerase chain reaction (PCR) assay. Medical history of hypertension, hyperlipidemia, and diabetes was collected for all participants. Results: Polymorphisms of genotype JAM-A SNP rs790056 showed statistically significant result when the subgroup with hyperlipidemia was analyzed (OR = 3.130, p = 0.042 for TC + CC genotypes with hyperlipidaemia vs controls). Similar result was found with diabetes (OR = 4.670, p = 0.031 for TC + CC genotypes vs controls). No significant result was found with hypertension. Borderline results of statistical significance were found for JAM-A SNP rs2481084 with hyperlipidemia (OR = 3.210, p = 0.054 for TC + CC genotypes vs controls) and with diabetes (OR = 3.620, p = 0.069 for TC + CC genotypes vs controls) but not for hypertension. The borderline results might have been due to lack of statistical power because of small sample size. Conclusions: These results lend further support that cerebrovascular risk factors interact with genetic polymorphisms of BBB proteins to increase the risk of vascular dementia.

Intensity-modulated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): 2-year toxicity results from an open-label, randomised, phase 3, non-inferiority trial.

BACKGROUND: Localised prostate cancer is commonly treated with external beam radiotherapy and moderate hypofractionation is non-inferior to longer schedules. Stereotactic body radiotherapy (SBRT) allows shorter treatment courses without impacting acute toxicity. We report 2-year toxicity findings from PACE-B, a randomised trial of conventionally fractionated or moderately hypofractionated radiotherapy versus SBRT. METHODS: PACE is an open-label, multicohort, randomised, controlled, phase 3 trial conducted at 35 hospitals in the UK, Ireland, and Canada. In PACE-B, men aged 18 years and older with a WHO performance status 0-2 and low-risk or intermediate-risk histologically-confirmed prostate adenocarcinoma (Gleason 4 + 3 excluded) were randomly allocated (1:1) by computerised central randomisation with permuted blocks (size four and six), stratified by centre and risk group to control radiotherapy (CRT; 78 Gy in 39 fractions over 7·8 weeks or, following protocol amendment on March 24, 2016, 62 Gy in 20 fractions over 4 weeks) or SBRT (36·25 Gy in five fractions over 1-2 weeks). Androgen deprivation was not permitted. Co-primary outcomes for this toxicity analysis were Radiation Therapy Oncology Group (RTOG) grade 2 or worse gastrointestinal and genitourinary toxicity at 24 months after radiotherapy. Analysis was by treatment received and included all patients with at least one fraction of study treatment assessed for late toxicity. Recruitment is complete. Follow-up for oncological outcomes continues. The trial is registered with ClinicalTrials.gov, NCT01584258. FINDINGS: We enrolled and randomly assigned 874 men between Aug 7, 2012, and Jan 4, 2018 (441 to CRT and 433 to SBRT). In this analysis, 430 patients were analysed in the CRT group and 414 in the SBRT group; a total of 844 (97%) of 874 randomly assigned patients. At 24 months, RTOG grade 2 or worse genitourinary toxicity was seen in eight (2%) of 381 participants assigned to CRT and 13 (3%) of 384 participants assigned to SBRT (absolute difference 1·3% [95% CI -1·3 to 4·0]; p=0·39); RTOG grade 2 or worse gastrointestinal toxicity was seen in 11 (3%) of 382 participants in the CRT group versus six (2%) of 384 participants in the SBRT group (absolute difference -1·3% [95% CI -3·9 to 1·1]; p=0·32). No serious adverse events (defined as RTOG grade 4 or worse) or treatment-related deaths were reported within the analysis timeframe. INTERPRETATION: In the PACE-B trial, 2-year RTOG toxicity rates were similar for five fraction SBRT and conventional schedules of radiotherapy. Prostate SBRT was found to be safe and associated with low rates of side-effects. Biochemical outcomes are awaited. FUNDING: Accuray.

Intensity-modulated fractionated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): acute toxicity findings from an international, randomised, open-label, phase 3, non-inferiority trial.

