A multicentre review of the direct-access mammography programme in Ireland for women with breast pain.

AIM: To assess the current use of the direct access mammography pathway for breast pain and the rate of breast cancer detection in this patient cohort. MATERIALS AND METHODS: A retrospective review of general practitioner (GP)-referred mammograms performed during a 12-month period from January to December 2022 across four tertiary referral centres. With the use of medical records and GP referrals, patient demographics, presenting symptoms, family history, and clinical outcomes were recorded. RESULTS: The present study comprised 2,046 patients of which 21.6% did not report breast pain at the time of referral. Thirty-five per cent had a positive family history with 40% of these patients having no breast pain. Twelve per cent were recalled with 30% of these patients requiring biopsy. An overall cancer detection rate (CDR) of 7 per 1000 was determined for women with mastalgia. A CDR of 0 per 1,000 was determined for women <50 years with mastalgia alone and no additional risk factors for malignancy. Fisher's exact test showed no statistically significant association between breast pain and breast cancer. CONCLUSION: There was no statistically significant relationship found between breast pain and breast cancer. This review suggests a low cancer detection rate in women <50 years. In women <50 years with mastalgia without additional symptoms or family history, breast imaging is not required.

Comparison of the utility of clinical breast examination and MRI in the surveillance of women with a high risk of breast cancer.

AIM: To review surveillance magnetic resonance imaging (MRI) and clinical breast examinations (CBE) performed for women at high risk of breast cancer in order to determine recall and cancer-detection rates. MATERIALS AND METHODS: Data were collected on all surveillance MRI examinations performed at St James's Hospital in 2016 for women at high risk of developing breast cancer. Data collected included age, indication for MRI, MRI score, ultrasound indications and scores, and histology findings. Ultrasound scores were recorded from CBEs that received a score of ≥3. RESULTS: A total of 385 breast surveillance MRI examinations and CBEs were performed for women at high risk of breast cancer. A recall rate of 11.2% was documented for breast MRI examinations, whereas a recall rate of 6.2% was identified for CBEs. The biopsy rate was 6.2% for MRI and 0.2% for CBE. The cancer detection rate was 1.6% or 16 per 1,000 for MRI screening and 0% for CBE. CONCLUSION: The high cancer detection rate in the present study supports the unparalleled sensitivity of breast MRI surveillance. Furthermore, the present study did not identify any breast cancers through CBE, suggesting it is not a critical component of the surveillance programme of high-risk women. The current UK guidelines recommending a target recall rate of 7% were not met in the present study or by other studies in the literature, collectively suggesting the guidelines may not be reflective of what is attainable in clinical practice.

NF-κB signalling is involved in immune-modulation, but not basal functioning, of the mouse suprachiasmatic circadian clock.

Circadian rhythms are recurring near-24 hour patterns driven by an endogenous circadian timekeeping system. The master pacemaker in this system is the hypothalamic suprachiasmatic nucleus (SCN). Recently interest has been drawn to how the SCN clock responds to immune system stimulation. A major signalling component in the immune system is nuclear factor (NF)-κB. In the present study we examined the role of NF-κB in SCN function. Whilst serum shocked fibroblasts showed rhythmic nuclear localisation of p65 and p65-dependent transcription, there were no circadian changes in the SCN in expression of the NF-κB components p65, c-Rel, p-IκB or p-IKK. Chronic treatment with the NF-κB inhibitor PDTC did not impact on circadian or diurnal rhythms. Phase-shifting light pulses did not impact on SCN expression of p65, and PDTC treatment did not attenuate the behavioural or molecular response to light pulses. Peripheral treatment with lipopolysaccharide resulted in increased NF-κB component expression in the SCN. In vitro experiments with SCN slice cultures showed that treatment with NF-κB inhibitors did not markedly alter rhythmic changes in PER2::LUC expression. Further, SCN slices from nf-κb::luc mice did not show any evidence for circadian rhythms in NF-κB-mediated transcription. Experiments utilising older mice (~16 months old) showed that SCN treatment in vitro with PDTC resulted in increased amplitude of rhythmic PER2::LUC expression, and LPS treatment resulted in altered PER2::LUC rhythm acrophase. Overall, we interpret our results as providing evidence for the involvement of NF-κB in the suprachiasmatic circadian clock following immune stimulation, but not under basal conditions.

X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes.

X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved families with XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these males were previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sanger sequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonic variants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM and USP27X) and potentially deleterious variants in 2 novel candidate XLID genes (CDK16 and TAF1). We show that the CLCN4 and CNKSR2 variants impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from Clcn4(-/-) mice or after mRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases.

