Radiation Therapy Dose Escalation in Unresectable Ewing Sarcoma: Final Results of a Phase 3 Randomized Controlled Trial.

PURPOSE: Our aim was to assess the effect of radiation therapy (RT) dose escalation on outcomes in surgically unresectable Ewing sarcoma (ES)/primitive neuroectodermal tumor (PNET). METHODS AND MATERIALS: Patients with nonmetastatic unresectable ES/PNET (excluding intracranial/chest wall) receiving vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide chemotherapy, planned for definitive RT, were accrued in this single-institution, open-label, phase 3 randomized controlled trial. Randomization was between standard dose RT (SDRT; 55.8 Gy/31 fractions/5 days a week) versus escalated dose RT (EDRT; 70.2 Gy/39 fractions/5 days a week) with a primary objective of improving local control (LC) by 17% (65%-82%). Secondary outcomes included disease-free survival (DFS), overall survival (OS), and functional outcomes by Musculoskeletal Tumor Society score. RESULTS: Between April 2005 and December 2015, 95 patients (SDRT 47 and EDRT 48) with a median age of 17 years (interquartile range, 13-23 years) were accrued. The majority of patients were male (59%). Pelvis was the most common site of primary disease (n = 60; 63%). The median largest tumor dimension (9.7 cm) and the median maximum standardized uptake value (8.2) on pretreatment fluorodeoxyglucose positron emission tomography-computed tomography were similar. At a median follow-up of 67 months, the 5-year LC, DFS, and OS for the entire cohort was 62.4%, 41.3%, and 51.9%, respectively. The 5-year LC was significantly better in EDRT compared with SDRT (76.4% vs 49.4%; P = .02). The differences in DFS and OS at 5 years (for EDRT vs SDRT) did not achieve statistical significance (DFS 46.7% vs 31.8%; P = .22 and OS 58.8% vs 45.4%; P = .08). There was a higher incidence of Radiation Therapy Oncology Group grade >2 skin toxic effects (acute) in the EDRT arm (10.4% vs 2.1%; P = .08) with excellent functional outcomes (median Musculoskeletal Tumor Society score = 29) in both arms. CONCLUSIONS: EDRT results in improved LC with good functional outcomes without a significant increase in toxic effects. Radiation dose escalation should be considered for surgically unresectable nonmetastatic ES/PNET.

Multiparametric Magnetic Resonance Imaging Correlates of Isocitrate Dehydrogenase Mutation in WHO high-Grade Astrocytomas.

Purpose and background: Isocitrate dehydrogenase (IDH) mutation and O-6 methyl guanine methyl transferase (MGMT) methylation are surrogate biomarkers of improved survival in gliomas. This study aims at studying the ability of semantic magnetic resonance imaging (MRI) features to predict the IDH mutation status confirmed by the gold standard molecular tests. Methods: The MRI of 148 patients were reviewed for various imaging parameters based on the Visually AcceSAble Rembrandt Images (VASARI) study. Their IDH status was determined using immunohistochemistry (IHC). Fisher's exact or chi-square tests for univariate and logistic regression for multivariate analysis were used. Results: Parameters such as mild and patchy enhancement, minimal edema, necrosis < 25%, presence of cysts, and less rCBV (relative cerebral blood volume) correlated with IDH mutation. The median age of IDH-mutant and IDH-wild patients were 34 years (IQR: 29−43) and 52 years (IQR: 45−59), respectively. Mild to moderate enhancement was observed in 15/19 IDH-mutant patients (79%), while 99/129 IDH-wildtype (77%) had severe enhancement (p-value <0.001). The volume of edema with respect to tumor volume distinguished IDH-mutants from wild phenotypes (peritumoral edema volume < tumor volume was associated with higher IDH-mutant phenotypes; p-value < 0.025). IDH-mutant patients had a median rCBV value of 1.8 (IQR: 1.4−2.0), while for IDH-wild phenotypes, it was 2.6 (IQR: 1.9−3.5) {p-value = 0.001}. On multivariate analysis, a cut-off of 25% necrosis was able to differentiate IDH-mutant from IDH-wildtype (p-value < 0.001), and a cut-off rCBV of 2.0 could differentiate IDH-mutant from IDH-wild phenotypes (p-value < 0.007). Conclusion: Semantic imaging features could reliably predict the IDH mutation status in high-grade gliomas. Presurgical prediction of IDH mutation status could help the treating oncologist to tailor the adjuvant therapy or use novel IDH inhibitors.