BACKGROUND: Localised prostate cancer is commonly treated with external-beam radiotherapy. Moderate hypofractionation has been shown to be non-inferior to conventional fractionation. Ultra-hypofractionated stereotactic body radiotherapy would allow shorter treatment courses but could increase acute toxicity compared with conventionally fractionated or moderately hypofractionated radiotherapy. We report the acute toxicity findings from a randomised trial of standard-of-care conventionally fractionated or moderately hypofractionated radiotherapy versus five-fraction stereotactic body radiotherapy for low-risk to intermediate-risk localised prostate cancer. METHODS: PACE is an international, phase 3, open-label, randomised, non-inferiority trial. In PACE-B, eligible men aged 18 years and older, with WHO performance status 0-2, low-risk or intermediate-risk prostate adenocarcinoma (Gleason 4 + 3 excluded), and scheduled to receive radiotherapy were recruited from 37 centres in three countries (UK, Ireland, and Canada). Participants were randomly allocated (1:1) by computerised central randomisation with permuted blocks (size four and six), stratified by centre and risk group, to conventionally fractionated or moderately hypofractionated radiotherapy (78 Gy in 39 fractions over 7·8 weeks or 62 Gy in 20 fractions over 4 weeks, respectively) or stereotactic body radiotherapy (36·25 Gy in five fractions over 1-2 weeks). Neither participants nor investigators were masked to allocation. Androgen deprivation was not permitted. The primary endpoint of PACE-B is freedom from biochemical or clinical failure. The coprimary outcomes for this acute toxicity substudy were worst grade 2 or more severe Radiation Therapy Oncology Group (RTOG) gastrointestinal or genitourinary toxic effects score up to 12 weeks after radiotherapy. Analysis was per protocol. This study is registered with ClinicalTrials.gov, NCT01584258. PACE-B recruitment is complete and follow-up is ongoing. FINDINGS: Between Aug 7, 2012, and Jan 4, 2018, we randomly assigned 874 men to conventionally fractionated or moderately hypofractionated radiotherapy (n=441) or stereotactic body radiotherapy (n=433). 432 (98%) of 441 patients allocated to conventionally fractionated or moderately hypofractionated radiotherapy and 415 (96%) of 433 patients allocated to stereotactic body radiotherapy received at least one fraction of allocated treatment. Worst acute RTOG gastrointestinal toxic effect proportions were as follows: grade 2 or more severe toxic events in 53 (12%) of 432 patients in the conventionally fractionated or moderately hypofractionated radiotherapy group versus 43 (10%) of 415 patients in the stereotactic body radiotherapy group (difference -1·9 percentage points, 95% CI -6·2 to 2·4; p=0·38). Worst acute RTOG genitourinary toxicity proportions were as follows: grade 2 or worse toxicity in 118 (27%) of 432 patients in the conventionally fractionated or moderately hypofractionated radiotherapy group versus 96 (23%) of 415 patients in the stereotactic body radiotherapy group (difference -4·2 percentage points, 95% CI -10·0 to 1·7; p=0·16). No treatment-related deaths occurred. INTERPRETATION: Previous evidence (from the HYPO-RT-PC trial) suggested higher patient-reported toxicity with ultrahypofractionation. By contrast, our results suggest that substantially shortening treatment courses with stereotactic body radiotherapy does not increase either gastrointestinal or genitourinary acute toxicity. FUNDING: Accuray and National Institute of Health Research.

Does walking protect against decline in cognitive functioning among breast cancer patients undergoing chemotherapy? Results from a small randomised controlled trial.

BACKGROUND: Cancer related cognitive impairments have been subjectively reported and objectively detected in breast cancer patients treated with chemotherapy and are known to have a profound negative impact on productivity, psychosocial well-being and overall quality of life. Moderate levels of walking are known to be of benefit to the psychosocial well-being of those affected by breast cancer and for managing cognitive impairment in healthy adults, children, and the elderly. The purpose of this study is to investigate the effects of a home-based, self-managed, moderate intensity walking intervention on subjective and objective cognitive functioning in breast cancer patients undergoing chemotherapy. METHODS: A home-based, self-managed intervention that consisted of moderate levels of walking was compared to usual care among breast cancer patients treated with chemotherapy in a randomised controlled trial. Outcome measures included changes in subjective (CFQ) and objectively detected cognitive functioning (Stroop, SART and two subscales from the WAIS- Digit Span and Block Design). Fifty participants were randomised to either the intervention group (n = 25), who completed 12 weeks of moderate intensity walking, or to the control group (n = 25) mid-way through chemotherapy. RESULTS: Compared with the control group, the self-managed walking intervention had positive effects on perceived cognitive function but not on sustained attention, executive function, memory or visual spatial skills when assessed objectively using neuropsychological measures. CONCLUSION: This home-based, self-managed intervention is beneficial for protecting against perceived cognitive decline in breast cancer patients treated with chemotherapy. There is a need for further research to objectively assess cognitive decline within this population with larger sample sizes of patients. TRIAL REGISTRATION: Current Controlled Trials ISRCTN50709297.

