Omission of radiation therapy post breast conserving surgery.

Radiation therapy (RT) after breast conserving surgery decreases the risks of local recurrence and breast cancer mortality in the multidisciplinary management of patients with breast cancer. However, breast cancer is a heterogeneous disease, and the absolute benefit of post-operative RT in individual patients varies substantially. Clinical trials aiming to identify patients with low-risk early breast cancer in whom post-operative RT may be safely omitted, based on conventional clinical-pathologic variables alone, have not provided sufficiently tailored information on local recurrence risk assessment to guide treatment decisions. The majority of patients with early breast cancer continue to be routinely treated with RT after breast conserving surgery. This approach may represent over-treatment for a substantial proportion of the patients. The clinical impact of genomic signatures on local therapy decisions for early breast cancer has been remarkably modest due to the lack of high-level evidence supporting their clinical validity for assessment of the risk of local recurrence. Efforts to personalise breast cancer care must be supported by high level evidence to enable balanced, informed treatment decisions. These considerations underpin the importance of ongoing biomarker-directed clinical trials to generate the high-level evidence necessary for setting the future standard of care in personalised local therapy for patients with early breast cancer.

Postoperative radiotherapy omission in selected patients with early breast cancer following preoperative breast MRI (PROSPECT): primary results of a prospective two-arm study.

BACKGROUND: Adjuvant breast radiotherapy as a standard component of breast-conserving treatment for early cancer can overtreat many women. Breast MRI is the most sensitive modality to assess local tumour burden. The aim of this study was to determine whether a combination of MRI and pathology findings can identify women with truly localised breast cancer who can safely avoid radiotherapy. METHODS: PROSPECT is a prospective, multicentre, two-arm, non-randomised trial of radiotherapy omission in patients selected using preoperative MRI and postoperative tumour pathology. It is being conducted at four academic hospitals in Australia. Women aged 50 years or older with cT1N0 non-triple-negative breast cancer were eligible. Those with apparently unifocal cancer had breast-conserving surgery (BCS) and, if pT1N0 or N1mi, had radiotherapy omitted (group 1). Standard treatment including excision of MRI-detected additional cancers was offered to the others (group 2). All were recommended systemic therapy. The primary outcome was ipsilateral invasive recurrence rate (IIRR) at 5 years in group 1. Primary analysis occurred after the 100th group 1 patient reached 5 years follow-up. Quality-adjusted life-years (QALYs) and cost-effectiveness of the PROSPECT pathway were analysed. This study is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12610000810011). FINDINGS: Between May 17, 2011, and May 6, 2019, 443 patients with breast cancer underwent MRI. Median age was 63·0 years. MRI detected 61 malignant occult lesions separate from the index cancer in 48 patients (11%). Of 201 group 1 patients who had BCS without radiotherapy, the IIRR at 5 years was 1·0% (upper 95% CI 5·4%). In group 1, one local recurrence occurred at 4·5 years and a second at 7·5 years. In group 2, nine patients had mastectomy (2% of total cohort), and the 5-year IIRR was 1·7% (upper 95% CI 6·1%). The only distant metastasis in the entire cohort was genetically distinct from the index cancer. The PROSPECT pathway increased QALYs by 0·019 (95% CI 0·008-0·029) and saved AU$1980 (95% CI 1396-2528) or £953 (672-1216) per patient. INTERPRETATION: PROSPECT suggests that women with unifocal breast cancer on MRI and favourable pathology can safely omit radiotherapy. FUNDING: Breast Cancer Trials, National Breast Cancer Foundation, Cancer Council Victoria, the Royal Melbourne Hospital Foundation, and the Breast Cancer Research Foundation.

The Microwave Temperature and Humidity Profiler: Description and Preliminary Results.

