Dinesh Singh

Optimizing Cancer Radiotherapy with 2-Deoxy-D-Glucose

Background and Purpose:Higher rates of glucose utilization and glycolysis generally correlate with poor prognosis in several types of malignant tumors. Own earlier studies on model systems demonstrated that the nonmetabolizable glucose analog 2-deoxy-D-glucose (2-DG) could enhance the efficacy of radiotherapy in a dose-dependent manner by selectively sensitizing cancer cells while protecting normal cells. Phase I/II clinical trials indicated that the combination of 2-DG, at an oral dose of 200 mg/kg body weight (BW), with large fractions of γ-radiation was well tolerated in cerebral glioma patients. Since higher 2-DG doses are expected to improve the therapeutic gain, present studies were undertaken to examine the tolerance and safety of escalating 2-DG dose during combined treatment (2-DG + radiotherapy) in glioblastoma multiforme patients.Patients and Methods:Untreated patients with histologically proven glioblastoma multiforme (WHO criteria) were included in the study. Seven weekly fractions of 60Co γ-rays (5 Gy/fraction) were delivered to the tumor volume (presurgical CT/MRI evaluation) plus 3 cm margin. Escalating 2-DG doses (200–250–300 mg/kg BW) were administered orally 30 min before irradiation after overnight fasting. Acute toxicity and tolerance were studied by monitoring the vital parameters and side effects. Late radiation damage and treatment responses were studied radiologically and clinically in surviving patients.Results:Transient side effects similar to hypoglycemia were observed in most of the patients. Tolerance and patient compliance to the combined treatment were very good up to a 2-DG dose of 250 mg/kg BW. However, at the higher dose of 300 mg/kg BW, two out of six patients were very restless and could not complete treatment, though significant changes in the vital parameters were not observed even at this dose. No significant damage to the normal brain tissue was observed during follow-up in seven out of ten patients who received complete treatment and survived between 11 and 46 months after treatment.Conclusion:Oral administration of 2-DG combined with large fractions of radiation (5 Gy/fraction/week) is safe and could be tolerated in glioblastoma patients without any acute toxicity and late radiation damage to the normal brain. Further clinical studies to evaluate the efficacy of the combined treatment are warranted.Hintergrund und Ziel:Erhöhter Glukoseverbrauch und verstärkte Glykolyse korrelieren bei einigen Malignomformen generell mit schlechter Prognose. Eigene Untersuchungen an Modellsystemen zeigten, dass die nichtmetabolisierbare Glukoseverbindung 2-Deoxy-D-Glukose (2-DG) die Wirksamkeit der Strahlentherapie dosisabhängig verstärken kann, indem sie selektiv Krebszellen sensibilisiert, dagegen auf normale Zellen protektiv wirkt. Klinische Phase-I/II-Studien sprechen dafür, dass die Kombination von 2-DG (in einer oralen Dosis von 200 mg/kg Körpergewicht) mit großen Fraktionen einer γ-Strahlung von Patienten mit Hirntumoren gut vertragen wird. Da man erwartet, dass höhere 2-DG-Dosierungen das therapeutische Ansprechen verbessern, wurden die hier vorgestellten Untersuchungen unternommen, um an Glioblastoma-multiforme-Patienten Verträglichkeit und Sicherheit der Dosiseskalation von 2-DG in der Kombinationsbehandlung (2-DG + Radiotherapie) zu prüfen.Patienten und Methodik:In die Studie wurden nicht vorbehandelte Patienten mit histologisch belegtem Glioblastoma multiforme (WHO-Kriterien) eingeschlossen. Das Tumorvolumen (gemäß präoperativer CT/MRT-Auswertung) plus ein 3-cm-Sicherheitssaum wurden wöchentlich mit sieben Fraktionen einer 60Co-γ-Strahlung (5 Gy/Fraktion) behandelt. In ansteigender Dosierung wurde 2-DG (200–250–300 mg/kg KW) nach nächtlicher Nahrungskarenz 30 min vor der Bestrahlung verabreicht. Akuttoxizität und Verträglichkeit wurden durch Überwachung von Vitalparametern und Nebenwirkungen untersucht. Langzeit-Strahlenfolgen und Ansprechen wurden bei überlebenden Patienten radiologisch und klinisch untersucht.Ergebnisse:Bei den meisten Patienten wurden vorübergehende, Hypoglykämie-ähnliche Symptome beobachtet. Verträglichkeit und Patienten-Compliance der Kombinationsbehandlung waren bis zu einer 2-DG-Dosis von 250 mg/kg KG sehr gut; bei der höheren Dosis von 300 mg/kg KG entwickelten zwei von sechs Patienten jedoch starke Unruhe und konnten die Behandlung nicht abschließen, obwohl auch unter dieser Dosis keine signifikanten Veränderungen der Vitalparameter festgestellt wurden. Im Follow-up war keine signifikante Schädigung des normalen Hirngewebes bei sieben von zehn Patienten zu beobachten, die die komplette Behandlung erhalten und zwischen 11 und 46 Monate nach der Behandlung überlebt hatten.Schlussfolgerung:Die orale Gabe von 2-DG kombiniert mit hohen Einzelfraktionen (5 Gy/Fraktion/Woche) ist sicher und wurde von Gliom-Patienten ohne Akuttoxizität und ohne Strahlungsspätschäden im Hirngewebe vertragen. Um die Wirksamkeit der Kombinationstherapie zu prüfen, sind weitere klinische Studien erforderlich.

