Current pediatric cancer survivorship practices: a report from the Children's Oncology Group.

PURPOSE: The purpose of this study is to describe current survivor services provided by COG institutions. METHODS: A 190-question online survey was distributed to 209 COG member institutions over a 5-month period in 2017. Descriptive statistics were used to describe survivor services and explore their changes between 2007 and 2017. RESULTS: Representatives from 153 (73%) institutions completed the survey. Of these, 96% of institutions reported that they provide pediatric cancer survivor care either in a specialized late effects program (75%) or a regular pediatric oncology clinic (24%). However, only 29.8% of institutions reported that > 75% of eligible patients were seen in a survivorship clinic. The most prevalent reported barriers to survivor care were lack of dedicated time (58%) and lack of funding for program development (41%). In 2017, 88% of institutions provided a treatment summary compared to 31% in 2007. CONCLUSION: The majority of COG institutions have dedicated care for pediatric and young adult survivors of childhood cancer; however, at most institutions, < 75% of eligible patients access this care. Research into more efficient technology strategies is needed to ensure all survivors the opportunity to receive appropriate follow-up care. IMPLICATIONS FOR CANCER SURVIVORS: This survey provides a snapshot of the status of late effects services within COG institutions and provides information on residual gaps in services. Next steps should focus on the importance of attendance in a survivorship clinic on the physical health and psychosocial outcomes in cancer survivors.

Subcutaneous Adipose Tissue Metabolic Function and Insulin Sensitivity in People With Obesity.

We used stable isotope-labeled glucose and palmitate tracer infusions, a hyperinsulinemic-euglycemic clamp, positron emission tomography of muscles and adipose tissue after [18F]fluorodeoxyglucose and [15O]water injections, and subcutaneous adipose tissue (SAT) biopsy to test the hypotheses that 1) increased glucose uptake in SAT is responsible for high insulin-stimulated whole-body glucose uptake in people with obesity who are insulin sensitive and 2) putative SAT factors thought to cause insulin resistance are present in people with obesity who are insulin resistant but not in those who are insulin sensitive. We found that high insulin-stimulated whole-body glucose uptake in insulin-sensitive participants with obesity was not due to channeling of glucose into SAT but, rather, was due to high insulin-stimulated muscle glucose uptake. Furthermore, insulin-stimulated muscle glucose uptake was not different between insulin-sensitive obese and lean participants even though adipocytes were larger, SAT perfusion and oxygenation were lower, and markers of SAT inflammation, fatty acid appearance in plasma in relation to fat-free mass, and plasma fatty acid concentration were higher in the insulin-sensitive obese than in lean participants. In addition, we observed only marginal or no differences in adipocyte size, SAT perfusion and oxygenation, and markers of SAT inflammation between insulin-resistant and insulin-sensitive obese participants. Plasma fatty acid concentration was also not different between insulin-sensitive and insulin-resistant obese participants, even though SAT was resistant to the inhibitory effect of insulin on lipolysis in the insulin-resistant obese group. These data suggest that several putative SAT factors commonly implicated in causing insulin resistance are normal consequences of SAT expansion unrelated to insulin resistance.

Heterogeneity in insulin-stimulated glucose uptake among different muscle groups in healthy lean people and people with obesity.

AIMS/HYPOTHESIS: It has been proposed that muscle fibre type composition and perfusion are key determinants of insulin-stimulated muscle glucose uptake, and alterations in muscle fibre type composition and perfusion contribute to muscle, and consequently whole-body, insulin resistance in people with obesity. The goal of the study was to evaluate the relationships among muscle fibre type composition, perfusion and insulin-stimulated glucose uptake rates in healthy, lean people and people with obesity. METHODS: We measured insulin-stimulated whole-body glucose disposal and glucose uptake and perfusion rates in five major muscle groups (erector spinae, obliques, rectus abdominis, hamstrings, quadriceps) in 15 healthy lean people and 37 people with obesity by using the hyperinsulinaemic-euglycaemic clamp procedure in conjunction with [2H]glucose tracer infusion (to assess whole-body glucose disposal) and positron emission tomography after injections of [15O]H2O (to assess muscle perfusion) and [18F]fluorodeoxyglucose (to assess muscle glucose uptake). A biopsy from the vastus lateralis was obtained to assess fibre type composition. RESULTS: We found: (1) a twofold difference in glucose uptake rates among muscles in both the lean and obese groups (rectus abdominis: 67 [51, 78] and 32 [21, 55] µmol kg-1 min-1 in the lean and obese groups, respectively; erector spinae: 134 [103, 160] and 66 [24, 129] µmol kg-1 min-1, respectively; median [IQR]) that was unrelated to perfusion or fibre type composition (assessed in the vastus only); (2) the impairment in insulin action in the obese compared with the lean group was not different among muscle groups; and (3) insulin-stimulated whole-body glucose disposal expressed per kg fat-free mass was linearly related with muscle glucose uptake rate (r2 = 0.65, p < 0.05). CONCLUSIONS/INTERPRETATION: Obesity-associated insulin resistance is generalised across all major muscles, and is not caused by alterations in muscle fibre type composition or perfusion. In addition, insulin-stimulated whole-body glucose disposal relative to fat-free mass provides a reliable index of muscle glucose uptake rate.