This manuscript presents the Microwave Temperature and Humidity Profiler (MTHP), a dual-band spectroradiometer designed for measuring multi-incidence angle temperature and humidity atmospheric profiles from an aircraft platform. The MTHP bands are at 60 GHz for measuring the oxygen complex lines, therefore at this band, MTHP has a hyperspectral radiometer able to provide 2048 channels over an 8 GHz bandwidth, and 183 GHz for measuring water vapor, which only uses four channels since this absorption band's spectral richness is simpler. The MTHP builds upon the Microwave Temperature Profiler (MTP) with the inclusion of the hyperspectral radiometer. The instrument's design, components, and calibration methods are discussed in detail, with a focus on the three-point calibration scheme involving internal calibration loads and static air temperature readings. Preliminary results from the Technological Innovation into Iodine and GV aircraft Environmental Research (TI3GER) campaign are presented, showcasing the instrument's performance during flights across diverse geographical regions. The manuscript presents successful antenna temperature measurements at 60 GHz and 183 GHz. The hyperspectral measurements are compared with a simulated antenna temperature using the Atmospheric Radiative Transfer Simulator (ARTS) showing an agreement better than R2 > 0.88 for three of the flights analyzed. Additionally, the manuscript draws attention to potential Radio Frequency Interference (RFI) effects observed during a specific flight, underscoring the instrument's sensitivity to external interference. This is the first-ever airborne demonstration of a broadband and hyperspectral multi-incidence angle 60 GHz measurement. Future work on the MTHP could result in an improved spatial resolution of the atmospheric temperature vertical profile and, hence, help in estimating the Planetary Boundary Layer (PBL) with better accuracy. The MTHP and its hyperspectral multi-incidence angle at 60 GHz have the potential to be a valuable tool for investigating the PBL's role in atmospheric dynamics, offering insights into its impact on Earth's energy, water, and carbon cycles.

Intrapartum care and management of complications in women with obesity.

Pregnant women with obesity are at considerable risk during their labor and delivery. The aim of obstetric care is the safe delivery of the baby and the maintenance of good health of the mother while providing an ongoing support for the family unit. The awareness and mitigation of risks associated with caring for women who are obese is vital in ensuring continued good outcomes. Transfer of women for labor care, presence of senior staff, bariatric resources, understanding of the progress of labor with an increase in body mass index, and preparation for complications are covered in this chapter.

Harnessing Real-World Evidence to Advance Cancer Research.

Randomized controlled trials (RCTs) form a cornerstone of oncology research by generating evidence about the efficacy of therapies in selected patient populations. However, their implementation is often resource- and cost-intensive, and their generalisability to patients treated in routine practice may be limited. Real-world evidence leverages data collected about patients receiving clinical care in routine practice outside of clinical trial settings and provides opportunities to identify and address gaps in clinical trial evidence. This review outlines the strengths and limitations of real-world and RCT evidence and proposes a framework for the complementary use of the two bodies of evidence to advance cancer research. There are challenges to the implementation of real-world research in oncology, including heterogeneity of data sources, timely access to high-quality data, and concerns about the quality of methods leveraging real-world data, particularly causal inference. Improved understanding of the strengths and limitations of real-world data and ongoing efforts to optimise the conduct of real-world evidence research will improve its reliability, understanding and acceptance, and enable the full potential of real-world evidence to be realised in oncology practice.

Dystrophic Myopathy of the Diaphragm with Recurrent Severe Respiratory Failure is Congenital Myasthenic Syndrome 11.

We here present the case of a patient with a congenital myasthenic syndrome (CMS) due to pathogenic variants in the RAPSN gene. During childhood he experienced recurrent episodes of respiratory failure during respiratory infections. This and other cases were reported as isolated dystrophy of the diaphragmatic musculature. In adulthood, whole exome sequencing revealed two heterozygous pathogenic variants in the RAPSN gene. This led to the revision of the diagnosis to rapsyn CMS11 (OMIM:616326, MONDO:0014588). EMG, muscle ultrasound and the revision of muscle biopsies taken in childhood support this diagnosis. After the revision of the diagnosis, treatment with pyridostigmine was started. This resulted in a reduction of fatigability and an improvement in functional abilities and quality of life.

Having an eye for myotonic dystrophy: A qualitative study on experiences and support needs in myotonic dystrophy type 1 patients with a diagnostic delay after early-onset cataract.

