Frequency of misdiagnosis in hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic Cardiomyopathy (HCM) is characterized by unexplained left ventricle hypertrophy (LVH) ≥15 mm. The condition is often hereditary and family screening is recommended to reduce the risk of adverse disease complications and premature death among relatives. Correct diagnosis of index patients is important to ensure that only relatives at risk of disease development are invited for family screening. PURPOSE: To investigate if patients with ICD-10 codes for HCM (DI421) or hypertrophic obstructive cardiomyopathy (DI422) fulfilled recognised diagnostic criteria. METHODS: All patients with ICD-10 codes for HCM or HOCM at a Department of Cardiology were identified and had their diagnosis validated by a cardiac investigation or a review of their medical records and previous investigations. RESULTS: Two hundred and forty patients had ICD-10 codes for HCM/HOCM, of whom 202 (84%, 202/240) underwent re-examination, while 38 (16%, 38/240) had their hospital notes reviewed. Seventy-six patients (32%, n = 76/240) did not fulfil diagnostic criteria, of whom 39, (51%, n = 39/76) had normal (10 mm) or modest LV wall thickness (11-14 mm). The remaining 37 patients (49%, n = 37/76) had LVH ≥15 mm, which was well-explained by uncontrolled hypertension, (32%, n = 24/76), aortic valve stenosis (19%, n = 7/76) or wild-type amyloidosis (16%, 6/76). CONCLUSION: One-third of patients with ICD-10 codes for HCM or HOCM did not fulfil recognised diagnostic criteria. Incorrect diagnosis of HCM may cause unnecessary family investigations which may be associated with anxiety, and a waste of health care resources. This highlights the need for specialised cardiomyopathy services to ensure correct diagnosis and management of HCM.

Patients With Hypertrophic Cardiomyopathy and Normal Genetic Investigations Have Few Affected Relatives.

BACKGROUND: Current guidelines recommend that relatives of index patients with hypertrophic cardiomyopathy (HCM) are offered clinical investigations to identify individuals at risk of adverse disease complications and sudden cardiac death. However, the value of family screening in relatives of index patients with a normal genetic investigation of recognized HCM genes is largely unknown. OBJECTIVES: The purpose of this study was to perform family screening among relatives of HCM index patients with a normal genetic investigation to establish the frequency of familial disease and the clinical characteristics of affected individuals. METHODS: Clinical and genetic investigations were performed in consecutive and unrelated HCM index patients. Relatives of index patients who did not carry pathogenic/likely pathogenic variants in recognized HCM genes were invited for clinical investigations. RESULTS: In total, 60% (270 of 453) of HCM index patients had a normal genetic investigation. A total of 80% of their relatives (751 of 938, median age 44 years) participated in the study. Of these, 5% (34 of 751) were diagnosed with HCM at baseline, whereas 0.3% (2 of 717 [751-34]) developed the condition during 5 years of follow-up. Their median age at diagnosis was 57 years (IQR: 51-70 years). Two-thirds (22 of 36) were diagnosed following family screening, whereas one-third (14 of 36) had been diagnosed previously because of cardiac symptoms, a murmur, or an abnormal electrocardiogram. None of the affected relatives experienced adverse disease complications. The risk of SCD was low. CONCLUSIONS: Systematic family screening of index patients with HCM and normal genetic investigations was associated with a low frequency of affected relatives who appeared to have a favorable prognosis.

Clinical and Genetic Investigations of 109 Index Patients With Dilated Cardiomyopathy and 445 of Their Relatives.

BACKGROUND: It was the aim to investigate the frequency and genetic basis of dilated cardiomyopathy (DCM) among relatives of index patients with unexplained heart failure at a tertiary referral center. METHODS: Clinical investigations were performed in 109 DCM index patients and 445 of their relatives. All index patients underwent genetic investigations of 76 disease-associated DCM genes. A family history of DCM occurred in 11% (n=12) while clinical investigations identified familial DCM in a total of 32% (n=35). One-fifth of all relatives (n=95) had DCM of whom 60% (n=57) had symptoms of heart failure at diagnosis, whereas 40% (n=38) were asymptomatic. Symptomatic relatives had a shorter event-free survival than asymptomatic DCM relatives (P<0.001). RESULTS: Genetic investigations identified 43 pathogenic (n=27) or likely pathogenic (n=16) variants according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria. Forty-four percent (n=48/109) of index patients carried a pathogenic/likely pathogenic variant of whom 36% (n=27/74) had sporadic DCM, whereas 60% (21/35) were familial cases. Thirteen of the pathogenic/likely pathogenic variants were also present in ≥7 affected individuals and thereby considered to be of sufficient high confidence for use in predictive genetic testing. CONCLUSIONS: A family history of DCM identified only 34% (n=12/35) of hereditary DCM, whereas systematic clinical screening identified the remaining 66% (n=23) of DCM families. This emphasized the importance of clinical investigations to identify familial DCM. The high number of pathogenic/likely pathogenic variants identified in familial DCM provides a firm basis for offering genetic investigations in affected families. This should also be considered in sporadic cases since adequate family evaluation may not always be possible and the results of the genetic investigations may carry prognostic information with an impact on individual management.

Proof of principle: Applicator-guided stereotactic IMRT boost in combination with 3D MRI-based brachytherapy in locally advanced cervical cancer.

