Correction to: Evaluation of RECIST, PERCIST, EORTC, and MDA Criteria for Assessing Treatment Response with Ga68-PSMA PET-CT in Metastatic Prostate Cancer Patient with Biochemical Progression: a Comparative Study.

[This corrects the article DOI: 10.1007/s13139-018-0548-3.].

Evaluation of response in patients of metastatic castration resistant prostate cancer undergoing systemic radiotherapy with lutetium177-prostate-specific membrane antigen: A comparison between response evaluation criteria in solid tumors, positron-emission tomography response criteria in solid tumors, European organization for research and treatment of cancer, and MDA criteria assessed by gallium 68-prostate-specific membrane antigen positron-emission tomography-computed tomography.

INTRODUCTION: We evaluated various morphological and molecular response criteria in metastatic castration-resistant prostate cancer (PCa) patient undergoing peptide receptor radioligand therapy (PRLT) with Lutetium177-prostate-specific membrane antigen (PSMA) by using Gallium 68-PSMA positron-emission tomography-computed tomography (Ga68-PSMA PET-CT). METHODS: A total of 46 pre- and 8-12 weeks' post-PRLT Ga68-PSMA PET-CT studies were reanalyzed (23 comparisons). Prostate-specific antigen drop of ≥50% and ≥25% increase was considered as partial response (PR) and progressive disease (PD), respectively, for biochemical response (BR) while change in-between was considered as stable disease (SD). Response evaluation criteria in solid tumors 1.1 (RECIST 1.1) and MD Anderson (MDA) criteria for morphological response while PET response criteria in solid tumors 1.0 (PERCIST 1.0) and European organization for research and treatment of cancer (EORTC) criteria for molecular response were used. Kappa coefficient was derived to see the level of agreement. RESULTS: The proportion of PD, PR, and SD by BR and RECIST criteria was 9 (39.13%), 3 (13.04%), and 11 (47.83%) and 5 (21.74%), 2 (8.70%), and 16 (69.57%), respectively. The proportion of PD, PR, and SD was same by PERCIST and EORTC criteria and which were 8 (34.78%), 5 (21.74%), and 10 (43.48%). The proportion of PD, PR, and SD by MDA criteria was 1 (4.35%), 1 (4.35%), and 21 (91.30%), respectively. Poor agreement between BR and both morphological criteria while a statistically significant agreement with both molecular criteria seen. CONCLUSION: We concluded that molecular criteria performed better than morphological criteria in response assessment by Ga68-PSMA PET-CT in metastatic castration resistant PCa patients undergoing PRLT.

Quantification of DNA damage in patients undergoing non-contrast and contrast enhanced whole body PET/CT investigations using comet assay and micronucleus assay.

Objective: To quantify DNA damage in patients undergoing non-contrast and contrast-enhanced 18F-FDG PET/CT whole body positron emission tomography/computed tomography (WB PET/CT) investigations using comet assay technique and micronucleus assay, and to study the effect of other baseline parameters of patients on DNA damage. Methodology: Eighty-four patients referred for 18F-FDG PET/CT investigation were included in the study of which 44 patients underwent contrast-enhanced WB PET/CT and 40 patients underwent non-contrast WB PET/CT investigations. The investigations were performed on Discovery 690 PET/CT. For contrast-enhanced investigation, Omnipaque300 was injected intravenously based on the patient body weight. Absorbed dose resulting from the intravenous administration of 18F-FDG was estimated using the ICRP 106 dose coefficients. Radiation dose from the acquisition of CT scans was estimated using CT dose index and dose-length product. Blood samples were collected from the patients for DNA damage analysis. Comet assay and MN assay was used to assess the DNA damage. The Differences in the comet TM (Tail Moment) and MNBC % in both groups were calculated. Result: The radiation dose received by the study population during 18F-FDG WB PET/CT examination was 27.03 ± 2.33 mSv. Comet TM and percentage frequency of MNBC % was 65.22 ± 35.42 and 18.55 ± 10.14, respectively in the patients injected with contrast and 42.49 ± 28.52 and 13.76 ± 7.52 for non-contrast group. Significant increase in DNA damage was observed in the contrast group as compared to non-contrast group. Significant association was observed between patient weight, contrast volume and TM and MNBC%. Baseline parameters of the patients did not show significant correlation with TM and MNBC%. Conclusion: The patients undergoing contrast-enhanced WB PET/CT investigations have demonstrated higher DNA damage. The DNA damage was also observed to be more in heavier patients. The other baseline parameters of patients like age, sex, CBG, serum creatinine did not show any correlation with DNA damage.

