Tata Memorial Centre Evidence Based Use of Nuclear medicine diagnostic and treatment modalities in cancer.

ABSTRACT: PET/CT and radioisotope therapy are diagnostic and therapeutic arms of Nuclear Medicine, respectively. With the emergence of better technology, PET/CT has become an accessible modality. Diagnostic tracers exploring disease-specific targets has led the clinicians to look beyond FDG PET. Moreover, with the emergence of theranostic pairs of radiopharmaceuticals, radioisotope therapy is gradually making it's way into treatment algorithm of common cancers in India. We therefore would like to discuss in detail the updates in PET/CT imaging and radionuclide therapy and generate a consensus-driven evidence based document which would guide the practitioners of Oncology.

FMRP deficiency leads to multifactorial dysregulation of splicing and mislocalization of MBNL1 to the cytoplasm.

Fragile X syndrome (FXS) is a neurodevelopmental disorder that is often modeled in Fmr1 knockout mice where the RNA-binding protein FMRP is absent. Here, we show that in Fmr1-deficient mice, RNA mis-splicing occurs in several brain regions and peripheral tissues. To assess molecular mechanisms of splicing mis-regulation, we employed N2A cells depleted of Fmr1. In the absence of FMRP, RNA-specific exon skipping events are linked to the splicing factors hnRNPF, PTBP1, and MBNL1. FMRP regulates the translation of Mbnl1 mRNA as well as Mbnl1 RNA auto-splicing. Elevated Mbnl1 auto-splicing in FMRP-deficient cells results in the loss of a nuclear localization signal (NLS)-containing exon. This in turn alters the nucleus-to-cytoplasm ratio of MBNL1. This redistribution of MBNL1 isoforms in Fmr1-deficient cells could result in downstream splicing changes in other RNAs. Indeed, further investigation revealed that splicing disruptions resulting from Fmr1 depletion could be rescued by overexpression of nuclear MBNL1. Altered Mbnl1 auto-splicing also occurs in human FXS postmortem brain. These data suggest that FMRP-controlled translation and RNA processing may cascade into a general dys-regulation of splicing in Fmr1-deficient cells.

Intracranial disease in pediatric Hodgkin lymphoma-case report and review of literature.

Central nervous system (CNS) involvement in Hodgkin lymphoma (HL) is an extremely rare presentation with dismal outcomes according to reported literature. An 8-year-old girl presented to us with complaints of on-off fever, right cervical swelling and bilateral ptosis. Positron emission tomography (PET) showed intracranial extra-axial soft tissue masses in right infero-lateral temporal lobe, sella and bilateral parasellar region along with cervical, mediastinal, axillary, abdominal and inguino-pelvic nodes, liver lesions and extensive marrow lesions involving the axial and appendicular skeleton. Histopathology of the cervical lymph node revealed a diagnosis of classical Hodgkin lymphoma. Child received 2 cycles of OEPA and 4 cycles of COPP followed by radiotherapy to bulky cervical lymph nodes and intracranial lesion. The child has been disease-free for 44 months with no neurological sequalae. Intracranial spread is rare in Hodgkin lymphoma and is associated with inferior outcomes. Due to its rarity, there are no specific treatment guidelines for this entity. The choice of ideal chemotherapeutic agents and role of whole-brain radiotherapy needs further evaluation.

Evaluation of post-chemotherapy residual seminomatous masses by 18F-fluorodeoxyglucose PET/CT using tumor-to-liver ratio - conundrum or solution?

OBJECTIVE: Assessment of diagnostic accuracy of FDG-PET/CT in the detection of viable disease in post-chemotherapy seminomatous residual masses using visual interpretation, SUVmax, and T/L ratio. METHODS: This is a retrospective study assessing the post-chemotherapy seminomatous residual masses of size >3 cm. The PET/CT scan findings were interpreted visually for presence of residual disease which were validated from histopathology reports or imaging follow-up for a maximum of 3 years. SUVmax and T/L ratios were also determined for all the residual lesions. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value NPV were calculated and compared for all three parameters along with ROC analysis to obtain an optimal cutoff value for SUVmax and T/L ratio, respectively. RESULTS: Sample size was 49. Out of these 49 patients, 8 had validation of PET results with histopathology. Rest was validated with imaging follow-up. FDG-PET was positive in 30 patients and negative in 19 patients by visual interpretation. The sensitivity, specificity, PPV, and NPV by this method were 100%, 62.5%, 73%, and 100%, respectively. The SUVmax and T/L ratios were also calculated for these lesions. The cutoff for these two variables was 4.56 and 1.21, respectively. The sensitivity, specificity, PPV, and NPV at these cutoffs were 76%, 87.5%, 86%, 77.7%, and 92%, 87.5%, 88%, 91%, respectively. CONCLUSION: FDG-PET has a favorable diagnostic value in predicting viable disease in post-chemotherapy seminomatous residual masses and using T/L ratio cutoff of 1.21 will increase the specificity of the test.

