Noninvasive Monitoring of Mantle Cell Lymphoma by Immunoglobulin Gene Next-Generation Sequencing in a Phase 2 Study of Sequential Chemoradioimmunotherapy Followed by Autologous Stem-Cell Rescue.

BACKGROUND: Minimal residual disease (MRD) monitoring has been used to identify early molecular relapse and predict clinical relapse in mantle cell lymphoma (MCL). Few published data exist in MCL on the performance of next-generation sequencing-based assay of immunoglobulin gene rearrangements for MRD assessment. PATIENTS AND METHODS: In a prospective clinical trial (NCT01484093) with intensive induction chemotherapy and autologous stem-cell transplantation, posttreatment peripheral blood samples were collected from 16 MCL patients and analyzed with an earlier version of the Adaptive Biotechnologies MRD assay. RESULTS: Of the 7 patients whose disease remained in remission, the MRD test remained negative in 5 (71%). Of the 9 patients who experienced relapse, the MRD test was positive at least 3 months before relapse in 6 patients (67%) and positive at the time of relapse in 1 patient (11%). All patients with at least 2 positive MRD tests experienced relapse. CONCLUSION: The next-generation sequencing-based MRD assay identified early molecular relapse, and we observed more sensitivity in the cellular (circulating leukocytes) versus acellular (plasma cell-free DNA) compartment. This observation may be due to availability of tumor target or a limitation of the assay.

Position paper: recommendations for a digital mammography quality assurance program V4.0.

In 2001 the ACPSEM published a position paper on quality assurance in screen film mammography which was subsequently adopted as a basis for the quality assurance programs of both the Royal Australian and New Zealand College of Radiologists (RANZCR) and of BreastScreen Australia. Since then the clinical implementation of digital mammography has been realised and it has become evident that existing screen-film protocols were not appropriate to assure the required image quality needed for reliable diagnosis or to address the new dose implications resulting from digital technology. In addition, the advantages and responsibilities inherent in teleradiology are most critical in mammography and also need to be addressed. The current document is the result of a review of current overseas practice and local experience in these areas. At this time the technology of digital imaging is undergoing significant development and there is still a lack of full international consensus about some of the detailed quality control (QC) tests that should be included in quality assurance (QA) programs. This document describes the current status in digital mammography QA and recommends test procedures that may be suitable in the Australasian environment. For completeness, this document also includes a review of the QA programs required for the various types of digital biopsy units used in mammography. In the future, international harmonisation of digital quality assurance in mammography and changes in the technology may require a review of this document. Version 2.0 represented the first of these updates and key changes related to image quality evaluation, ghost image evaluation and interpretation of signal to noise ratio measurements. In Version 3.0 some significant changes, made in light of further experience gained in testing digital mammography equipment were introduced. In Version 4.0, further changes have been made, most notably digital breast tomosynthesis (DBT) testing and QC have been addressed. Some additional testing for conventional projection imaging has been added in order that sites may have the capability to undertake dose surveys to confirm compliance with diagnostic reference levels (DRLs) that may be established at the National or State level. A key recommendation is that dosimetry calculations are now to be undertaken using the methodology of Dance et al. Some minor changes to existing facility QC tests have been made to ensure the suggested procedures align with those most recently adopted by the Royal Australian and New Zealand College of Radiologists and BreastScreen Australia. Future updates of this document may be provided as deemed necessary in electronic format on the ACPSEM's website ( https://www.acpsem.org.au/whatacpsemdoes/standards-position-papers and see also http://www.ranzcr.edu.au/quality-a-safety/radiology/practice-quality-activities/mqap ).

Diagnostic accuracy of ¹8F-FDG PET/CT for detection of advanced colorectal adenoma.