The value of routine screening mammography in women aged 35-39 years in a symptomatic breast unit.

AIM: To determine the breast cancer detection rate at routine bilateral screening mammography in women aged 35-39 years attending a symptomatic breast clinic, in women of population-risk profile with a normal clinical examination. METHODS AND MATERIALS: A retrospective analysis of all mammograms performed on patients aged 35-39 years at St James's Hospital from 2011-2015 was carried out. Patients with moderate or high familial risk of breast cancer, personal breast cancer history or chest radiation, males, general practitioner (GP) and internal hospital referrals, and those with abnormal clinical examinations were excluded. Included women had "normal", "benign", or undocumented examination findings. Results of imaging, including ultrasound and histopathological results, were recorded. Information was extracted from the hospital's electronic record systems. RESULTS: Of 4,087 patients aged 35-39 who had bilateral mammograms from 2011-2015, 2,148 patients were excluded from analysis. Of 1,939 included women, four (0.21%) were diagnosed with breast cancer confirmed at histology based on mammographic findings: two invasive ductal carcinoma (8 and 2 mm) and two ductal carcinoma in situ (DCIS; 4.5 mm high-grade DCIS and 2 mm low-grade DCIS). Other histological findings included two B3, 46 B2, and three B1 lesions. Overall, 115 biopsies were performed in this cohort; 55 (47.8%) were attributable to mammographic screening, producing a biopsy rate of 2.8% due to mammography alone. CONCLUSION: Per 1,000 women screened, 2.1 cases of cancer were detected. This figure would be below accepted international thresholds to undertake screening mammography and raises radiation protection issues. Additionally, a large number of benign biopsies were undertaken, with likely resultant psychological impact. Further studies could inform national guidance.

Imaging features and diagnosis of tuberculosis of the breast.

AIM: To outline the pathophysiology, clinical presentation, imaging features, and relevant investigations of the different subtypes of breast tuberculosis (TB). MATERIALS AND METHODS: A review was undertaken of all cases (33 in total) of breast TB presenting to Barts Health NHS Trust within a 10-year period, including patient demographics, imaging features, and route of diagnosis. RESULTS: Thirty-three cases of proven granulomatous TB of the breast were identified (11 mastitis obliterans, 10 nodular caseous form, five sclerosing form, four disseminated disease, and three abnormal axillary lymph nodes). No cases of miliary breast TB were identified. Fine-needle aspiration cytology aided diagnosis in six patients (<20% of cases); however, the majority of patients required further investigation; namely core biopsy. Over a third of patients (12/33) had multiple clinic attendances prior to diagnosis. Mean delay in diagnosis was 3.7 months (median 0 months, IQR= 3). CONCLUSION: Breast TB is a rare challenging diagnosis with a wide range of imaging features. Core biopsy is essential for definitive diagnosis. A multidisciplinary approach involving surgeons, radiologists, TB consultants, and microbiologists is required, coupled with a high index of clinical suspicion in order to aid timely diagnosis, and initiate prompt treatment to reduce complications.

Determination of recall rates for assessment in high-risk women undergoing annual surveillance breast MRI.

AIM: To review all surveillance breast magnetic resonance imaging (MRI) examinations performed over a 6-year period at an Irish national centre to determine the recall rate, biopsy rate, and cancer-detection rates. MATERIALS AND METHODS: All breast MRI examinations performed for surveillance purposes in women at high risk of developing breast cancer between January 2009 and December 2014 were reviewed. The Breast Imaging-Reporting and Data System (BI-RADS) score for each MRI examination was determined, the type of additional imaging performed, and the method of biopsy, if performed, was recorded. Histology of the biopsy specimens was reviewed. RESULTS: Data for 715 women undergoing 1445 surveillance MRI examinations were identified. Of the examinations, 10.9% (157/1445) had MRI BI-RADS scores that required recall for further imaging and 6.3% (91/1445) required a biopsy. Recall rates were 14.2% (86/607) and 8.5% (71/838) in the prevalent and incident rounds, respectively. The overall cancer detection rate was 17 per 1000. CONCLUSION: The current UK guideline was not achieved and no studies to date have achieved the target of <7%. Aiming for this target could risk lowering the cancer-detection rate. The authors would suggest a target rate of <15% and <10% for the prevalent round and incident rounds, respectively.

The Z0011 Trial: Is this the end of axillary ultrasound in the pre-operative assessment of breast cancer patients?