8th edition AJCC and imaging TNM: Time to break-in and assert in the staging process!

The current practice of oncology focuses not only on early diagnosis, staging, and treatment of cancer but also defies the concept of "One size fits all." This paradigm shift of the 8th edition American Joint Committee on Cancer (AJCC) manual to a "personalized medicine" approach sets the stage for introducing Imaging TNM (iTNM). The iTNM would provide physicians with a clear assessment of the disease extent derived exclusively from a combination of anatomical and functional imaging modalities and simplify decision-making in practice. Introduction of iTNM will complement the existing cTNM and pTNM and help to guide a personalized approach to patient management.

Radiomics based detection and characterization of suspicious lesions on full field digital mammograms.

BACKGROUND AND OBJECTIVE: Early detection is the important key to reduce breast cancer mortality rate. Detecting the mammographic abnormality as a subtle sign of breast cancer is essential for the proper diagnosis and treatment. The aim of this preliminary study is to develop algorithms which detect suspicious lesions and characterize them to reduce the diagnostic errors regarding false positives and false negatives. METHODS: The proposed hybrid mechanism detects suspicious lesions automatically using connected component labeling and adaptive fuzzy region growing algorithm. A novel neighboring pixel selection algorithm reduces the computational complexity of the seeded region growing algorithm used to finalize lesion contours. These lesions are characterized using radiomic features and then classified as benign mass or malignant tumor using k-NN and SVM classifiers. Two datasets of 460 full field digital mammograms (FFDM) utilized in this clinical study consists of 210 images with malignant tumors, 30 with benign masses and 220 normal breast images that are validated by radiologists expert in mammography. RESULTS: The qualitative assessment of segmentation results by the expert radiologists shows 91.67% sensitivity and 58.33% specificity. The effects of seven geometric and 48 textural features on classification accuracy, false positives per image (FPsI), sensitivity and specificity are studied separately and together. The features together achieved the sensitivity of 84.44% and 85.56%, specificity of 91.11% and 91.67% with FPsI of 0.54 and 0.55 using k-NN and SVM classifiers respectively on local dataset. CONCLUSIONS: The overall breast cancer detection performance of proposed scheme after combining geometric and textural features with both classifiers is improved in terms of sensitivity, specificity, and FPsI.

Analysis of bone and soft-tissue sarcomas registered during the year 2012 at Tata Memorial Hospital, Mumbai, with clinical outcomes.

INTRODUCTION: Primary bone and soft tissue sarcomas are rare, but diagnostically and therapeutically challenging group of tumors, requiring multidisciplinary management. There are limited documented studies from multidisciplinary teams , in the form of comprehensive analysis of these tumors, from our country. This study is an analysis of cases of osteosarcomas, Ewing sarcomas (ESs), chondrosarcomas (CSs), and soft-tissue sarcomas (STSs), registered at our institution during 2012. METHODS: Clinical details, including outcomes of cases of bone and STSs, during the year 2012, were retrieved from the medical records of our institution and were further analyzed. RESULTS: Ninety-five high-grade, extremity-based, treatment-naïve cases of osteosarcomas were treated with a novel, dose-dense, nonhigh-dose methotrexate-based OGS-12 protocol. Good histopathologic response (necrosis ≥90%) was achieved in 59% nonmetastatic and 56% metastatic patients. At a median follow-up of 48 months, the estimated 5-year event-free survival and overall survival (OS) were 67% and 78%, respectively. In the metastatic cohort at a median follow-up of 51 months, the 5-year estimated progression-free survival was 24% and OS was 26%. Among 87 (73.2%) nonmetastatic and 32 (26.8%) metastatic, analyzable cases of ES, at a median follow-up of 40 months, the disease-free survival (DFS) and OS in the nonmetastatic group were 62% and 83%; in the metastatic group, they were 37.5% and 65.6%, respectively. Among 40 cases of CSs (33 nonmetastatic and 7 metastatic), 21 had limb salvage surgery while 5 had amputation. Microscopically, 90.4% were Grade II CSs. Five-year OS and DFS were 84.6% and 71%, respectively. Among 189 high-grade, extremity-based STSs (89% nonmetastatic), synovial sarcoma was the most common subtype (31%). Eighty-five percent had limb preservation surgery; a majority were offered adjuvant radiation with or without chemotherapy. At a median follow-up of 51 (1-63) months, 3-year local control, DFS, and OS were 81%, 48%, and 64%, respectively. CONCLUSIONS: The novel OGS 12 and Ewing Family of Tumors 2001 protocols have shown comparable outcomes to international standards in cases of osteosarcoma and ES, respectively, and merit wider applications, especially in low- and middle-income countries (LMICs). Outcomes in STS and CSs were also comparable and underscore the importance of a multidisciplinary approach for the management of sarcomas in LMICS.