Comparative evaluation of F-18 FDOPA, F-18 FDG, and F-18 FLT-PET/CT for metabolic imaging of low grade gliomas.

Introduction: We undertook this prospective study to compare amino acid metabolism, glucose metabolism, and proliferation in primary and recurrent low grade gliomas using positron emission tomography (PET)/computed tomography with F-18 FDOPA, F-18 FDG, and F-18 FLT. Methods: Fifteen patients with newly diagnosed or previously treated low grade gliomas (WHO grade I or II) were subjected to F-18-FDOPA, F-18 FDG, and F-18 FLT PET/computed tomography studies on consecutive days. This included 2 patients in remission as control subjects. Uptake of all the 3 tracers were analyzed visually and quantified using standardized uptake values and tumor to normal (T/N) ratios. The accuracy of all the 3 PET tracers in the detection of newly diagnosed and recurrent low grade gliomas was compared. Results: F-18 FDOPA was positive in all cases of primary and recurrent low grade gliomas and negative in the patients in remission. Tumor was visualized on F-18 FDG in 7 of 13 cases, F-18-FLT was positive in 4 of 13 cases. Average tumor standardized uptake values max for F-18 FDOPA (5.75 ± 4.9) and F-18 FLT (1.8 ± 0.91) was lower than that of F-18 FDG (8.5 ± 4.4). T/N ratios for F-18-FDOPA (2.3 ± 0.51) and F-18 FLT (1.8 ± 0.91) were higher than F-18 FDG (1.03 ± 0.64) providing good image contrast for tumor detection in positive cases. Conclusion: F-18 FDOPA scan is superior to both F-18 FLT and F-18 FDG for visualization of primary and recurrent low grade gliomas. F-18-FLT should not be considered for evaluation of recurrent low grade gliomas.

Prospective evaluation of CECT and 18F-FDG-PET/CT in detection of hepatic metastases.

ObjectivesThe purpose of this study was to evaluate the performance of 18F-fluorodeoxy-D-glucose (FDG)-PET/computed tomography (CT) and contrast-enhanced CT (CECT) in the detection and characterization of hepatic metastases. MethodsForty-five patients harboring an extrahepatic primary malignancy, with suspected hepatic metastases on clinical or ultrasonographic examination were enroled prospectively. Each patient underwent contrast-enhanced abdominal CT and 18F-FDG-PET/CT within 72 h of each other, reported by an experienced radiologist and nuclear medicine specialist, respectively in a blinded manner. CECT and PET-CT findings were compared and analyzed. Final diagnosis was based on histology and/or follow-up (ranging from 6 to 12 months). ResultsThe sensitivity and specificity of CECT in the detection of hepatic metastases was 87.9 and 16.7%, respectively, whereas that of PET/CT was 97 and 75%, respectively. This study showed the superiority of PET/CT over CECT in the detection of hepatic metastases, irrespective of the primary site. This was especially owing to the latters inability to reliably distinguish small (less than 15 mm) lesions as benign or malignant. ConclusionMany studies have been conducted on the impact of FDG-PET/CT in the evaluation of hepatic metastases, especially from colorectal primary. Very few prospective studies, however, have been conducted on its role in evaluation of hepatic metastases from nongastrointestinal primaries. Despite its superior performance, it cannot replace CECT for this purpose, owing to the low but definite risk of false positivity based on PET-CT findings alone. Inclusion of CECT in PET/CT protocols may enable us to achieve a higher diagnostic accuracy. This suggests the need for a large prospective study with serial evaluations and pathological correlation.

Cervical and uterine metastasis from carcinoma of breast diagnosed by PET/CT: an unusual presentation.