AIM: To determine the accuracy of 2-[(18)F]-fluoro-2-deoxy-d-glucose (FDG) positron-emission tomography (PET) in the detection of advanced colorectal adenomas. MATERIALS AND METHODS: In this retrospective study, patient consent was waived by the institutional review board. Combined FDG whole-body PET and computed tomography (CT) images (2000-2009) were re-read and compared with reports of complete colonoscopy performed up to 1 year after the PET examination. One or more areas of focal colonic uptake greater than the background indicated a positive PET result, irrespective of standardized uptake value (SUV). Lesion and patient-level measures of PET accuracy with their 95% confidence intervals (CI) were calculated. RESULTS: One hundred and eighty patients undergoing colonoscopy with or without biopsy underwent PET within 1 year prior to colonoscopy. There were 92 women and 88 men (mean age 63.3 years). Indications for PET were extent of disease and treatment response in all cases. Patients had non-colorectal cancer (n = 160) or colon cancer (n = 20). One hundred and fourteen FDG-avid lesions were present. In 33, there was no colonoscopic correlate. Two hundred and fifty-eight biopsies revealed tubular adenomas (n = 91, one with intra-mucosal cancer), tubulovillous adenomas (n = 28), adenocarcinoma (n = 37), inflammation (n = 22), hyperplastic polyps (n = 54), serrated adenoma (n = 5), metastatic disease (n = 5), normal/benign mucosa or submucosal benign tumors (n = 13) or miscellaneous (n = 3). Per-lesion performance of PET showed a sensitivity of 38% (95% CI: 31-46; 64/167) for all adenomas and carcinomas and 58% (95% CI: 49-67; 57/98) for lesions ≥ 10 mm. At the patient level, for all adenomas and carcinomas the sensitivity was 54% (95% CI: 44-63; 61/113), specificity 100% (pre-defined), positive predictive value (PPV) 100% (pre-defined), and negative predictive value (NPV) 56% (95% CI: 47-65; 67/119). For patients with advanced adenoma, PET sensitivity was 49% (95% CI: 35-63; 26/53) specificity, 100%, PPV 100% and NPV 82% (95% CI: 76-88; 127/154). Five of 37 adenocarcinomas were not detected, one of which was mucinous at histology. CONCLUSION: FDG PET detected most cancers, but only identified one-half of patients harbouring advanced adenomas. Based on the data, PET cannot be relied upon to accurately identify patients with advanced adenoma.

Clinical outcomes and molecular profile of differentiated thyroid cancers with radioiodine-avid distant metastases.

BACKGROUND: Radioiodine (RAI) remains the mainstay of therapy for RAI-avid (RAIA) distant metastatic thyroid carcinoma. We previously demonstrated that RAI-refractory distant metastatic thyroid cancers commonly harbor BRAF mutations. However, the molecular profile of RAIA metastatic thyroid cancer is unknown. Here we describe the mutational profile of thyroid tumors from follicular cell-derived cancer (FCDTC) patients presenting with RAIA distant metastases. In addition, we aimed to correlate clinical outcomes of RAI therapy with clinicopathological factors and tumor mutational status. METHODS: We retrospectively identified 43 patients with FCDTC who had RAI uptake in the lungs and/or bones on their initial ¹³¹I postablation scan. Primary tumors were genotyped for known mutations in thyroid cancer genes. Structural response to RAI was assessed 6-18 months after each administered RAI activity and at the end of follow-up. RESULTS: RAS, BRAF, RET/PTC, and PIK3CA mutations were found in 42, 23, 10, and 2% of tumors, respectively, and the remaining 23% were wild type. None of these patients achieved cure after repeat RAI therapies, and most patients (54%) experienced disease progression despite repeated RAI administration. There was an increased prevalence of RAS mutations in these RAIA tumors. RAS-mutant cancers were more likely to concentrate iodine on diagnostic whole body scans. Despite this, structural response to RAI was not influenced by tumor genotype. CONCLUSIONS: RAIA metastatic FCDTC are overrepresented with RAS mutations, whereas RAI refractory metastatic thyroid cancers are enriched with BRAF mutations. Despite a seemingly preserved ability to concentrate iodine, RAI therapy is ineffective in achieving cure in most patients with RAIA metastatic FCDTC, even in RAS-mutant disease. These poor outcomes may be improved based on recent evidence that pretreatment with MAPK kinase 1/2 inhibitors enhances responses to RAI, particularly in patients with RAS-mutant tumors.

Digital chest radiography image quality assessment with dose reduction.

A retrospective study of digital chest radiography was performed to compare the image quality and dose parameters from two X-ray rooms in different areas of the same hospital using identical X-ray units but different local protocol for obtaining chest PA and lateral radiographs. Image quality of radiographs was assessed from the printed films using well established European guidelines and modified criteria. Patient entrance surface air kerma was calculated using technical data recorded for each radiograph and measured output of the X-ray unit. Effective dose and dose to radiosensitive organs was estimated using dose calculation software PCXMC. There was no statistical significant difference in the evaluated image quality using either technique, median entrance surface air kerma to the patient reduced significantly with added filtration technique and use of normal density setting. Phantom measurements indicated that an additional filtration of 0.1 mm Cu + 1 mm Al in the X-ray beam alone reduced the entrance surface air kerma by 35%.