OBJECTIVES: The Z0011 trial questioned the role of axillary ultrasound (AxUS) in preoperative staging of breast cancer in patients with ≤2 positive sentinel lymph nodes (SLN). The purpose of this study was to correlate the number of abnormal nodes on AxUS with final nodal burden and determine the utility of AxUS with sampling (AxUS + S) in preoperative staging. METHODS: Six hundred and seventy-nine patients underwent pre-operative AxUS. Suspicious nodes were sampled. Negative axillae proceeded to SLN biopsy. The number of abnormal nodes identified on ultrasound and final histology as well as sensitivity and specificity for AxUS + S were calculated. Subgroup analysis was performed on Z0011 eligible patients. RESULTS: Two hundred and ninety-six patients had positive axillary nodes on final histology with 169 detected by AxUS + S (sensitivity 86.2%, specificity 100%, PPV 100 %, NPV 71.9%). Patients with nodal metastases identified by AxUS had a mean burden of 7.3 nodes on histology (1 node on AxUS = 5.2 nodes on histology, 2 nodes on AxUS = 7.5 nodes, >2 nodes = 10.1 nodes). Patients diagnosed on SLNB had a mean burden of 2.2 nodes. CONCLUSION: A single nodal metastasis detected on AxUS + S correlated with a mean of 5.2 nodes on final histology highlighting that AxUS remains essential in guiding appropriate management of the axilla in breast cancer. KEY POINTS: • Axillary ultrasound +/- sampling is an essential technique in preoperative axillary staging. • Axillary ultrasound findings correlate with final histological axillary node disease burden. • Axillary ultrasound can help triage patients who require axillary lymph node dissection. • The role of axillary ultrasound in breast cancer staging continues to evolve.

A radiological approach to benign and malignant lesions of the mandible.

There is a wide range of pathological conditions that affect the mandible. Although some lesions demonstrate characteristic imaging features, many of the pathological processes encountered in the mandible often exhibit similar imaging appearances resulting in uncertainty for the reporting radiologist. Many mandibular lesions remain impossible to distinguish without histological analysis. Therefore, this review aims to reassure the radiologist that although imaging findings may not always lead to a specific diagnosis, they narrow the differential diagnosis and guide further work-up. In this regard, we aim to provide a clinically useful framework and approach for radiologists to use when they encounter lesions within the mandible.

Imaging features of extrapulmonary small cell carcinoma.

Small cell carcinoma accounts for approximately 20% of lung cancers; however, it rarely occurs at other sites. Extrapulmonary small cell carcinoma (EPSCC) is notoriously aggressive with a strong propensity for both regional and distant spread. The majority of the literature on these uncommon tumours is from a clinicopathological viewpoint with a relative paucity of detail regarding the radiological findings. This review will focus on the imaging features of EPSCC in its predominant sites of origin: the gastrointestinal tract, genitourinary tract, head, neck, and breast. We will also discuss the role of positron-emission tomography (PET)/computed tomography (CT) in the staging of EPSCC.

There is more to this fever than meets the eye: A case of neuroleptic malignant-like syndrome (NMLS) secondary to withdrawal of procyclidine and L-dopa on a background of long-standing flupenthixol depot use.

This case report highlights the risk of development of Neuroleptic Malignant-Like Syndrome secondary to withdrawal of procyclidine with brief withdrawal of L-dopa and long-term typical antipsychotic depot. The patient responded to reintroduction of procyclidine, sedation and supportive treatment. The mechanism and management of NMS and NMLS is also reviewed. This case emphasises that any changes in antipsychotic and antiparkinsonian medications should be undertaken with extreme caution and patient should be closely monitored for development of NMLS after alteration in these medications.

Ultrasound elastography as an adjuvant to conventional ultrasound in the preoperative assessment of axillary lymph nodes in suspected breast cancer: a pilot study.

AIMS: To compare the performance of ultrasound elastography with conventional ultrasound in the assessment of axillary lymph nodes in suspected breast cancer and whether ultrasound elastography as an adjunct to conventional ultrasound can increase the sensitivity of conventional ultrasound used alone. MATERIALS AND METHODS: Fifty symptomatic women with a sonographic suspicion for breast cancer underwent ultrasound elastography of the ipsilateral axilla concurrent with conventional ultrasound being performed as part of triple assessment. Elastograms were visually scored, strain measurements calculated and node area and perimeter measurements taken. Theoretical biopsy cut points were selected. The sensitivity, specificity, positive predictive value (PPV), and negative predictive values (NPV) were calculated and receiver operating characteristic (ROC) analysis was performed and compared for elastograms and conventional ultrasound images with surgical histology as the reference standard. RESULTS: The mean age of the women was 57 years. Twenty-nine out of 50 of the nodes were histologically negative on surgical histology and 21 were positive. The sensitivity, specificity, PPV, and NPV for conventional ultrasound were 76, 78, 70, and 81%, respectively; 90, 86, 83, and 93%, respectively, for visual ultrasound elastography; and for strain scoring, 100, 48, 58 and 100%, respectively. There was no significant difference between any of the node measurements CONCLUSIONS: Initial experience with ultrasound elastography of axillary lymph nodes, showed that it is more sensitive than conventional ultrasound in detecting abnormal nodes in the axilla in cases of suspected breast cancer. The specificity remained acceptable and ultrasound elastography used as an adjunct to conventional ultrasound has the potential to improve the performance of conventional ultrasound alone.