Myotonic dystrophy type 1 is a neuromuscular disorder affecting multiple organ systems and is characterized by a variety of clinical presentations. Anticipation leads to an earlier and more severe phenotype in subsequent generations. Early-onset cataract is a common initial manifestation of the late or adult-onset type of myotonic dystrophy 1. Due to its multicausal nature, early-onset cataract is often not recognized as a feature of this disease, leading to diagnostic delay resulting in consequences for successive generations, treatment and counseling. A qualitative study with semi-structured interviews was performed with purposive sampling of eight participants with myotonic dystrophy type 1 and early-onset cataract to investigate the physical and psychosocial consequences experienced due to diagnostic delay. Prior to the early-onset cataract, all participants experienced other multisystem symptoms that could have been explained by myotonic dystrophy. The diagnostic delay had severe hereditary consequences: a subsequent generation with more severely affected (grand)children was born resulting in large emotional burden for the patients. To conclude, early-onset cataract is a warning sign and ophthalmologists play a crucial role in the early detection of myotonic dystrophy type 1 by recognizing this symptom and preventing the birth of severely affected children leading to emotional and psychosocial consequences.

Radiation doses and fractionation schedules in non-low-risk ductal carcinoma in situ in the breast (BIG 3-07/TROG 07.01): a randomised, factorial, multicentre, open-label, phase 3 study.

BACKGROUND: Whole breast irradiation (WBI) after conservative surgery for ductal carcinoma in situ (DCIS) reduces local recurrence. We investigated whether a tumour bed boost after WBI improved outcomes, and examined radiation dose fractionation sensitivity for non-low-risk DCIS. METHODS: The study was an international, randomised, unmasked, phase 3 trial involving 136 participating centres of six clinical trials organisations in 11 countries (Australia, New Zealand, Singapore, Canada, the Netherlands, Belgium, France, Switzerland, Italy, Ireland, and the UK). Eligible patients were women aged 18 years or older with unilateral, histologically proven, non-low-risk DCIS treated by breast-conserving surgery with at least 1 mm of clear radial resection margins. They were assigned to one of four groups (1:1:1:1) of no tumour bed boost versus boost after conventional versus hypofractionated WBI, or randomly assigned to one of two groups (1:1) of no boost versus boost after each centre prespecified conventional or hypofractionated WBI. The conventional WBI used was 50 Gy in 25 fractions, and hypofractionated WBI was 42·5 Gy in 16 fractions. A boost dose of 16 Gy in eight fractions, if allocated, was delivered after WBI. Patients and clinicians were not masked to treatment allocation. The primary endpoint was time to local recurrence. This trial is registered with ClinicalTrials.gov (NCT00470236). FINDINGS: Between June 25, 2007, and June 30, 2014, 1608 patients were randomly assigned to have no boost (805 patients) or boost (803 patients). Conventional WBI was given to 831 patients, and hypofractionated WBI was given to 777 patients. Median follow-up was 6·6 years. The 5-year free-from-local-recurrence rates were 92·7% (95% CI 90·6-94·4%) in the no-boost group and 97·1% (95·6-98·1%) in the boost group (hazard ratio 0·47; 0·31-0·72; p<0·001). The boost group had higher rates of grade 2 or higher breast pain (10% [8-12%] vs 14% [12-17%], p=0·003) and induration (6% [5-8%] vs 14% [11-16%], p<0·001). INTERPRETATION: In patients with resected non-low-risk DCIS, a tumour bed boost after WBI reduced local recurrence with an increase in grade 2 or greater toxicity. The results provide the first randomised trial data to support the use of boost radiation after postoperative WBI in these patients to improve local control. The international scale of the study supports the generalisability of the results. FUNDING: National Health and Medical Research Council of Australia, Susan G Komen for the Cure, Breast Cancer Now, OncoSuisse, Dutch Cancer Society, Canadian Cancer Trials Group.

Imaging Modalities for Early Detection of Pancreatic Cancer: Current State and Future Research Opportunities.

