Active surveillance selection and 3-year durability in intermediate-risk prostate cancer following genomic testing.

BACKGROUND: Genomic testing can add risk stratification information to clinicopathological features in prostate cancer, aiding in shared medical decision-making between the clinician and patient regarding whether active surveillance (AS) or definitive treatment (DT) is most appropriate. Here we examined initial AS selection and 3-year AS durability in patients diagnosed with localized intermediate-risk prostate cancer who underwent Prolaris testing before treatment decision-making. METHODS: This retrospective observational cohort study included 3208 patients from 10 study sites who underwent Prolaris testing at diagnosis from September 2015 to December 2018. Prolaris utilizes a combined clinical cell cycle risk score calculated at diagnostic biopsy to stratify patients by the Prolaris AS threshold (below threshold, patient recommended to AS or above threshold, patient recommended to DT). AS selection rates and 3-year AS durability were compared in patients recommended to AS or DT by Prolaris testing. Univariable and multivariable logistic regression models and Cox proportional hazard models were used with molecular and clinical variables as predictors of initial treatment decision and AS durability, respectively. RESULTS: AS selection was ~2 times higher in patients recommended to AS by Prolaris testing than in those recommended to DT (p < 0.0001). Three-year AS durability was ~1.5 times higher in patients recommended to AS by Prolaris testing than in those recommended to DT (p < 0.0001). Prolaris treatment recommendation remained a statistically significant predictor of initial AS selection and AS durability after accounting for CAPRA or Gleason scores. CONCLUSIONS: Prolaris added significant information to clinical risk stratification to aid in treatment decision making. Intermediate-risk prostate cancer patients who were recommended to AS by Prolaris were more likely to initially pursue AS and were more likely to remain on AS at 3 years post-diagnosis than patients recommended to DT.

Using the Cell-Cycle Risk Score to Predict the Benefit of Androgen-Deprivation Therapy Added to Radiation Therapy in Patients With Newly Diagnosed Prostate Cancer.

PURPOSE: Guidelines recommend adding androgen-deprivation therapy (ADT) to radiation therapy (RT) in certain patients with localized prostate cancer. Individualized genomic testing may improve the prognostic accuracy of risk assessments. Herein, we describe a mathematical model of the benefit of adding ADT to RT as a function of the personalized clinical cell-cycle risk (CCR) score to inform 10-year metastasis risk. METHODS: A model of absolute risk reduction (ARR) was built using a retrospective cohort of men tested with Prolaris who received RT alone (N = 467). The relative benefit of ADT added to RT to reduce distant metastasis was estimated at 41% on the basis of a meta-analysis of randomized trials. The ARR and number needed to treat (NNT) were computationally derived in patients clinically tested with Prolaris between January 1, 2020, and October 31, 2022 (N = 56,485). Risks were predicted using a cause-specific Cox proportional hazards model with CCR score predicting time to metastasis. A CCR score of 2.112 represents the validated multimodal treatment (MMT) threshold. RESULTS: The ARR from ADT increased from almost zero at low CCR scores to 17.1% at CCR = 3.690 with the corresponding NNT = 6, indicating that adding ADT to RT would prevent metastasis within 10 years for one of every six treated individuals. In the clinical cohort, the average ARR was 0.86% in individuals under the MMT threshold (NNT = 116). The average ARR was 8.19% in individuals above the MMT threshold (NNT = 12). Broad ranges of ADT benefit were observed within National Comprehensive Cancer Network risk categories. CONCLUSION: The precise and personalized risk estimate of metastasis provided by the CCR score can help inform patients and physicians when considering treatment intensification.

Multi-omic features of oesophageal adenocarcinoma in patients treated with preoperative neoadjuvant therapy.