Focal myocardial uptake in a patient with carcinoid tumor by indium-111-pentetreotide on SPECT/CT.

We present a case of a 44 year old man with flushing, diarrhea and markedly elevated 24 hour urinary 5-HIAA level, who was referred for an indium-111 pentetreotide study, after the excision of a carcinoid tumor in the terminal ileum. Scan findings revealed focal uptake in the myocardium and liver, suspicious for metastases. Subsequent transthoracic echocardiogram failed to demonstrate a cardiac lesion. Previously, our group has unequivocally demonstrated the usefulness of software fusion of SPECT and CT imaging in the evaluation of a carcinoid metastasizing to the myocardium. This case illustrates that hardware SPECT/CT fusion imaging utilizing indium-111 pentetreotide to evaluate metastatic carcinoid tumors can be useful. In addition, the echocardiogram can yield false negative results, because of a smaller lesion size and the influence of an operator-dependent factor.

Captación focal miocárdica con 111 In-pentetreótido (spect/tac), en un paciente con tumor carcinoide / Focal myocardial uptake in a patient with carcinoid tumor by indium-111-pentetreotide on SPECT/CT

We present a case of a 44 year old man with flushing, diarrhea and markedly elevated 24 hour urinary 5-HIAA level, who was referred for an indium-111 pentetreotide study, after the excision of a carcinoid tumor in the terminal ileum. Scan findings revealed focal uptake in the myocardium and liver, suspicious for metastases. Subsequent transthoracic echocardiogram failed to demonstrate a cardiac lesion. Previously, our group has unequivocally demonstrated the usefulness of software fusion of SPECT and CT imaging in the evaluation of a carcinoid metastasizing to the myocardium. This case illustrates that hardware SPECT/CT fusion imaging utilizing indium-111 pentetreotide to evaluate metastatic carcinoid tumors can be useful. In addition, the echocardiogram can yield false negative results, because of a smaller lesion size and the influence of an operator-dependent factor

Presentamos un caso de un paciente de 44 años con rubefacción, diarrea y un nivel considerablemente elevado de 5-HIAA urinario en 24 horas, y que fue referido para la realización de un estudio 111In-pentetreótido, tras la escisión de un tumor carcinoide del íleon terminal. Los hallazgos de la gammagrafía revelaban captación focal en miocardio e hígado, sospechosa de metástasis. Un ecocardiograma transtorácico posterior no logró demostrar una lesión cardíaca. Anteriormente nuestro grupo había demostrado sin lugar a dudas la utilidad del software de fusión de imágenes de tomografía computarizada por emisión de fotón único (SPECT) y tomografía axial computarizada (TAC) para la evaluación de un tumor carcinoide que metastatiza en miocardio. Este caso demuestra que el hardware de fusión de imágenes SPECT/TAC utilizando 111In-pentetreótido para evaluar los tumores carcinoides metastásicos puede ser útil. Además, el ecocardiograma puede dar lugar a falsos resultados negativos, debido a un tamaño de lesión más pequeño y a la influencia de un factor dependiente del operador (AU)

Interim recommendations for a digital mammography quality assurance program.

In 2001 the ACPSEM published a position paper on quality assurance in screen film mammography which was subsequently adopted as a basis for the quality assurance programs of both the Royal Australian and New Zealand College of Radiologists (RANZCR) and of BreastScreen Australia. Since then the clinical implementation of digital mammography has been realised and it has become evident that existing screen-film protocols were not appropriate to assure the required image quality needed for reliable diagnosis or to address the new dose implications resulting from digital technology. In addition, the advantages and responsibilities inherent in teleradiology are most critical in mammography and also need to be addressed. The current document is the result of a review of current overseas practice and local experience in these areas. At this time the technology of digital imaging is undergoing significant development and there is still a lack of full international consensus about some of the detailed Quality Control tests that should be included in quality assurance (QA) programs. This document describes the current status in digital mammography QA and recommends test procedures that may be suitable in the Australasian environment. For completeness, this document also includes a review of the QA programs required for the various types of digital biopsy units used in mammography. In the future, international harmonisation of digital quality assurance in mammography and changes in the technology may require a review of this document. Accordingly, updates of this document will be provided as deemed necessary in electronic format on the ACPSEM's website (see http://www.acpsem.org.au/au/subgroup/radiology/RadiologySG_index.html).