Trends and Correlates of Mean Lung Dose in Patients Receiving Breast Radiotherapy in a Single Institution from 2014 to 2018.

AIMS: Higher mean lung dose (MLD) in breast cancer patients has been associated with pneumonitis, pulmonary fibrosis and secondary lung cancer primaries. This study examined MLD in a single institution from 2014 to 18 to assess trends in median MLD (Gy) over time and factors associated with higher MLD to determine best practices for limiting lung toxicity. MATERIALS AND METHODS: General linear regressions were analysed to determine significant change in median MLD over time in patients receiving conventional or hypofractionated schedules for whole breast/chest wall (WB) radiotherapy with or without sequential boost or simultaneous integrated boost, WB tangential radiotherapy only and WB locoregional radiotherapy. Univariate and multivariable linear regression analysed identified factors associated with MLD. RESULTS: In total, 3894 patients were included in the analysis. The total median MLD across all years was 6.8 Gy in patients treated with conventional fractionation and 3.4 Gy in patients treated with hypofractionation. A significant increase in MLD was observed between 2014 and 2018 in patients receiving conventional or hypofractionation, conventional WB treatment with locoregional radiotherapy, conventional WB radiotherapy with simultaneous integrated boost and hypofractionated WB radiotherapy with sequential boost. Increased MLD was significantly correlated with lower lung volume and larger treatment volume due to locoregional radiotherapy, inclusion of a boost, chest wall treatment and reverse decubitus or supine positioning (P < 0.0001). CONCLUSION: A significant increase in MLD was observed over the years in patients receiving conventional and hypofractionated radiotherapy. Techniques such as prone positioning should be considered to lower MLD, particularly for patients with predisposing pulmonary risk.

COVID-19: Initial experience of an international group of hand surgeons.

The emergence of the COVID-19 pandemic has severely affected medical treatment protocols throughout the world. While the pandemic does not affect hand surgeons at first glance, they have a role to play. The purpose of this study was to describe the different measures that have been put in place in response to the COVID-19 pandemic by hand surgeons throughout the world. The survey comprised 47 surgeons working in 34 countries who responded to an online questionnaire. We found that the protocols varied in terms of visitors, health professionals in the operating room, patient waiting areas, wards and emergency rooms. Based on these preliminary findings, an international consensus on hand surgery practices for the current viral pandemic, and future ones, needs to be built rapidly.

Framing of the opioid problem in cancer pain management in Canada.

Two guidelines about opioid use in chronic pain management were published in 2017: the Canadian Guideline for Opioids for Chronic Non-Cancer Pain and the European Pain Federation position paper on appropriate opioid use in chronic pain management. Though the target populations for the guidelines are the same, their recommendations differ depending on their purpose. The intent of the Canadian guideline is to reduce the incidence of serious adverse effects. Its goal was therefore to set limits on the use of opioids. In contrast, the European Pain Federation position paper is meant to promote safe and appropriate opioid use for chronic pain. The content of the two guidelines could have unintentional consequences on other populations that receive opioid therapy for symptom management, such as patients with cancer. In this article, we present expert opinion about those chronic pain management guidelines and their impact on patients with cancer diagnoses, especially those with histories of substance use disorder and psychiatric conditions. Though some principles of chronic pain management can be extrapolated, we recommend that guidelines for cancer pain management should be developed using empirical data primarily from patients with cancer who are receiving opioid therapy.