Initial risk stratification and staging in prostate cancer with prostatic-specific membrane antigen positron emission tomography/computed tomography: A first-stop-shop.

Current imaging for prostate cancer (PCa) had limitations for risk stratification and staging. Magnetic resonance imaging frequently underestimated lymph node metastasis while bone scintigraphy often had diagnostic dilemmas. Prostatic-specific membrane antigen (PSMA) positron emission tomography-computed tomography (PET/CT) has been remarkable in PCa recurrence. Ninety-seven PSMA PET-CT scans were reanalyzed for tumor node metastases staging and risk stratification of lymph node and distant metastasis proportion. Histopathology of 23/97 patients was available as gold standard. Chi-square test was used for proportion comparison. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), overestimation, underestimation, and correct estimation of T and N stages were calculated. Kappa coefficient (κ) was derived for inter-rater agreement. Lymph node or distant metastasis detection on PSMA PET/CT increased significantly with increase in risk category. PSMA PET/CT sensitivity, specificity, PPV, and NPV for extraprostatic extension, seminal vesicle invasion, and lymph node metastases were 63.16%, 100%, 100%, 36.36%; 55%, 100%, 100%, 25%; and 65.62%, 99.31%, 87.50%, and 97.53%, respectively. Kappa coefficient showed substantial agreement between PSMA PET/CT and histopathological lymph node metastases (κ = 0.734); however, it was just in fair agreement (κ = 0.277) with T stage. PSMA PET/CT overestimated, underestimated, and correct estimated T and N stages in 8.71%, 39.13%, 52.17% and 8.71%, 4.35%, and 86.96% cases, respectively. PSMA PET/CT has potential for initial risk stratification with reasonable correct N stage estimation, however underestimates T stage. Hence, we concluded that PSMA PET/CT should be used as " first-stop-shop" for staging and initial risk stratification of PCa with regional magnetic resonance imaging in surgically resectable cases.

Evaluation of RECIST, PERCIST, EORTC, and MDA Criteria for Assessing Treatment Response with Ga68-PSMA PET-CT in Metastatic Prostate Cancer Patient with Biochemical Progression: a Comparative Study.

PURPOSE: The aim of the study was to compare response evaluation criteria in solid tumours 1.1 (RECIST 1.1), positron emission tomography response criteria in solid tumours (PERCIST), European organisation for research and treatment of cancer (EORTC), and MD Anderson (MDA) criteria for response assessment by Gallium 68-prostate-specific membrane antigen positron emission tomography-computed tomography (Ga68-PSMA PET-CT) in metastatic adenocarcinoma prostate cancer (mPCa) patients with biochemical progression. METHODS: Eighty-eight mPCa patients with pre and post treatment Ga68-PSMA PET-CT were included. A ≥ 25% increase and ≥ 2 ng/ml above the nadir if prostate specific antigen (PSA) drop or ≥ 2 ng/ml above the baseline if PSA does not drop was considered as biochemical progression. RECIST 1.1 and MDA criteria for morphology and PERCIST and EORTC criteria for molecular response were investigated. Percentages of progressive disease (PD), partial response (PR), and stable disease (SD) were calculated. Chi-square test was used for statistical significance. RESULTS: Proportion of PD, SD, and PR by RECIST 1.1 and MDA criteria were 44 (50.57%), 39 (44.83%), 4 (4.6%), and 33 (39.76%), 48 (57.83%), 2 (2.41%) respectively. Proportion of PD, SD, and PR by PERCIST and EORTC criteria were 71 (80.68%), 11 (12.50%), 6 (6.82%), and 74 (84.09%), 8 (9.09%), 6 (6.82%) respectively. Chi-square test showed statistically significant (P < 0.05) higher proportion of progression detected by both molecular criteria as compare to both morphological criteria. CONCLUSION: We concluded that for Ga68-PSMA PET-CT response evaluation, molecular criteria performed better than morphological criteria in mPCa patient with PSA progression.