Association of genetic polymorphisms of claudin-1 with small vessel vascular dementia.

The most recent hypothesis of the development of small vessel vascular dementia (VaD) emphasises the role of blood-brain barrier (BBB) dysfunction. It is hypothesised that certain genetic polymorphisms of the BBB tight junction claudin-1 protein, in combination with adverse environmental risk factors, increase the risk of BBB dysfunction and small vessel VaD. In this case-control study, 97 control participants, with a mean Mini Mental State Exam (MMSE) score of 29.1, and 38 VaD participants were recruited and completed a questionnaire on their medical history and lifestyle factors. Blood was also collected and two single nucleotide polymorphisms (SNPs), rs17501010 and rs893051 of claudin-1 genotyping, were analysed by real-time polymerase chain reaction (PCR) assay. A significantly higher frequency of all rs893051 SNP genotypes (GC and CC) was found in the VaD population (OR=4.8, P=0.006 and OR=6, P<0.001 respectively). Patients with TT genotype of rs17501010 were also more likely to have VaD (OR=3.25, P=0.022). Stratification analysis revealed that having combined haplotype GC+CC of rs893051 and lipid disorders was associated with higher risk of VaD (OR=9.9, P<0.001). For patients with type 2 diabetes the odds ratio of VaD increased significantly in GC+CC genotypes of rs893051 (OR=12.57, P<0.0001) and GT+TT of rs17501010 (OR=5.33, P=0.01).

Effects of a self-managed home-based walking intervention on psychosocial health outcomes for breast cancer patients receiving chemotherapy: a randomised controlled trial.

PURPOSE: This study evaluated the effectiveness of a self-managed home-based moderate intensity walking intervention on psychosocial health outcomes among breast cancer patients undergoing chemotherapy. METHODS: The randomised controlled trial compared a self-managed, home-based walking intervention to usual care alone among breast cancer patients receiving chemotherapy. Outcome measures included changes in self-report measures of anxiety, depression, fatigue, self-esteem, mood and physical activity. Fifty participants were randomised to either the intervention group (n = 25), who received 12 weeks of moderate intensity walking, or the control group (n = 25) mid-way through chemotherapy. Participants in the intervention group were provided with a pedometer and were asked to set goals and keep weekly diaries outlining the duration, intensity and exertion of their walking. Levels of psychosocial functioning and physical activity were assessed pre- and post-intervention in both groups. RESULTS: The intervention had positive effects on fatigue (F = 5.77, p = 0.02), self-esteem (F = 8.93, p ≤ 0.001), mood (F = 4.73, p = 0.03) and levels of physical activity (x (2) = 17.15, p = 0.0011) but not anxiety (F = 0.90, p = 0.35) and depression (F = 0.26, p = 0.60) as assessed using the HADS. We found an 80% adherence rate to completing the 12-week intervention and recording weekly logs. CONCLUSION: This self-managed, home-based intervention was beneficial for improving psychosocial well-being and levels of physical activity among breast cancer patients treated with chemotherapy. TRIAL REGISTRATION: Current Controlled Trials ISRCTN50709297.

Can physical activity help to maintain cognitive functioning and psychosocial well-being among breast cancer patients treated with chemotherapy? A randomised controlled trial: study protocol.

BACKGROUND: Evidence suggests chemotherapy treatment for breast cancer is associated with side effects such as cognitive impairment in domains of memory, attention, concentration and executive function. Cognitive impairments reported by patients have been associated with higher levels of emotional distress. To date, intervention studies to alleviate cognitive impairment associated with chemotherapy have focused on psycho-educational techniques or cognitive training. Studies have not yet considered physical activity as a potential for alleviating cognitive problems. Physical activity interventions are reported to be effective in alleviating emotional distress and fatigue in those with breast cancer. They have also been reported to improve cognitive functioning in the elderly, in those suffering with dementia and in children. We propose that physical activity could also help to alleviate cognitive impairments in women diagnosed with breast cancer. The study has been designed using a recently developed taxonomy of behaviour change techniques to reliably report the content of the intervention to allow future replication. METHOD: This study will deliver a home-based moderate intensity walking intervention to women diagnosed with breast cancer mid-way through their chemotherapy treatment and will compare them to patients receiving usual care alone. The primary outcome measure for this intervention is changes in an objective measure of memory assessed using the Digit Span. Secondary outcome measures include: objective measures of executive function; attention; visual spatial skills; self report cognitive function; self-report fatigue; anxiety; depression; mood and self-esteem. As emotional distress has been associated with self-reporting of cognitive problems, this intervention will further test whether emotional distress mediates between the amount of walking undertaken during the intervention period and levels of self-reported cognitive functioning. DISCUSSION: The development of an effective intervention for preventing difficulties in emotional and cognitive functioning of cancer patients' post-treatment will help to guide health care professionals to improve patients' overall quality of life. It will also provide direction for future research, ultimately to improve the day to day functioning of breast cancer survivors. TRIAL REGISTRATION: Current Controlled Trials ISRCTN50709297.