Treatment Outcomes in Male Breast Cancer: A Retrospective Analysis of 161 Patients.

AIMS: Male breast cancer is a rare disease with limited evidence-based guidelines for treatment. This study aimed to identify demographic, pathological and clinical factors associated with its prognosis. MATERIALS AND METHODS: A retrospective review of 161 male breast cancer patients diagnosed at a single institution from 1987 to June 2017 was conducted. Patient demographics, disease characteristics, treatment and outcome were extracted and included in competing-risk analysis and the univariate Cox proportional hazard model for univariate analysis. Factors with P < 0.10 were included in multivariable analysis. RESULTS: The mean age at diagnosis was 67 years (standard deviation = 11.2) and the median follow-up duration was 5.3 years (range 0-25 years). There were 48 deaths, including 23 cancer-specific deaths. The actuarial median survival was 19.9 years. In multivariable analysis, factors associated with overall survival were size of tumours (hazard ratio 2.0; 95% confidence interval 1.4-2.7, P < 0.0001) and diagnosis of metastatic disease (hazard ratio 8.7; 95% confidence interval 1.9-40.6; P = 0.006). Of 138 patients without metastases at diagnoses, 11 had local-regional recurrence and 26 had distant metastases. In the multivariable model for local-regional recurrence, a more recent year of diagnosis was associated with reduced risk (hazard ratio 0.9, 95% confidence interval 0.8-1.0, P = 0.008), whereas more positive lymph nodes was associated with higher risk (hazard ratio 2.2, 95% confidence interval 1.2-4.0, P = 0.01). A higher risk of metastases was associated with more positive lymph nodes (hazard ratio 1.9; 95% confidence interval 1.1-3.3; P = 0.03) and tumour size (hazard ratio 1.8; 95% confidence interval 1.1-2.9; P = 0.01). A higher risk of any recurrence or metastases was associated with the number of positive nodes (hazard ratio 1.9; 95% confidence interval 1.2-3.0; P = 0.005) and tumour size (hazard ratio 1.6; 95% confidence interval 1.1-2.2; P = 0.01). CONCLUSION: In general, tumour size and more positive lymph nodes were associated with worse prognosis. Larger powered studies are needed to identify prognostic factors with smaller effect sizes.

High risk of conversion to diabetes in first-degree relatives of individuals with young-onset type 2 diabetes: a 12-year follow-up analysis.

AIM: Family history of diabetes is an established risk factor for Type 2 diabetes, but the impact of a family history of young-onset diabetes (onset < 40 years) on future risk of diabetes among first-degree relatives is unclear. In this prospective study, we examined the influence of family history of late- versus young-onset diabetes on the development of diabetes in a young to middle-aged Chinese population. METHODS: Some 365 siblings identified through probands with Type 2 diabetes and 452 participants from a community-based health awareness project (aged 18-55 years) who underwent metabolic assessment during the period 1998-2002 were followed to 2012-2013 to determine their glycaemic status. Multivariate logistic regression was performed to investigate the association of family history of diabetes presented at different age categories with development of diabetes. RESULTS: In this cohort, 53.4% (n = 167) of participants with a family history of young-onset diabetes, 30.1% (n = 68) of those with a family history of late-onset diabetes and 14.4% (n = 40) of those without a family history developed diabetes. Using logistic regression, family history of diabetes presented at ages ≥ 50, 40-49, 30-39 and < 30 years, increased conversion to diabetes with respective odds ratios of 2.4, 5.8, 9.4 and 7.0 (P < 0.001 for all), after adjustment for socio-economic status, smoking, obesity, hypertension and dyslipidaemia. Among participants without diabetes at baseline, risk association of family history of late-onset diabetes with incident diabetes was not sustained, whereas that of family history of young-onset diabetes remained robust on further adjustment for baseline glycaemic measurements. CONCLUSIONS: First-degree relatives of people with Type 2 diabetes, especially relatives of those with young-onset diabetes, are at high risk for diabetes.

Asymptomatic and symptomatic urethral gonorrhoea in men who have sex with men attending a sexual health service.