Potential role of whole-body diffusion magnetic resonance imaging in tumor staging for pregnant patients with cancer.

Malignancy during pregnancy poses a serious threat to the growing fetus. In this special situation, the diagnostic procedures and treatment to cancer will be more damaging to the developing fetus than the cancer itself. However, to safeguard the health of the mother from cancer, appropriate diagnostic and therapeutic tools are to be used that would minimize risk to fetal health. Diffusion-weighted whole-body imaging with background body signal suppression has the potential to answer most of these diagnostic dilemmas in the case of malignancy in pregnancy. This is one of the first such reports highlighting the role of a noninvasive, nonionizing whole-body imaging technique which does not require external contrast injection and can also be used for monitoring treatment response.

Second Opinion by In-House Radiologists: Present Picture and Emphasis on Standardizing Imaging Protocol in Oncology.

Standardization of imaging acquisition protocol, modification in protocols for specific tumor and standardization in providing image data sets for outside referral, will help not only patients but also oncologists (who requests the second read) and the radiologists (who provides the second read on outside imaging). The practical benefits to patients include, cost savings (limiting the repeat radiological examination), timely initiation of treatment; the unrealized benefits include prevention of unnecessary anxiety and discomfort. In such second opinions, the radiologists should answer key clinical issues about resectability and other relevant findings in provisionally diagnosed cancers. In this article we will discuss the present scenario regarding second opinion of outside diagnostic imaging, the current approach, challenges and its optimization.

Pulmonary cement embolism in a child following total elbow replacement for primitive neuroectodermal tumour (PNET) of the humerus.

Pulmonary bone cement embolism (PCE) is an uncommon event occurring after implantation of polymethylmethacrylate (PMMA) in orthopaedic surgeries involving adult patients, more so in the elderly. Its incidence in the paediatric population is extremely rare. We herein describe a case of PCE in a 15-year-old girl, 9 days after she underwent total elbow replacement with PMMA placement for a primitive neuroectodermal tumour (PNET) of the distal humerus. This report describes the occurrence of a common post-operative complication of bone cement embolism in an uncommon scenario of total elbow replacement for a bone tumour in a child, which masqueraded initially as acute pneumonitis.

Case of victims of modern imaging technology: Increased information noise concealing the diagnosis.

We present a case of tubercular arthritis who underwent numerous unnecessary investigations what is known as "victims of modern imaging technology" or VOMIT. Today there is an exponential rise in the volume of the medical imaging, part of which is contributed by unnecessary and unjustified indications. We discuss about the untoward effects of the uninhibited and careless use of modern imaging modalities and possible ways to avoid. Skeletal manifestation of the tuberculosis is still common in the endemic countries like India. Although the final diagnosis of the skeletal tuberculosis like tubercular arthritis is made by bacteriological and histological studies, few demographic, clinical and radiological features might help making early diagnosis.

Nonsubsampled rotated complex wavelet transform (NSRCxWT) for medical image fusion related to clinical aspects in neurocysticercosis.