PURPOSE: To describe a new technique involving high-precision stereotactic intensity-modulated radiation therapy (IMRT) boost in combination with intracavitary-interstitial (IC-IS) brachytherapy (BT) in cervical tumors that cannot be sufficiently covered by IC-IS-BT due to extensive residual disease and/or difficult topography at the time of BT. METHODS AND MATERIALS: Three patients with stage IIIB-IVA cervical cancer had significant residual disease at the time of BT. MRI-guided IC-IS-BT (pulsed-dose rate) was combined with a stereotactic IMRT boost guided according to the BT applicator in situ, using cone beam CT. The planning aim dose (total external beam radiotherapy and BT) for the high-risk clinical target volume (HR-CTV) was D90 >70-85 Gy, whereas constraints for organs at risk were D2cm3 <70 Gy for rectum, sigmoid, and bowel and <90 Gy for bladder in terms of equivalent total dose in 2 Gy fractions. An IMRT boost adapted to the BT dose distribution was optimized to target the regions poorly covered by BT. RESULTS: HR-CTV doses of D90 >81 Gy were obtained in the central HR-CTV and D90 >69 Gy in the distal regions of HR-CTV. Image-guided set up of the IMRT boost with the applicator in situ was feasible. The dose plans were robust to intra-fraction uncertainties of 3 mm. Local control with acceptable morbidity was obtained at a followup of 3, 2.5, and 1 year, respectively. CONCLUSIONS: The combination of MRI-guided BT with an applicator-guided stereotactic IMRT boost is feasible. This technique seems to be useful in the few cases where HR-CTV coverage cannot be obtained even with IS-IC-BT.

Feasibility of applying a single treatment plan for both fractions in PDR image guided brachytherapy in cervix cancer.

PURPOSE: This study explores the feasibility of limiting dose optimisation to the first brachytherapy fraction (BT1) and applying the same plan for the second fraction (BT2). MATERIAL AND METHODS: Seventy one consecutive patients were analysed. Pulsed dose rate (PDR) BT was initiated after about 4 weeks of external beam radiotherapy (EBRT). Thirty eight patients had only intracavitary applicator (IC), and 33 had combined IC with interstitial needles (IC/IS). The optimised BT1 plan was copied to BT2 images with no further optimisation (single plan scenario) and dose volume histogram (DVH) parameters were compared with those of full dose optimisation for every fraction (optimised plan scenario). RESULTS: 31/38 IC patients had similar applicator geometry in both fractions and mean DVH parameters were comparable between full optimisation and single plan. The mean HR CTV D90 in total EQD2 with optimisation was 94.5 Gy and with single plan scenario was 94.4 Gy (p=0.89). Organs at risk (OARs) planning aims were fulfilled with the single plan, although 5/31 patients would receive 3-10 Gy extra to the D(2cm(3)). The mean doses in total EQD2 for the D(2cm(3)) of the bladder, rectum, sigmoid and bowel were respectively 68.5, 61.0, 64.9 and 60.6 Gy for the optimised plan, and for the single plan scenario were 69.0, 61.3, 65.1 and 60.8 Gy respectively. The difference was statistically not significant. The standard deviation (SD) of the difference between the single plan and the optimised plan was 3.2 Gy for HR CTV and 2.9, 1.4, 1.2, 1.6 Gy for the bladder, rectum, sigmoid and bowel D(2cm(3)), respectively. Only 4/33 IC/IS patients had the same applicator geometry and single plan was therefore not feasible for the majority of these patients. CONCLUSION: For IC BT in small volume tumours (primarily stage IB-IIB) with mean HR CTV volume at BT1=24±12 cm(3), comparable mean DVH parameters resulted when applying a single plan, but with considerable variations in individual patients. Yet since in our population the applied target doses are high and the OARs doses are lower than the dose volume constraints these variations may not have considerable clinical consequences. Individual optimisation for each BT fraction is recommended when interstitial needles are used.

A dose planning study on applicator guided stereotactic IMRT boost in combination with 3D MRI based brachytherapy in locally advanced cervical cancer.

PURPOSE: Locally advanced cervical cancer is usually treated with external beam radiotherapy followed by brachytherapy (BT). However, if response or tumour topography is unfavourable it may be difficult to reach a sufficient BT dose. The purpose of this study was to explore whether an applicator guided stereotactic IMRT boost could be combined with brachytherapy to improve dose volume parameters. MATERIAL AND METHODS: Dose plans of 6 patients with HR CTV volumes of 31-100cc at the time of BT were analysed. MRI was performed with a combined intracavitary (IC)-interstitial (IS) ring applicator in situ. A radiotherapy schedule consisting of 45Gy (1.8Gy x 25) IMRT followed by boost of 28Gy (7Gy x 4fx) was modelled. Four different boost techniques were evaluated: IC-BT, IC/IS-BT, IC-BT+IMRT and IMRT. Dose plans were optimised for maximal tumour dose (D90) and coverage (V85Gy) while respecting DVH constraints in organs at risk: D2cc <75Gy in rectum and sigmoid and <90Gy in bladder (EQD2). In combined BT+IMRT dose plans, the IMRT plan was optimised on top of the BT dose distribution. Volumes irradiated to more than 60 Gy EQD2 (V60Gy) were evaluated. RESULTS: Median dose coverage in IC plans was 74% [66-93%]. By using IC/IS or IC-BT+IMRT boost, the median coverage was improved to 95% [78-99%], and to 96% [69-99%] respectively. For IMRT alone, a median coverage of 98% [90-100%] was achieved, but V60Gy volumes were significantly increased by a median factor of 2.0 [1.4-2.3] as compared to IC/IS. It depended on the individual tumour topography whether IC/IS-BT or IC-BT+IMRT boost was the most favourable technique. CONCLUSION: It is technically possible to create dose plans that combine image guided BT and IMRT. In this study the dose coverage could be significantly increased by adding IS-BT or IMRT boost to the intracavitary dose. Using IMRT alone for boost cannot be advocated since this results in a significant increase of the volume irradiated to 60Gy.