Comparative evaluation of an II based and a flat panel based cardiovascular fluoroscopy system within a clinical environment.

The image quality and dose parameters from a 2004 Siemens Axiom Artis dBC cardiac biplane with flat panel detector were evaluated and compared to similar parameters evaluated for a 1977 Toshiba DPF 2000A biplane cardiac unit with a conventional image intensifier. Image quality assessment was performed with the Westmead test object; using solid water as a patient equivalent absorber. The patient dose comparison of the two systems is based on dose area product meter readings for 1512 patient cases recorded over 6 months following installation of the Siemens flat panel digital unit. The image quality results indicate that: (a) high contrast resolution was better with the digital flat panel unit, (b) low contrast resolution is similar between systems, and (c) the threshold contrast of the flat panel system is the same or inferior to that of the image intensifier system. Input dose to the surface of the flat panel detector showed a strong dependence on field size, similar to the behaviour of image intensifier system. For the most common clinical procedure--Left Heart Study via Judkins--the average total dose area product reading was 64.0 Gy-cm2 against 67.7 Gy-cm2 for the digital and conventional units respectively (p = 0.27) indicating no significant difference in dose performance between the two x-ray machines.

Recommendations for a technical quality control program for diagnostic X-ray equipment.

This position paper was produced by a working party set up by the Radiology Special Interest Group of the ACPSEM in 2001. It is designed to give the consensus view of College members in Australia and New Zealand on the nature and frequency of tests which should be performed on diagnostic x-ray equipment to maintain adequate quality control of imaging performance and radiation safety. Tests on mammographic equipment have been excluded having been covered in a previous ACPSEM position paper (Australas Phys Eng Sci Med, 24(3):107-131, 2001). Detailed descriptions of test procedures are not given but it is intended that a series of workbooks should be produced giving College recommended test methods for each imaging modality. The recommendations are produced here in an easy-to-read, tabular form giving the nature and purpose of each test and the implications of non-compliance with regard to image quality and radiation safety.

A study of prevalence of Chlamydia trachomatis infection in women with first trimester pregnancy losses.

The study included 125 patients in the first trimester of pregnancy, who were divided into group A (50 control subjects with normal intrauterine pregnancy), Group B (50 patients with spontaneous abortion), group C (25 patients with ectopic pregnancy). All the patients were investigated including routine blood and urine tests and special tests related to the cause of pregnancy loss. The patients were tested for IgG antibodies to Chlamydia trachomatis by ELISA technique and conjunctival smear were tested for presence of inclusion bodies to C. trachomatis. It was concluded that C. trachomatis is one of the important cause of spontaneous abortion and ectopic pregnancy. It is highly prevalent in our population, the prevalence being 10% in group A, 26% in group B, 28% in group C. Conjunctival smear showed presence of inclusion bodies in 0.8% patients. With abortions then risk of lower genital tract chlamydia infection spreading to upper genital tract increases. ELISA for C. trachomatis should be done when women are being investigated for the cause of spontaneous abortion and ectopic pregnancy.

Mutation analysis of oculopharyngeal muscular dystrophy in Hispanic American families.

BACKGROUND: Oculopharyngeal muscular dystrophy (OPMD) is a late-onset autosomal dominant muscular dystrophy characterized by progressive ptosis, swallowing difficulties, and proximal limb weakness. Recently, the genetic basis of this disease has been characterized by mutations in the PABP2 gene that involve short expansions of the trinucleotide repeat GCG. OBJECTIVES: To independently confirm the presence and study the meiotic stability of the GCG expansion mutations in a distinct ethnic population with OPMD. SETTINGS: Hospital and university research laboratories in Los Angeles, Calif. SUBJECTS AND METHODS: Three unrelated families of Hispanic American descent were identified in whom OPMD was transmitted in an autosomal dominant pattern. All of these families can trace affected ancestors to the southwestern United States or to the bordering states of Mexico. In these families, 14 persons with OPMD were identified and studied. RESULTS: Our results confirm that in these families, expansion mutations characterized by a gain of 3 GCG repeats in the wild-type allele result in an abnormal nucleotide length of 9 GCG repeats in the PABP2 gene. In these families, these mutations are associated with the OPMD phenotype. The identical repeat mutation ([GCG]9) is found in all affected members of these unrelated families and shows relative meiotic stability. CONCLUSIONS: These results support and extend our study of haplotype analysis and suggest that a founder effect may have occurred for OPMD in this Hispanic American population.