Neurocysticercosis (NCC) is a parasite infection caused by the tapeworm Taenia solium in its larvae stage which affects the central nervous system of the human body (a definite host). It results in the formation of multiple lesions in the brain at different locations during its various stages. During diagnosis of such symptomatic patients, these lesions can be better visualized using a feature based fusion of Computed Tomography (CT) and Magnetic Resonance Imaging (MRI). This paper presents a novel approach to Multimodality Medical Image Fusion (MMIF) used for the analysis of the lesions for the diagnostic purpose and post treatment review of NCC. The MMIF presented here is a technique of combining CT and MRI data of the same patient into a new slice using a Nonsubsampled Rotated Complex Wavelet Transform (NSRCxWT). The forward NSRCxWT is applied on both the source modalities separately to extract the complementary and the edge related features. These features are then combined to form a composite spectral plane using average and maximum value selection fusion rules. The inverse transformation on this composite plane results into a new, visually better, and enriched fused image. The proposed technique is tested on the pilot study data sets of patients infected with NCC. The quality of these fused images is measured using objective and subjective evaluation metrics. Objective evaluation is performed by estimating the fusion parameters like entropy, fusion factor, image quality index, edge quality measure, mean structural similarity index measure, etc. The fused images are also evaluated for their visual quality using subjective analysis with the help of three expert radiologists. The experimental results on 43 image data sets of 17 patients are promising and superior when compared with the state of the art wavelet based fusion algorithms. The proposed algorithm can be a part of computer-aided detection and diagnosis (CADD) system which assists the radiologists in clinical practices.

Clinicopathological Features of a Series of 27 Cases of Post-Denosumab Treated Giant Cell Tumors of Bones: A Single Institutional Experience at a Tertiary Cancer Referral Centre, India.

Giant cell tumor of bone (GCTB) is mostly a benign tumor, but associated with recurrences and metastasis. Lately, denosumab is being utilized in the treatment of certain GCTBs. Twenty-seven tumors, analyzed in the present study, occurred in 16 males and 11 females (M: F = 1.45:1), in the age-range of 16 to 47 years (mean = 29.5, median = 29). Most tumors were identified in the tibia(6) and femur(6), followed by the humerus(3), radius(3), pelvis(3), fibula(3), sacrum(1), metacarpal(1) and metatarsal(1) bones. There were 18(66.6 %) primary and 9(33.3 %) recurrent tumors. Exact tumor size (19 cases) varied from 3.7 to 15 cm (mean = 7.8, median = 6.4). Eight of the 19 tumors (42.1 %) had size more than or equal to 8 cm. On histopathologic examination of post-denosumab treated specimens, more than half cases (15)(55.5 %) revealed complete absence of osteoclast-like giant cells (OCLGs) and 12 cases revealed residual OCLGCs. In addition, there was replacement by fibro-osseous tissue, including reactive woven bone or osteoid in most cases, followed by variable amount of spindle cells, hyalinisation, fibrosis and chronic inflammatory cells, including lymphocytes, macrophages and plasma cells. Post-treatment follow-up (25 cases, 92.5 %), over 7-27 months duration (median = 18), revealed 20 cases continuously disease-free. Five patients developed recurrences at 9, 12, 13, 14 and 18 months, respectively. Out of these, who underwent repeat surgical intervention, 4 patients are alive with no evidence of disease and a single patient, planned for a second surgery, is alive-with-disease. Denosumab was mostly offered to patients with large sized, borderline salvageable tumors, in order to decrease the morbidity of index surgical procedure, that led to disappearance of OCLGCs in most cases. Post-denosumab treated GCT cases appear as low grade osteosarcomas on histopathologic examination, but lack the clinical behaviour of an osteosarcoma, therefore may be considered as pseudo malignant bony lesions.

Iatrogenic implantation of giant cell tumor at bone graft donor site and clinical recommendations to prevent "a rare avoidable complication".