A 44-year-old apparently healthy woman presented with a 5-month history of intermittent vaginal bleeding. Clinical examination raised the suspicion of cervical neoplasia which was confirmed to be a metastatic adenocarcinoma on subsequent histopathological evaluation. An F-18 FDG PET/CT scan performed soon after revealed increased uptake in the cervix, extending upwards into the endometrial cavity. Additionally, small FDG avid spiculated soft tissue density masses were visualized in bilateral breast parenchyma, which proved to be lobular carcinoma on sonomammography followed by histopathology. Multiple lytic FDG avid skeletal metastases were also noted. Endometrial biopsy showed infiltrative malignant tumor with cytologic features similar to those observed in the breast biopsy specimen. The entire spectrum of findings pointed to a diagnosis of bilateral lobular carcinoma with uterine, cervical, and skeletal metastasis. Metastasis to the uterus and cervix from a breast primary is extremely rare. Most cases have been diagnosed in the follow-up of known cases of breast carcinoma. Our case is unique in that the patient, who had no prior history of breast carcinoma, was suspected to have a breast primary with cervical and uterine metastasis, based on the PET/CT findings.

F-18 flurodeoxyglucose negative, F-18 fluoride accumulating in a brain metastasis in a treated case of carcinoma of the breast.

Abstract:A 52-year-old woman undergoing treatment for carcinoma of the left breast with brain and bone metastases was referred for F-18 fluoride positron emission tomography-computed tomography (PET/CT) bone scan (FBS) to evaluate the status of a bone metastasis. Review of the plain fluoride-PET ima

A comparison study of 11 C-methionine and 18 F-fluorodeoxyglucose positron emission tomography-computed tomography scans in evaluation of patients with recurrent brain tumors

Introduction: 11 C-methonine ([11 C]-MET) positron emission tomography-computed tomography (PET-CT) is a well-established technique for evaluation of tumor for diagnosis and treatment planning in neurooncology. [ 11 C]-MET reflects amino acid transport and has been shown to be more sensitive than magnetic resonance imaging (MRI) in stereotactic biopsy planning. This study compared fluorodeoxyglucose (FDG) PET-CT and MET PET-CT in the detection of various brain tumors. Materials and Methods: Sixty-four subjects of brain tumor treated by surgery, chemotherapy, and/or radiotherapy were subjected to [ 18 F]-FDG, [ 11 C]-MET, and MRI scan. The lesion was analyzed semiquantitatively using tumor to normal contralateral ratio. The diagnosis was confirmed by surgery, stereotactic biopsy, clinical follow-up, MRI, or CT scans. Results: Tumor recurrence was found in 5 out of 22 patients on [F-18] FDG scan while [ 11 C]-MET was able to detect recurrence in 18 out of 22 patients in low-grade gliomas. Two of these patients were false positive for the presence of recurrence of tumor and later found to be harboring necrosis. Among oligodendroglioma, medulloblastoma and high-grade glioma out of 42 patients 39 were found to be concordant MET and FDG scans. On semiquantitative analysis, mean T/NT ratio was found to be 2.96 ± 0.94 for lesions positive for recurrence of tumors and 1.18 ± 0.74 for lesions negative for recurrence of tumor on [ 11 C]-MET scan. While the ratio for FDG scan on semiquantitative analysis was found to be 2.05 ± 1.04 for lesions positive for recurrence of tumors and 0.52 ± 0.15 for lesions negative for recurrence of tumors. Conclusion: The study highlight that [ 11 C]-MET is superior to [ 18 F]-FDG PET scans to detect recurrence in low-grade glioma. A cut-off value of target to nontarget value of 1.47 is a useful parameter to distinguish benign from malignant lesion on an [ 11 C]-MET Scan. Both [ 18 F]-FDG and [ 11 C]-MET scans were found to be useful in high-grade astrocytoma, oligodendroglioma, and medulloblastoma.

Utility of intrastriatal ratios of FDOPA to differentiate idiopathic Parkinson's disease from atypical parkinsonian disorders.