Pancreatic cancer, one of the most lethal malignancies, is increasing in incidence. While survival rates for many cancers have improved dramatically over the last 20 years, people with pancreatic cancer have persistently poor outcomes. Potential cure for pancreatic cancer involves surgical resection and adjuvant therapy. However, approximately 85% of patients diagnosed with pancreatic cancer are not suitable for potentially curative therapy due to locally advanced or metastatic disease stage. Because of this stark survival contrast, any improvement in early detection would likely significantly improve survival of patients with pancreatic cancer through earlier intervention. This comprehensive scoping review describes the current evidence on groups at high risk for developing pancreatic cancer, including individuals with inherited predisposition, pancreatic cystic lesions, diabetes, and pancreatitis. We review the current roles of imaging modalities focusing on early detection of pancreatic cancer. Additionally, we propose the use of advanced imaging modalities to identify early, potentially curable pancreatic cancer in high-risk cohorts. We discuss innovative imaging techniques for early detection of pancreatic cancer, but its widespread application requires further investigation and potentially a combination with other non-invasive biomarkers.

Breast Irradiation in Ductal Carcinoma In Situ.

There is strong and consistent evidence that whole breast irradiation after breast conserving surgery significantly decreases the risk of ipsilateral breast events, in situ or invasive, underpinning its established role in patients with ductal carcinoma in situ (DCIS). Pending publication of the full results of BIG 3-07/TROG 07.01 randomised trial, addition of tumour bed boost to whole breast irradiation is recommended in the presence of adverse clinical-pathologic features, and the use of moderately hypofractionated whole breast dose-fractionation schedules is supported. As published data supporting the use of adjuvant partial breast irradiation in patients with low-risk DCIS are limited, its off-study application should be limited to low-risk patients defined by international and national guidelines. Finally, low-risk patients may not derive clinically meaningful benefits from radiation therapy and research on molecular profiling is ongoing to improve prognostic precision and guide safe omission of radiation therapy after breast conserving surgery.

Factors involved in treatment decision making for women diagnosed with ductal carcinoma in situ: A qualitative study.

Whilst some of the diversity in management of women with ductal carcinoma in situ (DCIS) may be explained by tumour characteristics, the role of patient preference and the factors underlying those preferences have been less frequently examined. We have used a descriptive qualitative study to explore treatment decisions for a group of Australian women diagnosed with DCIS through mammographic screening. Semi-structured telephone interviews were performed with 16 women diagnosed with DCIS between January 2012 and December 2018, recruited through the LifePool dataset (a subset of BreastScreen participants who have agreed to participate in research). Content analysis using deductive coding identified three themes: participants did not have a clear understanding of their diagnosis or prognosis; reported involvement in decision making about management varied; specific factors including the psychosexual impact of mastectomy and perceptions of radiotherapy, could act as barriers or facilitators to specific decisions about treatment. The treatment the women received was not simply determined by the characteristics of their disease. Interaction with the managing clinician was pivotal, however many other factors played a part in individual decisions. Recognising that decisions are not purely a function of disease characteristics is important for both women with DCIS and the clinicians who care for them.

Postmastectomy radiotherapy: a review.

PURPOSE OF REVIEW: We review the role of postmastectomy radiotherapy (PMRT) in the management of patients with early breast cancer. RECENT FINDINGS: PMRT in patients with 4 or more involved axillary lymph nodes is the current standard of care but the indications for PMRT in patients with 1-3 involved nodes remain controversial. The Early Breast Cancer Trialists' Collaborative Group meta-analysis of randomised trials of PMRT provides the most comprehensive level 1 evidence base. However, its applicability in contemporary practice in the context of recent multidisciplinary advances in surgery, radiation therapy and systemic therapy remains challenging. SUMMARY: The lack of consensus on the indications for PMRT in patients with 1-3 positive nodes underpins the variations in the national and international guidelines on PMRT. We emphasise the need for contemporary randomised trial data, and the potential to refine patient selection for PMRT using novel biomarkers of recurrence and radiosensitivity.

Axillary dissection in sentinel lymph node positive breast cancer: Is the staging information worthwhile for patients?