Radiobiological analysis of stereotactic body radiation therapy for an evidence-based planning target volume of the lung using multiphase CT images obtained with a pneumatic abdominal compression apparatus: a case study.

This study evaluated the efficiency of stereotactic body radiation therapy of lung (SBRT-Lung) in generating a treatment volume using conventional multiple-phase three-dimensional computed tomography (3D-CT) of a patient immobilized with pneumatic abdominal compression. The institutional protocol for SBRT-Lung using the RapidArc technique relied on a planning target volume (PTV) delineated using 3D-CT and accounted for linear and angular displacement of the tumor during respiratory movements. The efficiency of the institutional protocol was compared with that of a conventional method for PTV delineation based on radiobiological estimates, such as tumor control probability (TCP) and normal tissue complication probability (NTCP), evaluated using dose-volume parameters. Pneumatic abdominal compression improved the TCP by 15%. This novel protocol improved the TCP by 0.5% but reduced the NTCP for lung pneumonitis (0.2%) and rib fracture (1.0%). Beyond the observed variations in the patient's treatment setup, the institutional protocol yielded a significantly consistent TCP (p < 0.005). The successful clinical outcome of this case study corroborates predictions based on radiobiological evaluation and deserves validation through an increased number of patients.

Risk stratification and staging in prostate cancer with prostatic specific membrane antigen PET/CTObjective: A one-stop-shop.

OBJECTIVE: Current imaging modalities for prostate cancer (PC) had limitations for risk stratification and staging. Magnetic resonance imaging (MRI) frequently underestimated lymphatic metastasis while bone scintigraphy often had diagnostic dilemmas. Prostatic specific membrane antigen (PSMA) positron emission tomography-computed tomography (PET/CT) has been remarkable in diagnosing PC recurrence and staging. We hypothesized it can become one-stop-shop for initial risk stratification and staging. SUBJECTS AND METHOD: Ninety seven PSMA PET-CT studies were re analysed for tumor node metastases (TNM) staging and risk stratification of lymphatic and distant metastases proportion. The histopathology of 23/97 patients was available as gold standard. Chi-square test was used for proportion comparison. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), over-estimation, under-estimation and correct-estimation of T and N stages were calculated. Cohen's kappa coefficient (k) was derived for inter-rater agreement. RESULTS: Lymphic or distant metastases detection on PSMA PET/CT increased significantly with increase in risk category. PSMA PET/CT sensitivity, specificity, PPV and NPV for extra prostatic extension (EPE), seminal vesicle invasion (SVI) and lymphatic metastases were 63.16%, 100%, 100%, 36.36% & 55%, 100%, 100%, 25% and 65.62%, 99.31%, 87.50%, 97.53%, respectively. Cohen's kappa coefficient showed substantial agreement between PSMA PET/CT and histopathological lymphic metastases (κ 0.734) however, it was just in fair agreement (κ 0.277) with T stage. PSMA PET/CT over-estimated, under-estimated and correct-estimated T and N stages in 8.71%, 39.13%, 52.17% and 8.71%, 4.35%, 86.96% cases, respectively. CONCLUSION: We found that PSMA PET/CT has potential for initial risk stratifications with reasonable correct estimation for N stage. However, it can underestimate T stage. Hence, we suggest that PSMA PET/CT should be used for staging and initial risk stratification of PC as one-stop-shop with regional MRI in surgically resectable cases.

Radioprotective potential of Lagenaria siceraria extract against radiation-induced gastrointestinal injury.