Approach to the Management of Hypernatraemia in Older Hospitalised Patients.

Hypernatraemia is associated with high morbidity and mortality and is more common in patients of older age, nursing home residents and those with cognitive impairment and restricted mobility. The most common cause in hospital settings is water dehydration due to reduced intake although other causes should be identified. Once identified, prompt management is necessary to avoid delayed correction as prolonged hypernatremia is associated with increased hospital stay and mortality. Comprehensive history-taking and physical examination, basic investigations and medication review are essential to identify causative and remediable factors in those admitted with hypernatraemia. Accurate calculation of fluid deficit and ongoing losses is essential in order to ensure adequate fluid replacement, The administration of appropriate, usually hypotonic, fluids is also essential to the timely restoration of eunatraemia. Although evidence of definite harm resulting from rapid correction is lacking, a serum sodium reduction rate of <12 mmol/l day is advised with the caveat that close monitoring of electrolytes is required to ensure the desired correction rate is being achieved. Medical and nursing professionals should have access to a local hospital protocol to guide management of patients with hypernatraemia to improve patient outcomes and mitigate the risk of harm, particularly from under-recognition and slow correction.

Optical fibre based real-time measurements during an LDR prostate brachytherapy implant simulation: using a 3D printed anthropomorphic phantom.

An optical fibre sensor based on radioluminescence, using the scintillation material terbium doped gadolinium oxysulphide (Gd2O2S:Tb) is evaluated, using a 3D printed anthropomorphic phantom for applications in low dose-rate (LDR) prostate brachytherapy. The scintillation material is embedded in a 700 µm diameter cavity within a 1 mm plastic optical fibre that is fixed within a brachytherapy needle. The high spatial resolution dosimeter is used to measure the dose contribution from Iodine-125 (I-125) seeds. Initially, the effects of sterilisation on the sensors (1) repeatability, (2) response as a function of angle, and (3) response as a function of distance, are evaluated in a custom polymethyl methacrylate phantom. Results obtained in this study demonstrate that the output response of the sensor, pre- and post-sterilisation are within the acceptable measurement uncertainty ranging from a maximum standard deviation of 4.7% pre and 5.5% post respectively, indicating that the low temperature sterilisation process does not damage the sensor or reduce performance. Subsequently, an LDR brachytherapy plan reconstructed using the VariSeed treatment planning system, in an anthropomorphic 3D printed training phantom, was used to assess the suitability of the sensor for applications in LDR brachytherapy. This phantom was printed based on patient anatomy, with the volume and dimensions of the prostate designed to represent that of the patient. I-125 brachytherapy seeds, with an average activity of 0.410 mCi, were implanted into the prostate phantom under trans-rectal ultrasound guidance; following the same techniques as employed in clinical practice by an experienced radiation oncologist. This work has demonstrated that this sensor is capable of accurately identifying when radioactive I-125 sources are introduced into the prostate via a brachytherapy needle.

A catalog of associations between rare coding variants and COVID-19 outcomes.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease-19 (COVID-19), a respiratory illness that can result in hospitalization or death. We investigated associations between rare genetic variants and seven COVID-19 outcomes in 543,213 individuals, including 8,248 with COVID-19. After accounting for multiple testing, we did not identify any clear associations with rare variants either exome-wide or when specifically focusing on (i) 14 interferon pathway genes in which rare deleterious variants have been reported in severe COVID-19 patients; (ii) 167 genes located in COVID-19 GWAS risk loci; or (iii) 32 additional genes of immunologic relevance and/or therapeutic potential. Our analyses indicate there are no significant associations with rare protein-coding variants with detectable effect sizes at our current sample sizes. Analyses will be updated as additional data become available, with results publicly browsable at https://rgc-covid19.regeneron.com.

Optical fiber dosimeter for real-time in-vivo dose monitoring during LDR brachytherapy.