Primary Neuroendocrine Tumor of Prostate in a Case of Metastatic Adenocarcinoma of Lung: Rare Entity with Histopathological and Gallium 68 DOTANOC Positron Emission Tomography Correlation.

Neuroendocrine tumor (NET) of the prostate is an extremely rare entity which represents <1% of the prostatic cancers, but with increasing incidence. Its spectrum encompasses several histological variants ranging from well-differentiated tumor which are often indolent in nature; to aggressive neuroendocrine carcinoma which portends aggressive management. Hence, such rare entities are to be characterized and treated accordingly. We report an unusual case of well-differentiated NET of prostate which was flagged on fluorodeoxyglucose positron emission tomography computed tomography (PET/CT) performed for other indication and confirmed on Gallium-68 DOTANOC PET/CT. Histopathology and immunohistochemistry confirmed the findings subsequently.

Post-intubation analgesia and sedation following succinylcholine vs. rocuronium in the emergency department.

BACKGROUND: Succinylcholine and rocuronium are the most commonly utilized neuromuscular blocker agents (NMBAs) for rapid sequence intubation (RSI) in the emergency department (ED). The duration of action of rocuronium is significantly longer (∼30 min) compared to succinylcholine (∼10 min) and previous studies have shown that patients receiving rocuronium are more likely to have longer time to sedation initiation following RSI. Furthermore, patients receiving rocuronium may be more likely to experience awareness with paralysis than those receiving succinylcholine. The primary goal for this study was to evaluate the association between NMBA use during RSI and post-intubation sedation and analgesia practices in the ED. METHODS: This was a retrospective, multicenter cohort study including patients 18 years and older that received succinylcholine or rocuronium during RSI in the ED between September 1, 2020 and August 31, 2021. Patients were excluded if they were intubated prior to ED arrival, experienced an out-of-hospital or in ED cardiac arrest, or received sugammadex within 60 min of rocuronium administration. Patients were screened in reverse chronological order until the targeted sample size was achieved and all data was abstracted from the electronic health record. The primary outcome was the time to initiation of analgesia or sedation. Secondary outcomes included dose of sedatives or analgesia administered at 30- and 60 min, and medications administered for post-intubation sedation or analgesia. FINDINGS: A total of 200 ED patients were included of which 100 received succinylcholine and 100 received rocuronium. There was no difference in the median time to initiation of analgesia or sedation between the succinylcholine and rocuronium groups (10 vs 8.5 min, p = 0.82) or in Kaplan-Meier cumulative probabilities (p = 0.17). At 60 min post-RSI, those receiving succinylcholine received significantly higher median doses of propofol (20 µg/kg/min vs. 10 µg/kg/min; p = 0.02) and fentanyl [100 µg vs. 84.2 µg; p = 0.02]. CONCLUSION: While no differences were observed in the time to initiation of post-intubation sedation or analgesia in ED patients receiving succinylcholine compared to rocuronium, differences in the intensity of post-intubation regimens was observed. Further investigation is needed to evaluate the adequacy of sedation following RSI in the ED.

Antisense oligonucleotide rescue of CGG expansion-dependent FMR1 mis-splicing in fragile X syndrome restores FMRP.

Aberrant alternative splicing of mRNAs results in dysregulated gene expression in multiple neurological disorders. Here, we show that hundreds of mRNAs are incorrectly expressed and spliced in white blood cells and brain tissues of individuals with fragile X syndrome (FXS). Surprisingly, the FMR1 (Fragile X Messenger Ribonucleoprotein 1) gene is transcribed in >70% of the FXS tissues. In all FMR1-expressing FXS tissues, FMR1 RNA itself is mis-spliced in a CGG expansion-dependent manner to generate the little-known FMR1-217 RNA isoform, which is comprised of FMR1 exon 1 and a pseudo-exon in intron 1. FMR1-217 is also expressed in FXS premutation carrier-derived skin fibroblasts and brain tissues. We show that in cells aberrantly expressing mis-spliced FMR1, antisense oligonucleotide (ASO) treatment reduces FMR1-217, rescues full-length FMR1 RNA, and restores FMRP (Fragile X Messenger RibonucleoProtein) to normal levels. Notably, FMR1 gene reactivation in transcriptionally silent FXS cells using 5-aza-2'-deoxycytidine (5-AzadC), which prevents DNA methylation, increases FMR1-217 RNA levels but not FMRP. ASO treatment of cells prior to 5-AzadC application rescues full-length FMR1 expression and restores FMRP. These findings indicate that misregulated RNA-processing events in blood could serve as potent biomarkers for FXS and that in those individuals expressing FMR1-217, ASO treatment may offer a therapeutic approach to mitigate the disorder.