The cucurbits (prebiotics) were investigated as novel agents for radio-modification against gastrointestinal injury. The cell-cycle fractions and DNA damage were monitored in HCT-15 cells. A cucurbit extract was added to culture medium 2 h before irradiation (6 Gy) and was substituted by fresh medium at 4 h post-irradiation. The whole extract of the fruits of Lagenaria siceraria, Luffa cylindrica, or Cucurbita pepo extract enhanced G2 fractions (42%, 34%, and 37%, respectively) as compared with control (20%) and irradiated control (31%). With cucurbits, the comet tail length remained shorter (L. siceraria, 28 µm; L. cylindrica, 34.2 µm; C. pepo, 36.75 µm) than irradiated control (41.75 µm). For in vivo studies, L. siceraria extract (2 mg/kg body weight) was administered orally to mice at 2 h before and 4 and 24 h after whole-body irradiation (10 Gy). L. siceraria treatment restored the glutathione contents to 48.8 µmol/gm as compared with control (27.6 µmol/gm) and irradiated control (19.6 µmol/gm). Irradiation reduced the villi height from 379 to 350 µm and width from 54 to 27 µm. L. siceraria administration countered the radiation effects (length, 366 µm; width, 30 µm, respectively) and improved the villi morphology and tight junction integrity. This study reveals the therapeutic potential of cucurbits against radiation-induced gastrointestinal injury.

Effect of Tinospora cordifolia on gamma ray-induced perturbations in macrophages and splenocytes.

Tinospora cordifolia (RTc) has already been reported to protect whole-body lethally irradiated mice. This study has focussed on certain aspects of immuno-competence, which are adversely affected by irradiation. This study included estimation of spleen size, cell count, DNA fragmentation and apoptosis in splenocytes. The adherence, spreading and phagocytic activities of macrophages were also assessed. Cytokines in serum and anti-oxidants in plasma were also estimated. Administration of RTc (200 mg/kg.b.wt.) one hour before irradiation showed recovery of spleen weight from 49% of control in irradiated group to 93%; apoptosis from 19% to 2.8%; DNA fragmentation from 43% to 20.4%; macrophage adherence form 75% of control to 120% and macrophage spread size from 8 microm to 15 microm. RTc also stimulated proliferation in splenocytes in a dose-dependent manner. RTc administration before irradiation also increased levels of IL-1beta and GM-CSF levels, from 56 pg/ml and 53 pg/ml respectively in irradiated group to 59 pg/ml and 63 pg/ml. Similarly, radiation-induced decrease of anti-oxidant potential of plasma (32 Fe(2+) equiv.) as compared to control (132 Fe(2+) equiv.) was countered by administration of RTc before irradiation (74.2 Fe(2+) equiv.) RTc treatment thus reveals several radio-protective mechanisms.

Anti-inflammatory effects of Podophyllum hexandrum (RP-1) against lipopolysaccharides induced inflammation in mice.

PURPOSE: Down-regulation of lipopolysaccharide (LPS) induced hyper-inflammatory response by non-toxic pharmacological agents acquires paramount importance for countering bacterial sepsis. Anti-inflammatory potential of aqueous extract of Podophyllum hexandrum, a plant well documented in Ayurvedic literature for various therapeutic purposes, was investigated. METHODS: In vivo studies were performed on Balb/c mice pre-treated with supra-lethal dose of LPS endotoxin (E.coli 055:B5) with or without treatment with P. hexandrum extract (RP-1). Mouse peritoneal macrophage cultures were used to understand ex vivo effects of RP-1 on LPS generated nitric oxide (NO), secretion of IFN-gamma, IL-6 and TNF-alpha. Griess assay and sandwich ELISA method were used to quantify inducible NO and cytokines respectively. RESULTS: Minimal dose of LPS that rendered 100% mortality to mice was found to be 450 microg/kg b.w. Administration of RP-1 (200 mg/kg b.w., i.p.) one hour before lethal LPS treatment (0.5 mg/kg b.w.) rendered maximum (78%) survival. Ex vivo study revealed that RP-1 (50 microg/ml) treatment to peritoneal macrophages inhibited LPS (5 microg/ml) induced nitrite generation to 37%, IFN-gamma secretion to 5%, IL-6 secretion to 50% and TNF-alpha secretion to 50 % of LPS treated control values. CONCLUSION: This study has demonstrated anti-inflammatory potential of aqueous extract of P. hexandrum.