Radiotherapy for node positive penile cancer: experience of the Leeds teaching hospitals.

PURPOSE: We studied the outcomes in patients with node positive penile cancer who received radiotherapy to inguinal and pelvic nodes. Although half of node positive cases are cured by lymphadenectomy, little data are available on the potential further benefits and toxicities of postoperative radiotherapy. MATERIALS AND METHODS: We retrospectively audited the clinical notes and electronic records of 23 patients referred to a specialist center from 2002 to 2008 who received radiotherapy to the inguinal/pelvic nodes as adjuvant treatment after lymphadenectomy (14), or as high grade palliation for extensive/fixed nodes (8) or extensive local tumor (1). The primary outcome measure was overall survival. Secondary end points were locoregional recurrence-free survival and toxicity. RESULTS: All 13 deaths were due to penile cancer. Patients with adjuvant therapy had better overall survival (66% vs 11%, p<0.001) and locoregional relapse-free survival (56% vs 22%, p=0.03) than those with high grade palliation. Six of 14 adjuvant cases and 7 of 9 with high grade palliation relapsed locoregionally. Of patients with adjuvant therapy and extracapsular spread 1 of 6 with N1, 1 of 4 with N2 and 3 of 4 with N3 disease relapsed (p=0.31). No life threatening toxicity was observed. It was difficult to determine the relative contributions of radiotherapy and surgery to leg/scrotal lymphedema. The study was limited by its small size, which reflects the rarity of this tumor. CONCLUSIONS: Adjuvant radiotherapy appears to have a role after inguinal lymphadenectomy, particularly in patients with extracapsular nodal spread, in whom historically survival rates have been poor. Our findings warrant further investigation in larger series of patients.

A single centre experience with sequential and concomitant chemoradiotherapy in locally advanced stage IV tonsillar cancer.

BACKGROUND: Chemo-radiotherapy offers an alternative to primary surgery and adjuvant therapy for the management of locally advanced stage IV squamous cell carcinomas of the tonsil. METHODS: A retrospective analysis was performed of the outcomes of 41 patients with locoregionally advanced squamous cell carcinoma of the tonsil treated non-surgically at the Yorkshire Cancer Centre between January 2004 and December 2005. Due to long radiotherapy waiting times, patients received induction chemotherapy with cisplatin and 5-fluorouracil followed by either cisplatin concurrent chemoradiotherapy or radiotherapy alone. RESULTS: Median age was 55 years (range 34-76 years) and 28 (68%) patients were male. 35/41 patients (85%) received 2 or more cycles of induction chemotherapy. Following induction chemotherapy, 32/41 patients (78%) had a clinical response. Concomitant chemotherapy was given to 30/41 (73%). All patients received the planned radiotherapy dose with no delays. There were no treatment related deaths. Six (15%) patients had gastrostomy tubes placed before treatment, and 22 (54%) required nasogastric tube placement during or after treatment for nutritional support. 17 patients required unplanned admissions during treatment for supportive care. At 4 months post treatment assessment 35 out of 41 (85%) patients achieved complete clinical and radiographic response. Median follow-up is 38 months (8-61 months). Local and regional control rate in complete responders at 3 years was 91%. Distant metastases have been found in 4 (9.8%) patients. Three year progression-free survival rate in all patients is 75%. The 3-year cause specific survival and overall survival are 75% and 66% respectively. CONCLUSION: Cisplatin-based induction and concurrent chemoradiotherapy provides excellent tumour control with acceptable toxicity for patients with locally advanced tonsillar cancer.