Oesophageal adenocarcinoma is a poor prognosis cancer and the molecular features underpinning response to treatment remain unclear. We investigate whole genome, transcriptomic and methylation data from 115 oesophageal adenocarcinoma patients mostly from the DOCTOR phase II clinical trial (Australian New Zealand Clinical Trials Registry-ACTRN12609000665235), with exploratory analysis pre-specified in the study protocol of the trial. We report genomic features associated with poorer overall survival, such as the APOBEC mutational and RS3-like rearrangement signatures. We also show that positron emission tomography non-responders have more sub-clonal genomic copy number alterations. Transcriptomic analysis categorises patients into four immune clusters correlated with survival. The immune suppressed cluster is associated with worse survival, enriched with myeloid-derived cells, and an epithelial-mesenchymal transition signature. The immune hot cluster is associated with better survival, enriched with lymphocytes, myeloid-derived cells, and an immune signature including CCL5, CD8A, and NKG7. The immune clusters highlight patients who may respond to immunotherapy and thus may guide future clinical trials.

Hereditary cancer risk assessment and genetic testing in the community urology practice setting.

OBJECTIVES: To evaluate the feasibility of integrating a hereditary cancer risk assessment (HCRA) process in the community urology practice setting for patients with prostate cancer (PCa). METHODS: In this prospective intervention, an HCRA process was implemented across six different community urology clinics between May 2019 and April 2020. The intervention included a process integration during which the workflow at each site was refined, a post-integration period during which HCRA was conducted in all patients with PCa, and a follow-up period during which healthcare providers and patients reported their satisfaction with the HCRA and genetic testing process. RESULTS: Among patients who completed a family history assessment during the post-integration period, 23.6% met guideline criteria for genetic testing. Of all patients seen at the clinic during the post-integration period, 8.7% completed genetic testing; this was a twofold increase over the period immediately preceding process integration (4.2%), and a sevenfold increase over the same period 1 year prior (1.2%). The majority of providers reported that the HCRA was as important as other regularly performed assessments (61.0%) and planned to continue using the process in their practice (68.3%). Most patients believed that the genetic test results were important for their future cancer care (84.7%) and had already shared their test results with at least one family member (63.2%). CONCLUSIONS: This study demonstrated that implementing an HCRA process in the community urology practice setting was feasible, generally favored by providers and patients, and resulted in an increase in the number of patients with PCa who completed genetic testing.

A prospective study of the impact of fluorodeoxyglucose positron emission tomography with concurrent non-contrast CT scanning on the management of operable pancreatic and peri-ampullary cancers.

BACKGROUND: The role of fluorodeoxyglucose (FDG) positron emission tomography (PET/CT) scanning in operable pancreas cancer is unclear. We, therefore, wanted to investigate the impact of PET/CT on management, by incorporating it into routine work-up. METHODS: This was a single-institution prospective study. Patients with suspected and potentially operable pancreas, distal bile duct or ampullary carcinomas underwent PET/CT in addition to routine work-up. The frequency that PET/CT changed the treatment plan or prompted other investigations was determined. The distribution of standard uptake values (SUV) among primary tumours, and adjacent to biliary stents was characterised. RESULTS: Fifty-six patients were recruited. The surgical plan was abandoned in 9 (16%; 95% CI: 6-26) patients as a result of PET/CT identified metastases. In four patients, metastases were missed and seven were inoperable at surgery, not predicted by PET/CT. Unexpected FDG uptake resulted in seven additional investigations, of which two were useful. Among primary pancreatic cancers, a median SUV was 4.9 (range 2-12.1). SUV was highest around the biliary stent in 17 out of 28 cases. PET/CT detected metastases in five patients whose primary pancreatic tumours demonstrated mild to moderate avidity (SUV < 5). CONCLUSIONS: PET/CT in potentially operable pancreas cancer has limitations. However, as a result of its ability to detect metastases, PET/CT scanning is a useful tool in the selection of such patients for surgery.

Spontaneous intrahepatic haemorrhage: two cases of segmental arterial mediolysis.