AimThe striatal-to-occipital ratio (SOR) is commonly used as an analytical parameter in L-3,4-dihydroxy-6-18F-fluorophenylalanine (FDOPA) PET studies. It has been shown to be useful in differentiating idiopathic Parkinson’s disease (IPD) patients from healthy individuals. We assessed the performance of SORs and subregional ratio of striatal-to-occipital ratios (RSORs) in the clinical assessment of nigrostriatal dopaminergic function for differentiating typical IPD from atypical parkinsonian disorders (APD). Materials and methodsA total of 117 patients referred from movement disorder clinics in speciality neurology centres underwent an FDOPA PET study and were kept under follow-up for at least 2 years. Sixty-five patients (43 IPD and 22 APD) completed the 2-year follow-up and were included in the final analysis. Their PET images were spatially normalized to occipital counts and analysed with three striatal subregional regions of interest (caudate, anterior putamen and posterior putamen) and two occipital regions of interest. The RSORs of the caudate and posterior putamen, the caudate and anterior putamen, the caudate and whole putamen and the anterior putamen and posterior putamen were also calculated and compared between the IPD and APD groups using the t-test. ResultsThe P values for these SORs were found to be insignificant between IPD and APD patients (caudate: 0.1325; anterior putamem: 0.5469; and posterior putamen: 0.9835). However, the RSORs of the caudate and posterior putamen showed significant differences between these two populations of patients. ConclusionThe SOR method is already known to be a good diagnostic tool to differentiate between IPD patients and the normal population. SOR, however, fails to distinguish IPD from APD patients, and hence the RSOR of the caudate and posterior putamen can be utilized to differentiate between them.

Spectrum of brain abnormalities detected on whole body F-18 FDG PET/CT in patients undergoing evaluation for non-CNS malignancies.

We present the pattern of metabolic brain abnormalities detected in patients undergoing whole body (WB) F-18 flurodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) examination for non-central nervous system (CNS) malignancies. Knowledge of the PET/CT appearance of various intracranial metabolic abnormalities enables correct interpretation of PET scans in oncological patients where differentiation of metastasis from benign intracranial pathologies is important and improves specificity of the PET study. A complete clinical history and correlation with CT and MRI greatly helps in arriving at a correct imaging diagnosis.

Spectrum of neurocognitive dysfunction in Indian population on FDG PET/CT imaging

Background: A variety of neurodegenerative disorders produce significant abnormal brain function which can be detected using fluorodeoxyglucose positron emission tomography (FDG PET) scan even when structural changes are not detected on CT or MRI Scan. A study was undertaken at our institute to evaluate the FDG PET/CT findings in Indian population suffering from mild cognitive impairment (MCI), Alzheimers disease (AD), fronto-temporal dementia (FTD), dementia with lewy body disease (DLBD) and other miscellaneous causes of dementia. Materials and Methods: 117 subjects having neurocognitive deficits and 36 normals were included in our study. All patients underwent a detailed history and clinical examination. This was followed by a mini mental state examination. Subsequently an FDG brain PET scan and an MRI were done. Results: In the patient population included in our study group 36 were normal, 39 had MCI, 40 had AD, 14 had FTD, and 13 had DLBD and 11 dementia due to other miscellaneous causes. MCI patients showed primarily reduced tracer uptake in the mesio-temporal cortex. AD patients showed reduced tracer concentration in temporo-parietal lobes, while patients with advanced diseases showed frontal lobe disease additionally. In subjects of FTD, reduced radiotracer uptake in the fronto-temporal lobes was noted. In addition, FTD patients also showed basal ganglia defects. In contrast the DLBD patients showed globally reduced FDG uptake including severely affecting the occipital cortices. Conclusion: In the current study the F18-FDG PET scans have been shown to be highly useful in the diagnosis of various neurocognitive disorders of the brain. AD was found to be the most common dementia in the Indian population followed by MCI. Diffuse Lewy body disease, FTD and other miscellaneous categories of dementia had a near similar incidence.

Combined 18 F-FDG and 11 C-Methionine PET/CT scans in a case of metastatic hepatocellular carcinoma

A 37-year-old male who underwent a central hepatectomy of the liver for hepatocellular carcinoma (HCC) was referred for an 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) study to rule out tumor recurrence or metastases. The scan showed a recurrent hepatic mass at the operative site, along with low-grade uptake in bilateral pulmonary metastases, mediastinal and hilar lymph nodes, and few skeletal sites. A non-FDG avid intracranial extradural mass was visualized in the right frontal lobe. The 11C-methionine PET/CT scan performed subsequently revealed a larger area of involvement at the primary site, along with widespread metastases to the lungs, mediastinal, hilar, and abdominal lymph nodes, and multiple skeletal sites. Further, dural metastasis with high tracer uptake was noted in the frontal region. To the best of our knowledge, this is the first case documented in the literature, wherein 11C-methionine PET/CT played a significant role in delineating the widespread dissemination, including the extremely rare dural involvement in a case of HCC. This report highlights the potential value of 11C-methionine PET/CT in assessing the hepatic and extrahepatic tumor burden in cases of HCC, especially in clinically unexpected locations.