Protection of mitochondrial system by Hippophae rhamnoides L. against radiation-induced oxidative damage in mice.

The whole extract of the fresh berries of Hippophae rhamnoides L. (RH-3), which has been reported to provide protection to whole mice, various tissues, cells and cell organelles against lethal irradiation, was further investigated for its effects on mitochondria isolated from mouse liver. Superoxide anion, reduced (GSH) and oxidized glutathione (GSSG) levels, NADH-ubiquinone oxidoreductase (complex I), NADH-cytochrome c oxidoreductase (complex I/II), succinate-cytochrome c oxidoreductase (complex II/III), mitochondrial membrane potential (MMP), lipid peroxidation (LPx) and protein oxidation (PO) were determined for RH-3-mediated radioprotective manifestation. Pre-irradiation treatment of mice with RH-3 (30 mg kg(-1,) i. p.; single dose; -30 min) significantly inhibited the radiation-induced increase in superoxide anions, GSSG, thiobarbituric acid reactive substances (TBARS), complex I, complex I/III activity and MMP maximally at 4 h (P < 0.05). This treatment inhibited the oxidation of proteins (P < 0.05) at all the time periods studied here. This study suggests that pre-irradiation treatment of mice with RH-3 protects the functional integrity of mitochondria from radiation-induced oxidative stress.

Radioprotective potential of an herbal extract of Tinospora cordifolia.

A preparation of Tinospora cordifolia (RTc) administered i.p. (200 mg/kg b.w.) to strain "A" male mice 1 h before whole body gamma-irradiation was evaluated for its radioprotective efficacy in terms of whole body survival, spleen colony forming units (CFU), hematological parameters, cell cycle progression, and micronuclei induction. Preirradiation treatment with RTc rendered 76.3% survival (30 days), compared to 100% mortality in irradiated control and prevented radiation induced weight loss. On 10th postirradiation day, the endogenous CFU counts in spleen were decreased with increasing radiation doses 12.0 (5 Gy), 2.16 (7.5 Gy) and 0.33 (10 Gy) but pre-irradiation administration of 200 mg/kg b.w. of RTc increased CFU counts to 31.16, 21.83 and 3.00 respectively. Pre-irradiation RTc treatment could restore total lymphocyte counts (TLC) by the 15th day to normal. It also increased the S-phase cell population that was reduced following 2 Gy irradiation in a time dependent manner. 2 Gy irradiation-induced micronuclei were also decreased by a pre-irradiation administration of RTc from 2.9 to 0.52%. Because the radioprotective manifestation of RTc observed in several systems in experimental animals can be exploited for human applications.

Induction of apoptosis in thymocytes by Hippophae rhamnoides: implications in radioprotection.

Hippophae rhamnoides (RH-3), which has been recently reported to elicit dose-dependent pro- and antioxidant properties in vitro, induced apoptosis in murine thymocytes. In a concentration-dependent manner, RH-3 induced apoptosis in thymocytes in ex vivo conditions. The maximum effect was observed with 100 microg/mL of RH-3. Beyond this dose, the induction of apoptosis was inhibited, as seen on the ladder formation. However, apoptotic body formation, another indicator of apoptosis, was not manifested when various doses of RH-3 (20-200 microg/mL) were administered. RH-3 (>100 microg/mL) compacted chromatin in the form of densely stained masses, and subsequent treatment with proteinase-K loosened them and developed a halo around each mass. RH-3 treatment of cells that had already undergone apoptosis induced chromatin compaction, which made the ladder invisible. During in vivo experiments in mice, the radioprotective dose of RH-3 (30 mg/kg b.w.) induced significant DNA fragmentation in thymocytes studied spectrofluorimetrically. RH-3 treatment before irradiation in vivo enhanced radiation-induced apoptosis. These results were confirmed by hypodiploid population studied flow-cytometrically and also by ladder formation. RH-3 treatment was prooxidative in nature because it depleted thiols and enhanced lipids peroxidation after 8 hours of treatment. The paradox between the prooxidant and the antioxidant effects of RH-3 in the context of its overall radioprotective efficacy has been explained.

Radioprotective effect of podophyllotoxin in Saccharomyces cerevisiae.