BACKGROUND: Segmental arterial mediolysis (SAM) is an under-recognized degenerative vascular disorder with variable clinical presentations. It affects medium to large calibre arteries, typically those arising from the coeliac axis, and its diagnosis is complicated by overlap with other clinical entities like fibromuscular dysplasia. Diagnosis requires histopathological examination of the affected tissue, although radiographic appearances can be suggestive of SAM. METHODS: We report on two patients presenting with acute rupture of an intrahepatic artery affected by SAM. RESULTS: Both patients ultimately required right hemi-hepatectomy in order to either control ongoing bleeding or for removal of liver rendered ischaemic by intra-arterial embolization. This was achieved safely despite additional SAM lesions present throughout the vasculature. CONCLUSION: In both cases described, presentation followed recent, unrelated abdominal surgery and we propose a link between these two events. Recent research has identified the potential role of noradrenaline in the development of SAM lesions in greyhounds, with levels of endogenous noradrenaline known to rise in the setting of surgery.

A Royal Chartered College joins Chiropractic & Manual Therapies.

From January 2013, The UK College of Chiropractors joins the partnership between the Chiropractic and Osteopathic College of Australasia (COCA) and the European Academy of Chiropractic (EAC) to publish Chiropractic & Manual Therapies. This new partnership will enable the journal to grow and flourish and further improve access to high quality research publications for interested researchers and clinicians worldwide.

Ionized calcium levels in umbilical cord blood of women with preeclampsia and normotensive pregnancies.

Calcium is essential for normal fetal growth and development. During intrauterine life, the fetus is entirely dependent on the mother and a normally functioning placenta for calcium accretion. Preeclampsia is associated with abnormal calcium metabolism and placental dysfunction. The objective of our study was to investigate ionized calcium levels in the umbilical cord arterial blood of women with preeclampsia and normotensive pregnancies. There were 24 women in the preeclampsia group and 25 in the normotensive group. There was no difference in the cord pH and fetal growth restriction between the two groups. Ionized calcium levels were significantly lower in the preeclampsia group (p < 0.001). Our results emphasize the need for further studies on the calcium status of infants born to mothers with preeclampsia.

Does the use of primary continuous positive airway pressure reduce the need for intubation and mechanical ventilation in infants ≤32 weeks' gestation?

BACKGROUND: Ventilator-induced lung injury is a recognized risk factor for bronchopulmonary dysplasia. OBJECTIVE: To determine whether primary continuous positive airway pressure (CPAP), defined as CPAP without previous endotracheal intubation for any indication, can reduce the need for intubation and mechanical ventilation in infants born at ≤32 weeks' gestational age. METHODS: The literature was reviewed using the methodology for systematic reviews for the Consensus on Resuscitation Science adapted from the American Heart Association's International Liaison Committee on Resuscitation. RESULTS: Fourteen studies were reviewed. Eleven studies provided varying degrees of supportive evidence (level of evidence 3 to 4) that the use of primary CPAP can reduce the need for intubation and mechanical ventilation. CONCLUSION: The use of CPAP as a primary intervention and mode of respiratory support is an option for infants ≤32 weeks' gestation, but avoidance of intubation and mechanical ventilation is more likely in mature infants >27 weeks' gestation.

Hepatic resection for colorectal metastasis: impact of tumour size.

BACKGROUND: Many colorectal liver metastasis patients are denied surgical resection on the basis of tumour size. The aim of this study was to explore the impact of metastasis size on modern liver resection. METHODS: Using a prospectively collected database, this was a retrospective analysis of 484 consecutive patients who underwent liver resection for colorectal liver metastases between 1993 and 2003. The cohort was divided into two groups: smaller metastases (< 8 cm) and larger metastases (> or = 8 cm). Those with larger metastases were then further stratified into big metastases (8-12 cm) and giant metastases (> 12 cm). Demographic, pathological, surgical technique and outcome data were compared between the groups. RESULTS: There were 88 (18%) patients with metastases measuring 8 cm or larger. There was an association between higher carcinoembryonic antigen (CEA) and cancer antigen (CA) 19-9 levels and larger metastases. The actuarial 5-year survival for patients with larger metastases was 38% compared with 42% for smaller metastases (not statistically significant). Patients with giant metastases had poorer overall and disease-free survival (both nonsignificant) compared with those with big metastases: 29% and 28% at 5 years, respectively. CONCLUSION: Patients with colorectal liver metastasis greater than 8 cm and up to 12 cm in size should not be treated differently from those with smaller lesions.