AIMS: The Z0011 randomized trial demonstrated no significant difference in axillary recurrence rate or survival with or without axillary dissection in patients with a positive sentinel node biopsy. However, there is continuing controversy regarding the generalizability of its results, and axillary dissection provides additional pathologic staging information that may guide adjuvant therapy. Thus, axillary dissection after positive sentinel node biopsy is being further investigated in an actively recruiting randomized trial. We elicited patients' preferences for axillary dissection versus no axillary dissection after positive sentinel node biopsy for early breast cancer. METHODS: Patients who had undergone axillary dissection after positive sentinel node biopsy as part of breast conserving therapy were provided with a validated, self-rated questionnaire. The questionnaire comprised two trade-off questions to determine the maximum chance of developing arm side-effects from axillary dissection to justify the benefit of additional axillary staging information. Social, demographic, and clinical details were collected. RESULTS: Ninety-nine of the 126 eligible patients returned the questionnaire and 76 completed the trade-off assessment. The median age of participants was 62 years. The median numbers of sentinel and axillary nodes removed were 2 and 12, respectively. Forty-seven percent of participants had arm swelling or tenderness of any severity. Seventy-five percent of participants would have axillary dissection even if the chance of arm side-effects like they had experienced was 100%. CONCLUSION: Most patients with early breast cancer preferred axillary dissection after positive sentinel node biopsy for the additional staging information even though there was no survival benefit from axillary dissection.

Power-Optimizing Repair for Distal Biceps Tendon Rupture: Stronger and Safer.

Purpose: Many approaches have been described to accomplish tendon reattachment to the radial tuberosity in a distal biceps tendon rupture, with significant success, but each is associated with potential postoperative complications, including posterior interosseous nerve (PIN) injury. To date, there has been no consensus on the best approach to the repair. The purpose of this study was to evaluate the supination strength and the distance of drill exit points from the PIN in a power-optimizing distal biceps repair method and compare the findings with those of a traditional anterior approach endobutton repair method. Methods: Cadaveric arms were dissected to allow for distal biceps tendon excision from its anatomic footprint. Each arm was repaired twice, first with the power-optimizing repair using an anterior single-incision approach with an ulnar drilling angle and biceps tendon radial tuberosity wraparound anatomic footprint attachment, then with the traditional anterior endobutton repair. Following each repair, the arm was mounted on a custom-built testing apparatus, and the supination torque was measured from 3 orientations. The PIN was then located posteriorly, and its distance from each repair exit hole was measured. Results: Five cadaveric arms, each with both the repairs, were included in the study. On average, the power-optimizing repair generated an 82%, 22%, and 13% greater supination torque than the traditional anterior endobutton repair in 45° supination, neutral, and 45° pronation orientations, respectively. On average, the power-optimizing repair produced drill hole exit points farther from the PIN (23 mm) than the traditional anterior endobutton repair (14 mm). Conclusions: The power-optimizing repair provides a significantly greater supination torque and produces a drill hole exit point significantly farther from the PIN than the traditional anterior endobutton approach. Type of study/level of evidence: Therapeutic III.

Metabolites of the ellagitannin, geraniin inhibit human ACE; in vitro and in silico evidence.

Hypertension is defined as the persistence of elevated blood pressure in the circulation system. The renin-angiotensin-aldosterone system is a major modulator of blood pressure. Among the risk factors of cardiovascular disease, hypertension is the most preventable and treatable, with drugs such as ACE inhibitors. Many ACE inhibitors are known to have undesirable side effects and hence, natural alternatives are being sought. Dietary polyphenols, particularly ellagitannins, are derived from plant products and are known to exhibit a variety of bioactivities. Geraniin, an ellagitannin has been shown to have antihypertensive activity in animal experiments. It is speculated that the metabolites of geraniin are responsible for its ACE inhibitory activity. We have performed in vitro ACE inhibition and in silico studies with geraniin and its metabolites (ellagic acid, urolithins). Our studies confirm that ellagic acid exhibited similar inhibitory potential to ACE as the positive control captopril.

Quality of life after breast-conserving therapy and adjuvant radiotherapy for non-low-risk ductal carcinoma in situ (BIG 3-07/TROG 07.01): 2-year results of a randomised, controlled, phase 3 trial.