OBJECTIVES: Guidelines regarding whether men who have sex with men (MSM) without symptoms of urethritis should be screened for urethral gonorrhoea differ between countries. We examined the rate of asymptomatic urethral gonorrhoea in MSM using sensitive nucleic acid amplification testing. METHODS: This study was conducted on consecutive MSM attending the Melbourne Sexual Health Centre between July 2015 and May 2016 for sexually transmitted infections screening. Gonorrhoea testing with the Aptima Combo 2 (AC2) assay was performed on all urine specimens obtained from MSM, whether symptoms of urethritis were present or not. Men were classified as having: typical discharge if they reported symptoms suggesting purulent discharge; other symptoms if they reported other symptoms of urethritis; and no symptoms if they reported no urethral symptoms. RESULTS: During the study period, there were 7941 clinic visits by 5947 individual MSM with 7090 urine specimens obtained from 5497 individual MSM tested with the AC2 assay. Urethral gonorrhoea was detected in 242 urine specimens from 228 individual MSM. The majority (189/242, 78%, 95% CI 73-83) reported typical discharge, 27/242 (11%, 95% CI 8-16) reported other urethral symptoms, and 26/242 (11%, 95% CI 7-15) reported no symptoms on the day of presentation and testing. Among men with urethral gonorrhoea, the proportions with concurrent pharyngeal or rectal gonorrhoea were 32% (134/210) and 64% (74/235), respectively. The mean interval between last reported sexual contact and onset of typical urethral discharge, where present, was 3.9 days. CONCLUSION: The findings from our study lend support to guidelines that recommend screening asymptomatic MSM for urethral gonorrhoea.

Does the Time of Radiotherapy Affect Treatment Outcomes? A Review of the Literature.

Circadian rhythm-dependent cell cycle progression produces daily variations in radiosensitivity. This literature review aims to summarise the data on whether radiotherapy outcomes differ depending on administration time. A literature search was conducted on Ovid Medline, Embase, Cochrane Central Register of Controlled Trials and PubMed using key words such as 'radiotherapy', 'circadian rhythm', 'treatment outcome' and 'survival'. Articles evaluating the correlation between radiotherapy time and outcomes in cancer patients were included and relevant information was extracted. Nine studies met the inclusion criteria. Four investigated lung cancer patients undergoing stereotactic radiosurgery for brain metastases, with one study observing improved local control and survival in patients treated in the morning. Another two studies with breast and cervical cancer patients observed that the prevalence of toxicities was higher in afternoon and morning cohorts, respectively. Two studies in head and neck cancer patients found trends indicating morning patients experienced less oral mucositis. Increased toxicities and biochemical failure rates were associated with evening treatment in prostate cancer patients. As inconsistencies in the literature exist regarding the time dependency of radiotherapy outcomes, further investigation is warranted.

Painless neutropenic enterocolitis in a patient undergoing chemotherapy.

CASE DESCRIPTION: A 60-year-old man developed painless neutropenic enterocolitis after induction chemotherapy for newly diagnosed acute myelogenous leukemia. The patient had recurrent fever while neutropenic, without experiencing abdominal pain or tenderness on physical examination. His diagnosis was delayed by the fact that he had no localizing symptoms. DISCUSSION: Neutropenic enterocolitis is a common complication, generally occurring in patients who are severely neutropenic; the condition presents with fever and abdominal pain. No cases of painless neutropenic enterocolitis have yet been reported. Review of the literature shows that patients can develop this condition in the absence of fever and, sometimes, neutropenia. Furthermore, few comprehensive studies or reviews have investigated the utility of computed tomography imaging in identifying a source for abdominal pain in neutropenic patients with fever. SUMMARY: Many potential causes of febrile neutropenia should be considered in chemotherapy patients.

Depletion of Abundant Sequences by Hybridization (DASH): using Cas9 to remove unwanted high-abundance species in sequencing libraries and molecular counting applications.

Next-generation sequencing has generated a need for a broadly applicable method to remove unwanted high-abundance species prior to sequencing. We introduce DASH (Depletion of Abundant Sequences by Hybridization). Sequencing libraries are 'DASHed' with recombinant Cas9 protein complexed with a library of guide RNAs targeting unwanted species for cleavage, thus preventing them from consuming sequencing space. We demonstrate a more than 99 % reduction of mitochondrial rRNA in HeLa cells, and enrichment of pathogen sequences in patient samples. We also demonstrate an application of DASH in cancer. This simple method can be adapted for any sample type and increases sequencing yield without additional cost.