Familial adenomatous polyposis and mental retardation caused by a de novo chromosomal deletion at 5q15-q22: report of a case.

Familial adenomatous polyposis, caused by mutations in the adenomatous polyposis coli gene located at chromosome 5q21, is an autosomal dominant syndrome characterized by polyposis of the colon and rectum and nearly 100 percent progression to colorectal cancer. We report a case of familial adenomatous polyposis and mental retardation caused by a chromosomal deletion at 5q15-q22. Chromosomal analysis is considered part of the evaluation of children with mental retardation and developmental delay. The resulting karyotypes from high-resolution chromosomal analysis can help characterize large deletions, some of which involve known tumor suppressor genes. Because familial adenomatous polyposis may arise from de novo chromosomal deletions involving the adenomatous polyposis coli gene locus, individuals with chromosomal deletions involving 5q21 should be considered at-risk for familial adenomatous polyposis and offered standard screening with flexible sigmoidoscopy by 10 to 12 years of age.

Laparoscopic gastric banding and crural repair in the obese patient with a hiatal hernia.

BACKGROUND: A hiatal hernia is present in up to 50% of patients undergoing bariatric surgery. It has been claimed that laparoscopic adjustable gastric banding (LAGB) can both improve and induce reflux symptoms. The effect of a simultaneous crural repair and gastric banding has not yet been reported. METHODS: Since 1999, all patients undergoing LAGB have a simultaneous crural repair if a hiatal hernia is present. Gastroesophageal reflux disease and dysphagia were assessed preoperatively and postoperatively using the modified DeMeester symptom-scoring system and the use of anti-reflux medication. RESULTS: 62 patients with a hiatal hernia have undergone simultaneous LAGB and crural repair, with a median follow up of 14 (3-38) months. There was no mortality, and complications occurred in 3 patients, namely pulmonary embolus, slippage requiring repositioning of the band and persistent dysphagia requiring band removal. 24 months following LAGB and crural repair, median BMI had fallen from 43 to 31 kg/m2 and median excess weight loss was 53%. Modified DeMeester symptom-score fell from a preoperative median of 3 (0-5) to a postoperative median of 0 (0-2) (P < 0.01, Mann Whitney U), and the number of patients on anti-reflux medication decreased from 44 to 6 (P < 0.01, Chi-squared). CONCLUSION: Crural repair in addition to LAGB does not increase the risk of slippage or dysphagia, significantly improves reflux symptoms and decreases the need for anti-reflux medication.

Autosomal dominant infantile gastroesophageal reflux disease: exclusion of a 13q14 locus in five well characterized families.

OBJECTIVES: A genetic locus for pediatric reflux was proposed on chromosome 13q14, but is unconfirmed in independent kindreds. We sought to test this locus in families with multiple affected infants from our database of well characterized infants with reflux. METHODS: We screened the database for families with multiple affected infants. Affected proband phenotype required histological esophagitis; affected sibling/cousin phenotype required a threshold score on a diagnostic questionnaire. Screened families were reduced to five based on pedigree, consent, and phenotypic clarity. Linkage of the phenotype with the four previously reported markers (D13S218, D13S1288, D13S1253, and D13S263) was tested, using an autosomal dominant, 70% penetrance model. Linkage required logarithm-of-odds score > or = 3. RESULTS: Of 54 individuals in the five probands' generation, 21 (39%) were affected based on questionnaire, of whom nearly one half also had histological confirmation of esophagitis. Linkage to the defined region was excluded for the five families by two-point LOD scores (-1.47 at D13S218, -1.32 at D13S1288, -3.43 at D13S1253, and -3.92 at D13S263) and by multipoint (multipoint LOD scores less than -2 between D13S218 and D13S263) linkage analysis. No family demonstrated even suggestive positive linkage (i.e., LOD score >1). CONCLUSIONS: In five rigorously phenotyped families with autosomal dominant pattern infantile reflux, we excluded genetic linkage to the region of 13ql4 previously identified responsible for an autosomal dominant form of pediatric reflux. These results suggest genetic heterogeneity, possibly related to phenotypic heterogeneity, in familial pediatric gastroesophageal reflux disease.