Outcome and prognostic variables in childhood rhabdomyosarcoma (RMS) with emphasis on impact of FOXO1 fusions in non-metastatic RMS: experience from a tertiary cancer centre in India.

While factors influencing outcomes of rhabdomyosarcoma (RMS) in developed countries have evolved from clinical characteristics to molecular profiles, similar data from developing countries are scarce. This is a single-centre analysis of outcomes in treated cases of RMS, with emphasis on prevalence, risk-migration and prognostic impact of Forkhead Box O1 (FOXO1) in non-metastatic RMS. All children with histopathologically proven RMS, treated between January 2013 and December 2018 were included. Intergroup Rhabdomyosarcoma Study-4 risk stratification was used, with treatment based on a multimodality-regimen with chemotherapy (Vincristine/Ifosfamide/Etoposide and Vincristine/Actinomycin-D/Cyclophosphamide) and appropriate local therapy. Formalin-fixed paraffin-embedded tissues were tested using Reverse Transcriptase-Polymerase Chain Reaction for FOXO1-fusions (PAX3(P3F); PAX7(P7F)). A total of 221 children (Cohort-1) were included, of which 182 patients had non-metastatic disease (Cohort-2). Thirty-six (16%), 146 (66%), 39 (18%) patients were low-risk (LR), intermediate-risk (IR) and high-risk, respectively. FOXO1-fusion status was available in 140 patients with localised RMS (Cohort 3). P3F and P7F were detected in 25/49 (51%) and 14/85 (16.5%) of alveolar and embryonal variants, respectively. The 5-year-event-free survival (EFS)/overall survival (OS) of Cohorts 1, 2 and 3 was 48.5%/55.5%, 54.6%/62.6% and 55.1%/63.7%, respectively. Amongst the localised RMS, presence of nodal metastases and primary tumour size > 10 cms were adverse prognostic factorvs (p < 0.05). On incorporating fusion-status in risk-stratification, 6/29 (21%) patients migrated from LR (A/B) to IR. All patients who re-categorised as LR (FOXO1 negative) had a 5-year EFS/OS of 80.81%/90.91%. FOXO1-negative tumours had a better 5-year relapse-free survival (58.92% versus 44.63%; p = 0.296) with a near-significant correlation in favourable-site tumours (75.10% versus 45.83%; p = 0.063). While FOXO1-fusions have superior prognostic utility compared to histology alone in localised, favourable-site RMS, traditional prognostic factors (tumour size and nodal metastases) impacted outcome the most in this subset. Strengthening of early referral systems in community and timely local intervention can help in improving outcome in resource-constrained countries.

A Rare Case of Plasmablastic Lymphoma of the Ovary with Synchronous Lung Malignancy.

Primary ovarian lymphoma is a rare malignancy with <1% incidence. Plasmablastic lymphoma usually associated with immunocompromised diseases such as HIV rarely involves the ovary; only two case studies are reported in the literature - plasmablastic lymphomatous involvement of an ovarian teratoma and another of plasmablastic variant of B-cell lymphoma involving bilateral ovaries. There are reported case series of synchronous presentation of carcinomas usually including lung, stomach, and colon and nonaggressive lymphomas. Here, we report a rare case of synchronous aggressive primary plasmablastic ovarian lymphoma with adenocarcinoma of the lung, both of which are associated with immune-compromised conditions.

Demonstration of Multiple Metastatic Sites by Positron Emission Tomography/Computed Tomography in a Rare Case of Epithelioid Angiosarcoma of the Scalp.

Epithelioid angiosarcoma is a rare subtype of angiosarcoma, with metastases occurring in more than 50% of cases and the lung is the most organ which is involved. Whole-body fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) has demonstrated its clinical utility in the early detection of metastases in angiosarcoma. It is helpful to differentiate between benign lesions with low FDG uptake as compared to malignancies with high FDG avidity. Here, we present a rare case of a young man with epithelioid angiosarcoma, in which FDG PET/CT has demonstrated metastatic sites (especially lung metastases).