An optical fiber sensor for monitoring low dose radiation is presented. The sensor, based on radiation sensitive scintillation material, terbium doped gadolinium oxysulphide (Gd2O2S:Tb), is embedded in a cavity of 700µm diameter within a 1mm plastic optical fiber. The sensor is compared with the treatment planning system for repeatability, angular dependency, distance and accumulated radiation activity. The sensor demonstrates a high sensitivity of 152 photon counts/Gy with a temporal resolution of 0.1 seconds, with the largest repeatability error of 4.1%, to 0.361mCi of Iodine-125 the radioactive source most commonly used in LDR brachytherapy for treating prostate cancer.

Establishing Benefit from Vitamin D Supplementation - Adherence to Defined Criteria and Targeting of High-Risk Groups Essential?

BACKGROUND: Vitamin D is the one of the most common nutritional deficiencies worldwide, and insufficiency or deficiency can be associated with musculoskeletal and non-skeletal conditions such as cancer, cardiovascular disease and diabetes mellitus. OBJECTIVE: Recent data suggests that Vitamin D is relatively safe and toxicity is rarer than previously indicated. However, international guidelines regarding dosage and target plasma levels are conflicting. Moreover multiple well-designed studies of healthy older adults, unselected in terms of Vitamin D status, have revealed largely negative results (with the possible exception of older patients in care homes/hospitals) in terms of improvement in musculoskeletal and non-skeletal conditions to date. CONCLUSION: On that basis, it is suggested that future trials regarding Vitamin D supplementation should be carried out in high-risk groups. The use of published criteria for evaluating the effect of nutrients and targeting of individuals with Vitamin D insufficiency and deficiency for inclusion in such studies is also proposed. The identification of specific subgroups that will benefit from supplementation and replacement, and the establishment of a scientific basis for such therapy, should be possible with this approach.

Randomised controlled trial of the effect of standard and detailed risk disclosure prior to bronchoscopy on peri-procedure anxiety and satisfaction.

BACKGROUND: Deciding what risks to disclose before a procedure is often challenging for clinicians. Consecutive patients undergoing elective fibreoptic bronchoscopy were randomised to receive simple or more detailed written information about the risks of the procedure and the effects on anxiety and satisfaction levels were compared. METHODS: A 100 mm anxiety visual analogue scale (VAS) and a modified Amsterdam preoperative anxiety (scored 4-20) scale (APAIS) were completed before and after reading the designated information leaflet. Following bronchoscopy, subjects completed a satisfaction questionnaire. RESULTS: Of 142 consecutive patients, 122 (86%) (mean age 57.8 years, 53% male) completed the study. Baseline demographic, clinical and anxiety measures were similar in the two groups. Those who received more detailed risk information had significantly greater increase in anxiety levels than those who received simple information on both the VAS (mean 14.0 (95% CI 10.1 to 17.9) vs 2.5 (95% CI -1.4 to 6.4), p<0.001) and the APAIS (1.73 (95% CI 1.19 to 2.26) vs 0.57 (95% CI 0.05 to 1.10), p<0.001). Almost twice as many of those receiving detailed risk information reported that they felt they had received too much information about complications or that the information they had received about bronchoscopy had been worrying. CONCLUSIONS: Provision of more detailed risk information before bronchoscopy may come at the cost of a small but significant increase in anxiety.

Changing attitudes to cardiopulmonary resuscitation in older people: a 15-year follow-up study.

BACKGROUND: while it is well established that individual patient preferences regarding cardiopulmonary resuscitation (CPR) may change with time, the stability of population preferences, especially during periods of social and economic change, has received little attention. OBJECTIVE: to elicit the resuscitation preferences of older Irish inpatients and to compare the results with an identical study conducted 15 years earlier. METHODS: one hundred and fifty older medical inpatients awaiting discharge in a university teaching hospital or a district general hospital subjects were asked about resuscitation preferences. Results were compared to those elicited from a hundred subjects in 1992. RESULTS: most patients (94%) felt it was a good idea for doctors to discuss CPR routinely with patients, compared with 39% in 1992. In their current health, 6% in 2007 and 76% in 1992 would refuse CPR. The independent predictors of refusal of CPR in current health on logistic regression were age and year of assessment. In the final model, those aged 75-84 years [OR 2.77 (95% CI 1.25-6.13), P = 0.02] and 85 years or more [OR 15.19 (4.26-54.15), P < 0.0001] were more likely than those aged 65-74 years (reference group) to refuse CPR. Those questioned in 2007 [OR 0.04 (0.02-0.81), P < 0.0001] were less likely than those questioned in 1992 (reference group) to refuse CPR. CONCLUSIONS: there has been a significant shift in the attitudes of older Irish inpatients over 15 years towards favouring greater patient participation in decision making and an increased desire for resuscitation.