The treatment of giant cell tumor of bone is directed toward local control without sacrificing joint function. This is achieved by intralesional curettage. When autograft is used for the reconstruction of the curetted cavity, there is always a theoretical risk of contamination of graft donor site. We report a case of iatrogenic implantation of giant cell tumor at the bone graft donor site after intralesional curettage and bone grafting of giant cell tumor of distal femur. Patient was treated with repeat intralesional curettage and excision of implantation lesion at bone graft donor site. We recommend precautionary measures to prevent this avoidable complication.

Melanotic neuroectodermal tumor of infancy in thigh of an infant--a rare case report with diagnostic implications.

Melanotic neuroectodermal tumor of infancy (MNTI) is an uncommon tumor of neural crest origin, almost invariably identified in the head and neck region. It is a relatively benign tumor but can recur and rarely metastasize. Herein, a rare case of MNTI in the thigh of an infant is documented. Radiographic imaging showed a sclerotic and lytic lesion in the metadiaphyseal region of the right femur with a soft tissue component. The clinicoradiological impression was of a malignant round cell tumor and osteomyelitis. The patient's urinary vanil mandelic acid (VMA) level was elevated. FNAC smears revealed a tumor with round to polygonal cells, focally containing black melanin pigment. Biopsy and tumor excision revealed a tumor with cells in cords and nests embedded in a fibrocollagenous stroma and showed bone and soft tissue infiltration. On immunohistochemistry, tumor cells displayed immunoreactivity to vimentin, cytokeratin (CK), CK7, CK19, and MIC2, and focal reactivity for synaptophysin and HMB45. Diagnosis of an MNTI was made. The patient underwent induction chemotherapy with extracorporeal radiotherapy, followed by a soft tissue excision that revealed residual tumor. Surgically, free marrow margins were accomplished, and the patient is currently being followed-up. To the best of our knowledge this case is the fifth documented case in the English literature of MNTI in the thigh. The diagnostic and therapeutic implications are discussed.

Rhinosporidiosis isolated to the distal clavicle: a rare presentation clinicoradiologically mimicking a bone tumor.

Rhinosporidiosis is a chronic granulomatous disease caused by Rhinosporidium seeberi, which commonly affects young men and predominantly involves the mucous membranes of the nose, nasopharynx and eyes. Involvement of extranasal sites including bone has been reported, but rarely. We present a case of a 32-year-old farmer, who presented with a non-tender, fixed swelling over his right shoulder. Radiography and CT imaging showed an expansile, lytic, destructive lesion involving the lateral end of the right clavicle with soft tissue extension. The clinicoradiological impression was that of a primary bone tumor. Biopsy and wide excision of the lesion revealed features of rhinosporidiosis. There were no mucocutaneous lesions. Involvement of bone without associated mucocutaneous lesions is exceedingly rare in rhinosporidiosis. Involvement of the clavicle, as seen in the present case, has not been reported in the English language-peer reviewed literature, to the best of our knowledge.

Epithelioid angiomyolipoma of kidney with atypical nuclear features and intranuclear inclusions on cytology.

Described herein are the cytological findings of epithelioid angiomyolipoma (EAML) of the kidney with atypical nuclear features mistaken for renal cell carcinoma (RCC) in a 61-year-old male patient. Aspirates from this large renal mass were cellular and showed epithelioid cell clusters with focally crowded nuclei showing moderate anisonucleosis, small nucleoli, and prominent eosinophilic intranuclear inclusions. Failure to recognize the scanty adipose tissue component and preponderance of epithelioid cells with nuclear pleomorphism lead to a diagnosis of RCC on cytology. On histology, the tumor was essentially composed of epithelioid and spindle cells that showed the typical immunoprofile of an angiomyolipoma and only occasional foci of typical AML were seen. The hilar lymph node was involved in contiguity. However, in view of lack of obvious features of malignancy, the tumor was labeled as EAML with atypical features. Immunocytochemistry on the destained cytology aspirates revealed strong smooth muscle actin staining of all cells. To conclude, EAML can mimic a RCC. In such instances, lack of arborizing vasculature, absence of cytoplasmic fatty vacoulation, crowded nuclei with intranuclear inclusions, and lack of prominent nucleoli along with typical immunophenotype of EAML may assist in the cytology diagnosis.