FAPI PET Positivity in Fibrolamellar Hepatocellular Carcinoma.

ABSTRACT: Fibrolamellar hepatocellular carcinoma (HCC) is a variant of HCC. It is a malignant tumor, but its imaging features often overlap focal nodular hyperplasia, which is a benign entity. FDG PET/CT is also not much help in these cases because both lesions do not concentrate FDG. We present one such case of fibrolamellar HCC with FAPI PET/CT positivity.

Diagnostic performance of F-18 FDG PET/CT in recurrent adenocarcinoma gallbladder and its impact on post-recurrence survival.

PURPOSE: To analyze diagnostic performance of F-18 FDG PET/CT in recurrent adenocarcinoma gallbladder (GBC) and to establish its possible impact on post-recurrence survival. METHOD: FDG PET/CT studies of suspected recurrent GBC were retrospectively analyzed alongside tumor markers serum CEA and CA 19-9. Abnormal FDG-avid lesions and abnormal morphological lesions were considered positive for recurrence, and were categorized as isolated abdominal wall recurrence, loco-regional recurrence, and distant metastatic disease. Histopathology, definite progression on imaging and positive response to treatment was considered as reference standard. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy were used as diagnostic performance parameters. Post-recurrence survival was calculated whenever appropriate follow-up was available, based on the abovementioned categories of sites of recurrence using survival curves and log-rank test. RESULTS: Out of 117 PET/CT studies, 93 (79.5%) were positive and 24 (20.5%) were negative for recurrence. 86 out of 93 were true positive and 23 of 24 were true negative. PET/CT demonstrated sensitivity, specificity, PPV, NPV and accuracy of 98.8%, 76.7%, 92.5%, 95.8% and 93.1%, respectively. Diagnostic performance of PET/CT was significantly better than combination tumor markers. Of 66 cases with available follow-up, isolated abdominal wall (port/scar site) recurrence and loco-regional recurrence demonstrated significantly higher post-recurrence survival as compared to distant metastasis; median survival being 39, 25 and 12 months, respectively. CONCLUSION: F-18 FDG PET/CT has better diagnostic performance than tumor markers combination. Isolated abdominal wall (port/scar site) recurrence and loco-regional recurrence on PET/CT demonstrated better survival than non-regional metastatic disease. These results suggest a possible role of PET/CT as a surveillance modality, as well as a guide to therapeutic decision-making in cases of recurrent GBC.

Sporadic Cerebellar Hemangioblastoma With Strong SSTR Expression on 68 Ga-DOTANOC PET/CT.

ABSTRACT: Sporadic cerebellar hemangioblastomas are rare with majority of these tumors presenting as a part of von Hippel-Lindau syndrome. We demonstrate an unusual case of a symptomatic sporadic cerebellar hemangioblastoma mimicking a meningioma on MRI and 68 Ga-DOTANOC PET imaging.

Human Immunodeficiency Virus Associated Plasmablastic Lymphoma Involving Bones and Peritoneum in a 4-Year-old Child.

In children with underlying Human Immunodeficiency virus infection and AIDS, hematolymphoid cancers, especially non-hodgkin lymphomas are common. Plasmablastic lymphoma is one such non-hodgkin lymphomas arising from the head and neck region (especially sinonasal) but extremely rare. We describe the clinical course in a 4-year-old boy who presented with a solitary bony swelling of the right knee joint, which on diagnostic work-up turned out to be plasmablastic lymphoma. With combination chemotherapy, intrathecal chemotherapy, and early institution ofHighly active anti-retroviral therapy, the child continues to be in remission.

Impact of a standardized order set and medication-use process on medication error rates in sexual assault patients presenting to the emergency department for HIV nonoccupational postexposure prophylaxis.

PURPOSE: To evaluate the impact of a standardized order set and medication-use process on antiretroviral medication errors in sexual assault (SA) patients presenting to the emergency department (ED) for nonoccupational postexposure prophylaxis (nPEP). METHODS: In November 2019, a multidisciplinary group collaborated on an initiative to improve the nPEP medication-use process for SA patients presenting to the EDs within a large integrated health system. Electronic medical records of patients 13 years of age or older who presented for SA examination and were prescribed nPEP during the pre- (February 2018-August 2019) and poststandardization (February 2020-August 2021) periods were included. The primary objective was to compare the proportion of patients experiencing a medication error before and after SA/nPEP process standardization. Data regarding the following medication errors were evaluated: incomplete regimen; inappropriate/duplicative regimen; dosing, frequency, or quantity prescribed error; and initiation of nPEP without an HIV test. RESULTS: Two hundred six patients met criteria for inclusion. A higher proportion of patients experienced medication errors in the prestandardization group relative to the poststandardization group (46.5% vs 11.9%, P < 0.001). Fifty-five errors were observed in the prestandardization group, compared to 16 errors in the poststandardization group. The majority of errors in the prestandardization group were directly related to antiretroviral regimens, while the majority of errors in the poststandardization group involved initiation of nPEP without an HIV test. CONCLUSION: The standardization of the SA/nPEP process was associated with significantly lower medication error rates. Optimization of medication-use technology is an effective strategy in reducing medication errors.