Genetic mapping and haplotype analysis of oculopharyngeal muscular dystrophy.

Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant muscular dystrophy characterized by late onset ptosis, proximal muscle weakness and swallowing difficulties. This disease has been recently linked to chromosome 14q11.2-q13 in French-Canadian pedigrees. We studied three unrelated American families with OPMD of Hispanic descent and our results indicate that in this ethnic group, this disease also maps to chromosome 14q11.2-q13 (marker MYH7.24; Zmax = 3.98; theta max = 0). These results represent an independent demonstration of disease linkage in a second distinct ethnic group. Furthermore, our analysis demonstrates a unique haplotype that is shared by affected individuals from all three families suggesting a founder effect for OPMD in this population. Meiotic recombinants and radiation hybrid mapping permit the narrowing of the critical region to 1 Mb which will facilitate positional cloning of the OPMD disease gene.

Apraclonidine and anterior segment laser surgery. Comparison of 0.5% versus 1.0% apraclonidine for prevention of postoperative intraocular pressure rise.

PURPOSE: To compare the efficacy of 0.5% and 1.0% apraclonidine in preventing laser-induced intraocular pressure (IOP) elevation after trabeculoplasty, neodymium: YAG (Nd: YAG) iridotomy, and capsulotomy. METHODS: This is a prospective, masked, and randomized study of 83 patients undergoing trabeculoplasty, 62 patients undergoing iridotomy, and 57 patients undergoing capsulotomy. Surgical eyes received one drop of 0.5% or 1.0% apraclonidine immediately after surgery. RESULTS: Intraocular pressure reduced 2 hours after trabeculoplasty in the 0.5% (P = 0.028) and 1.0% (P = 0.004) groups. Intraocular pressure was higher than baseline in a greater number of eyes treated with 0.5% (12 of 39 eyes, 31%) compared with 1.0% apraclonidine (5 of 44 eyes, 11%) (P = 0.032). Intraocular pressure in eyes with a narrow chamber angle was reduced in 16 (85%) of 19 eyes treated with 0.5% and in 10 (84%) of 12 eyes treated with 1.0% apraclonidine after iridotomy. Of patients with chronic angle-closure glaucoma, IOP was similar to prelaser values in 11 (69%) of 16 eyes treated with 0.5% (P > 0.7) and 12 (80%) of 15 eyes treated with 1.0% apraclonidine (P > 0.3). In patients undergoing capsulotomy, pressure was significantly lowered in the 0.5% group (P = 0.04) but not in the 1.0% apraclonidine group. After capsulotomy, both treatment groups had similar (P > 0.3) numbers of eyes with an IOP less than baseline (83% for 0.5% apraclonidine and 81% for 1.0% apraclonidine). CONCLUSION: The single postoperative administration of 0.5% apraclonidine is as effective as the 1.0% concentration in preventing IOP elevation immediately after trabeculoplasty, iridotomy, or capsulotomy.

A comparative study of ophthalmodynamometry in hypertensive and non-hypertensive cases.

Ophthalmodynamometry was done on 100 hypertensive cases and 100 non-hypertensive cases who had clear media and no glaucoma. The ratio of the pressure mean ophthalmic: pressure mean brachial in the non-hypertensive group was 0.71:1.0, which rose to 0.78:1.0 in the hypertensive group. The ophthalmic humeral diastolic ratio increased with the severity of fundus changes. The pressure mean ophthalmic showed higher values with increasing grades of fundus changes. Those cases having a pressure mean opthalmic higher than the expected value in the hypertensive group as compared to the cases having a pressure mean ophthalmic lower than the expected value, were at a greater risk or had a graver prognosis. The importance of ophthalmodynamometry is stressed for the prognosis of hypertension along with the fundus examination.