Recent reports showed that whole extract of Podophyllum hexandrum was radioprotective in mice. Podophyllotoxin is one of the major constituents of the whole extract of Podophyllum. In this study we report on the radioprotective action of podophyllotoxin in Saccharomyces cerevisiae yeast. Proliferating yeast cells pretreated with podophyllotoxin (2.5-5.0 microg/mL) for > or =3 hours showed a higher surviving fraction after (60)Co-gamma-irradiation (200-600 Gy) than did the irradiated cells not pretreated with podophyllotoxin. The maximum increase (2.0 times) in surviving fraction was observed in cells treated with 2.5 microg/mL podophyllotoxin, 5 hours before (60)Co-gamma-irradiation (400 Gy). Podophyllotoxin was not mutagenic or recombinogenic at radioprotective doses (2.5 microg/mL). A post-irradiation decrease in revertants and gene convertants was observed in cells treated with podophyllotoxin (2.5 microg/mL podophyllotoxin, -5 hours, 400 Gy). This study indicates that podophyllotoxin is radioprotective in yeast, and its radioprotective effects in higher eukaryotes would be worth investigating.

Modification of radiation damage to mitochondrial system in vivo by Podophyllum hexandrum: mechanistic aspects.

The present study was undertaken to investigate whether RP-1 treatment protected mitochondrial system against radiation damage and also to unravel the mechanism associated with this process. Radioprotection of mitochondrial system by Podophyllum hexandrum (RP-1) was investigated to understand its mechanism of action. Levels of superoxide anion (O2-), reduced or oxidized glutathione (GSH or GSSG), thiobarbituric acid reactive substance (TBARS), protein carbonyl (PC), ATP, NADH-ubiquinone oxidoreductase (complex-I), NADH-cytochrome c oxidoreductase (complex I/II), succinate-cytochrome c oxidoreductase (complex II/III) and mitochondrial membrane potential (MMP) were studied in mitochondria isolated from liver of mice belonging to various treatment groups. Whole body y-irradiation (10 Gy) significantly (p < 0.01) increased the formation of O2-, PC, and TBARS, upto 24 h as compared to untreated control. RP-1 treatment (200 mg/kg b.w.) to mice 2 h before irradiation reduced the radiation-induced O2- generation within 4 h and formation of TBARS and PC upto 24 h significantly (p < 0.01). Singularly irradiation or RP-1 treatment significantly (p < 0.01) increased the levels of glutathione within an hour, as compared to untreated control. Pre-irradiation administration of RP-1 enhanced levels of GSH induced increase in complex I (upto 16 h), complex I/III (4 h) complex II/III activity (upto 24 h; p < 0.01) and inhibited the radiation-induced decrease in MMP significantly (24 h; p < 0.01). The present study indicates that RP-1 itself modulates several mitichondrial perameters due to its influence on the biochemical milieu within and outside the cells. However, RP-1 treatment before irradiation modulates radiation induced perturbations such as the increase in electron transport chain enzyme activity, formation of O2-, TBARS and PC to offer radioprotection.

Radiation protection of HepG2 cells by Podophyllum hexandrum Royale.

Radioprotection by an aqueous extract of Podophyllum hexandrum (RP-1) was investigated in HepG2 cells by evaluating colony forming efficacy (CFE), redox status of mitochondria, reactive oxygen species (ROS), generation of nitric oxide (NO), peroxidation of lipids and intracellular glutathione. Lower concentrations of RP-1 (0.1 and 1 microg/ml) rendered maximum radioprotection when administered 1 or 2 h before irradiation. Higher concentrations (5 and 10 microg/ml) however were less effective when administered 1 or 2 h before irradiation, but were more effective with increased time intervals (4 or 8 h) between RP-1 administration and irradiation. RP-1 pre-treatment also significantly inhibited radiation-induced MTT reduction in a concentration and time-dependent manner by decreasing gamma radiation-induced leakage of electrons from electron transport chain. Pre-irradiation administration of RP-1 significantly reduced both ROS and NO generation and enhanced glutathione levels, thereby inhibiting lipid peroxidation.