Can 18 F-FDG-Positron Emission Tomography be a Prognostic Tool in Children With Rhabdomyosarcoma Treated With Definitive Radiotherapy?

BACKGROUND: Persisting residual masses at treatment completion are known in rhabdomyosarcoma (RMS) treated with definitive radiotherapy (RT) to the primary site, but their prognostic significance is uncertain. Tumor response as assessed by anatomic imaging is not prognostic and studies based on 18 F-FDG-PET response are limited. We report the prognostic significance of persistent FDG-avidity in residual masses, assessed 3-month postdefinitive RT, in pediatric RMS. MATERIALS AND METHODS: Children 15 years old or below with Group III/IV RMS who received only definitive radiotherapy for local control from June 2013 to December 2018, and had 18 F-FDG-PET CT at 3 months post-RT were retrospectively analyzed for outcomes and other prognostic factors. RESULTS: Sixty-three children were eligible (Group III-55, Group IV-8). 18 F-FDG-PET CT scan done 3 months postradiotherapy showed FDG-avid residual masses in 10 patients (15.9%), anatomic residual in 24 (38.1%), and no anatomic/FDG-avid residual in 29(46.0%). At a median follow-up of 38 months (interquartile range, 24 to 55 mo), 3-year EFS of patients with FDG-avid residual masses was 40.0% (95% CI: 18.7% to 85.5%) versus the rest of the cohort, which was 71.9% (95% CI: 59.8% to 86.5%) ( P =0.008). Three-year OS of patients with FDG-avid residual masses was 50.8% (95% CI: 25.7% to 100.0%) versus the rest of the cohort, which was 77.0% (95% CI: 65.1% to 91.0%) ( P =0.037). Presence of FDG-avid residual disease persisting post-RT affected both EFS [HR-3.34 (95% CI: 1.29 to 8.68) ( P =0.013)] and OS [HR-3.20 (95% CI: 1.01 to 10.12) ( P =0.048)] on univariate analysis and this significance was retained for EFS in multivariate analysis [HR-3.52 (95% CI: 1.33 to 9.30) ( P =0.011)]. CONCLUSIONS: Persistent metabolic activity in residual disease post-chemoradiotherapy in RMS may portend a poorer prognosis with an increased risk of relapse. This subset of high-risk patients needs to be identified, and further trials are warranted to develop strategies to improve their outcomes.

A Quality Improvement Approach to Modification of a Point-of-Care Ultrasound Curriculum.

Background: There is increasing emphasis on resident involvement in quality improvement (QI) efforts, yet resident engagement in QI has remained low for many reasons. Although QI methods are classically applied to clinical processes, there are many opportunities to incorporate QI principles into curricular design and implementation. Objective: Demonstrate the utility of QI methods when applied to curricular design and the implementation of a novel point-of-care ultrasound portfolio development and quality assurance program at a large internal medicine residency program. Methods: We applied foundational QI methods, including process mapping, plan-do-study-act (PDSA) cycles, time-trap identification, run-chart analysis, and qualitative interviews throughout the curricular design and implementation phases to rapidly identify areas for improvement and perform timely tests of change. Results: Fifty-one interns participated in the curriculum, submitting 731 images in the first trimester. Process mapping and submission review revealed that 29% of images were saved to the incorrect digital archive. Resident-reviewer interpretation concordance was present in 80.7% of submissions. In 95.2% of completed quality assurance cards, the same information was provided in the commentary feedback and the evaluator's checklists, representing a time trap. Interventions included restricting access to image archives and removing redundant fields from quality assurance cards. The time to feedback fell from 69.5 to 6.5 days, demonstrating nonrandom variation via run-chart analysis. Conclusion: This pilot study demonstrates the successful application of QI methods to a novel point-of-care ultrasound curriculum. The systematic use of these methodologies in curricular design and implementation allows expeditious curricular improvement. Emphasizing the relevance of QI methods to subject matter beyond clinical processes may increase resident engagement in QI efforts.