A Risk Index for Living Donor Kidney Transplantation.

Choosing between multiple living kidney donors, or evaluating offers in kidney paired donation, can be challenging because no metric currently exists for living donor quality. Furthermore, some deceased donor (DD) kidneys can result in better outcomes than some living donor kidneys, yet there is no way to compare them on the same scale. To better inform clinical decision-making, we created a living kidney donor profile index (LKDPI) on the same scale as the DD KDPI, using Cox regression and adjusting for recipient characteristics. Donor age over 50 (hazard ratio [HR] per 10 years = 1.15 1.241.33 ), elevated BMI (HR per 10 units = 1.01 1.091.16 ), African-American race (HR = 1.15 1.251.37 ), cigarette use (HR = 1.09 1.161.23 ), as well as ABO incompatibility (HR = 1.03 1.271.58 ), HLA B (HR = 1.03 1.081.14 ) mismatches, and DR (HR = 1.04 1.091.15 ) mismatches were associated with greater risk of graft loss after living donor transplantation (all p < 0.05). Median (interquartile range) LKDPI score was 13 (1-27); 24.2% of donors had LKDPI < 0 (less risk than any DD kidney), and 4.4% of donors had LKDPI > 50 (more risk than the median DD kidney). The LKDPI is a useful tool for comparing living donor kidneys to each other and to deceased donor kidneys.

Duration of syphilis symptoms at presentations in men who have sex with men in Australia: are current public health campaigns effective?

The rapid rise in syphilis cases has prompted a number of public health campaigns to assist men who have sex with men (MSM) recognize and present early with symptoms. This study aimed to investigate the temporal trend of the duration of self-report symptoms and titre of rapid plasma reagin (RPR) in MSM with infectious syphilis. Seven hundred and sixty-one syphilis cases in MSM diagnosed at the Melbourne Sexual Health Centre (MSHC) from 2007-2013 were reviewed. Median duration of symptoms and RPR titres in each year were calculated. The median durations of symptoms with primary and secondary syphilis were 9 [interquartile range (IQR) 6-14] days and 14 (IQR 7-30) days, respectively. The overall median titre of RPR in secondary syphilis (median 128, IQR 64-256) was higher than in primary syphilis (median 4, IQR 1-32) and in early latent syphilis (median 32, IQR 4-64). The median duration of symptoms for primary syphilis, secondary syphilis and titre of RPR level did not change over time. Public health campaigns were not associated with a significant shorter time from onset of symptoms to treatment. Alternative strategies such as more frequent testing of MSM should be promoted to control the syphilis epidemic in Australia.

E3 ligase EDD1/UBR5 is utilized by the HPV E6 oncogene to destabilize tumor suppressor TIP60.

Tat-interacting protein of 60 kDa (TIP60) is an essential lysine acetyltransferase implicated in transcription, DNA damage response and apoptosis. TIP60 protein expression is reduced in cancers. In cervical cancers, human papillomavirus (HPV) E6 oncogene targets cellular p53, Bak and some of the PDZ domain-containing proteins for proteasome-mediated degradation through E6AP ligase. Recently, E6 oncogene from high-risk and low-risk categories was also shown to target TIP60. However, the molecular mechanisms and whether destabilization of TIP60 contributes to HPV E6-mediated transformation remain unanswered. Our proteomic analyses revealed EDD1 (E3 identified by differential display), an E3 ligase generally overexpressed in cancers as a novel interacting partner of TIP60. By investigating protein turnover and ubiquitination assays, we show that EDD1 negatively regulates TIP60's stability through the proteasome pathway. Strikingly, HPV E6 uses this function of EDD1 to destabilize TIP60. Colony-formation assays and soft agar assays show that gain of function of TIP60 or depletion of EDD1 in HPV-positive cervical cancer cells significantly inhibits cell growth in vitro. This phenotype is strongly supported by the in-vivo studies where re-activation of TIP60 in cervical cancer cells dramatically reduces tumor formation. In summary, we have discovered a novel ligase through which E6 destabilizes TIP60. Currently, in the absence of an effective therapeutic vaccine for malignant cervical cancers, cervical cancer still remains to be a major disease burden. Hence, our studies implying a distinct tumor suppressor role for TIP60 in cervical cancers show that reactivation of TIP60 could be of therapeutic value.