BACKGROUND: BIG 3-07/TROG 07.01 is an international, multicentre, randomised, controlled, phase 3 trial evaluating tumour bed boost and hypofractionation in patients with non-low-risk ductal carcinoma in situ following breast-conserving surgery and whole breast radiotherapy. Here, we report the effects of diagnosis and treatment on health-related quality of life (HRQOL) at 2 years. METHODS: The BIG 3-07/TROG 07.01 trial is ongoing at 118 hospitals in 11 countries. Women aged 18 years or older with completely excised non-low-risk ductal carcinoma in situ were randomly assigned, by use of a minimisation algorithm, to tumour bed boost or no tumour bed boost, following conventional whole breast radiotherapy or hypofractionated whole breast radiotherapy using one of three randomisation categories. Category A was a 4-arm randomisation of tumour bed boost versus no boost following conventional whole breast radiotherapy (50 Gy in 25 fractions over 5 weeks) versus hypofractionated whole breast radiotherapy (42·5 Gy in 16 fractions over 3·5 weeks). Category B was a 2-arm randomisation between tumour bed boost versus no boost following conventional whole breast radiotherapy, and category C was a 2-arm randomisation between tumour bed boost versus no boost following hypofractionated whole breast radiotherapy. Stratification factors were age at diagnosis, planned endocrine therapy, and treating centre. The primary endpoint, time to local recurrence, will be reported when participants have completed 5 years of follow-up. The HRQOL statistical analysis plan prespecified eight aspects of HRQOL, assessed by four questionnaires at baseline, end of treatment, and at 6, 12, and 24 months after radiotherapy: fatigue and physical functioning (EORTC QLQ-C30); cosmetic status, breast-specific symptoms, arm and shoulder functional status (Breast Cancer Treatment Outcome Scale); body image and sexuality (Body Image Scale); and perceived risk of invasive breast cancer (Cancer Worry Scale and a study-specific question). For each of these measures, tumour bed boost was compared with no boost, and conventional whole breast radiotherapy compared with hypofractionated whole breast radiotherapy, by use of generalised estimating equation models. Analyses were by intention to treat, with Hochberg adjustment for multiple testing. This trial is registered with ClinicalTrials.gov, NCT00470236. FINDINGS: Between June 1, 2007, and Aug 14, 2013, 1208 women were enrolled and randomly assigned to receive no tumour bed boost (n=605) or tumour bed boost (n=603). 396 of 1208 women were assigned to category A: conventional whole breast radiotherapy with tumour bed boost (n=100) or no boost (n=98), or to hypofractionated whole breast radiotherapy with tumour bed boost (n=98) or no boost (n=100). 447 were assigned to category B: conventional whole breast radiotherapy with tumour bed boost (n=223) or no boost (n=224). 365 were assigned to category C: hypofractionated whole breast radiotherapy with tumour bed boost (n=182) or no boost (n=183). All patients were followed up at 2 years for the HRQOL analysis. 1098 (91%) of 1208 patients received their allocated treatment, and most completed their scheduled HRQOL assessments (1147 [95%] of 1208 at baseline; 988 [87%] of 1141 at 2 years). Cosmetic status was worse with tumour bed boost than with no boost across all timepoints (difference 0·10 [95% CI 0·05-0·15], global p=0·00014, Hochberg-adjusted p=0·0016); at the end of treatment, the estimated difference between tumour bed boost and no boost was 0·13 (95% CI 0·06-0·20; p=0·00021), persisting at 24 months (0·13 [0·06-0·20]; p=0·00021). Arm and shoulder function was also adversely affected by tumour bed boost across all timepoints (0·08 [95% CI 0·03-0·13], global p=0·0033, Hochberg adjusted p=0·045); the difference between tumour bed boost and no boost at the end of treatment was 0·08 (0·01 to 0·15, p=0·021), and did not persist at 24 months (0·04 [-0·03 to 0·11], p=0·29). None of the other six prespecified aspects of HRQOL differed significantly after adjustment for multiple testing. Conventional whole breast radiotherapy was associated with worse body image than hypofractionated whole breast radiotherapy at the end of treatment (difference -1·10 [95% CI -1·79 to -0·42], p=0·0016). No significant differences were reported in the other PROs between conventional whole breast radiotherapy compared with hypofractionated whole breast radiotherapy. INTERPRETATION: Tumour bed boost was associated with persistent adverse effects on cosmetic status and arm and shoulder functional status, which might inform shared decision making while local recurrence analysis is pending. FUNDING: National Health and Medical Research Council, Susan G Komen for the Cure, Breast Cancer Now, OncoSuisse, Dutch Cancer Society.