The Demographic and Clinicopathological Characteristics of Hepatopancreatobiliary Cancers From a Specialized Center in India.

Introduction Hepatopancreatobiliary (HPB) cancers are a distinct group requiring specialized multidisciplinary care. The present study was an analysis of HPB cancers. Methods The institutional data for two years from 2017 to 2018 was retrieved from the hospital-based cancer registry (HBCR) database in Excel format (Microsoft® Corp., Redmond, WA). The demographic details, method of diagnosis, tumor characteristics, and disease extent of the patients with HPB primary sites were retrospectively analyzed. Results Out of the 1417 patients with HPB malignancies, 1193 were analyzed. Most of the patients at our center hailed from North India. The distribution of HPB cancers was as follows: hepatocellular carcinoma (HCC) (n=717, 60.1%), gallbladder (GB) (n=230, 19.3%), periampullary carcinoma (n=76, 6.37%), head of the pancreas (HOP) (n=55, 4.61%), extrahepatic bile duct (EBD) (n=53, 4.44%), intrahepatic bile duct (IBD) (n=32, 2.68%), and body of the pancreas (BOP) (n=30, 2.52%). The most common disease presentation of HPB cancers was in the seventh and sixth decades of life. Male predominance was seen in all HPB cancers except in GB with a higher incidence in females. The predominant cause of chronic liver disease (CLD) with HCC was viral-related (53.7%) with hepatitis B virus (HBV) (34.3%) higher than hepatitis C virus (HCV) (19.2%) followed by non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) (24.8%) and then alcohol. Adenocarcinoma was the most common morphology in pancreatobiliary malignancies. The disease presentation was locoregional in 63.4% of HCC, 69.7% of periampullary carcinoma, and 50.9% of HOP cases. The patients with EBD and IBD cancers presented commonly with locoregional disease extent in 60.4% and 62.5%, respectively. Perihilar subsite was more commonly detected (71.7%) as compared to the distal one in the patients with EBD cancers. The patients with GB cancers (GBC) presented with distant metastases in 53.5% and locoregional disease in 33%. Distant metastases were present in 76.7% of the patients with BOP cancers. The liver was a common site of distant metastases in GB, periampullary, and pancreatic cancers. Conclusions The present study highlights the characteristics and the variations in disease presentation in different primary tumor sites of HPB cancers. In view of the common locoregionally advanced disease presentation of HCC, the patients with CLD need surveillance for the early detection of lesions. As the patients with HPB cancers show advanced disease presentation, effective locoregional and systemic therapies are needed.

Optimized addition of nitric oxide compounds in semen extender improves post-thaw seminal attributes of Murrah buffaloes.

Semen dilution and cryopreservation alter the homogeneity of seminal plasma, resulting in a non-physiological redox milieu and consequently poor sperm functionality. Considering the concentration-specific bimodal action of nitric oxide (NO) in the regulation of sperm functions, cryopreservation media supplemented with optimized concentrations can improve the semen attributes. The present study aimed to evaluate the effect of adding an optimized concentration of sodium nitroprusside (SNP) and N-nitro-L-arginine methyl ester (L-NAME) in an extender on in vitro semen quality. An aliquot of semen samples (n = 32) from Murrah buffalo bulls (n = 8) was divided into control (C) and treatment (T-I: SNP in extender at 1 µmol/L; T-II: L-NAME in extender at 10 µmol/L). Fresh semen quality parameters showed no significant difference at 0 h except for the structural integrity in the T-II group. Post-thaw semen quality parameters and sperm kinematics using computer-aided sperm analysis (CASA) revealed significantly higher (p < 0.05) cryoresistance in the treatment groups. Viability, acrosome integrity, and membrane integrity were significantly higher (p < 0.05) in both treatment groups; however, the results were pervasive in T-II. Lower abnormal spermatozoa were observed in both T-I and T-II. SNP supplementation led to a significant rise (p < 0.05) in NO, whereas L-NAME reduced the NO concentration in post-thawed samples, which was directly correlated with different sperm functionality and associated biomarkers viz. total antioxidant capacity (TAC) and thiobarbituric acid reactive substance (TBARS). It was concluded that the cryopreservation media supplemented with SNP and L-NAME at 1 µmol/L and 10 µmol/L, respectively, lower the cryo-damage and improve post-thaw seminal attributes.

Effect of over dilution of semen with tris extender on motion and functional attributes of bull spermatozoa during cryopreservation.

The present study was aimed to evaluate the effect of over dilution of semen with tris extender on motion and functional attributes of bull sperm post-thaw. Ejaculates (n = 24; mass motility ≥3+) were collected from bulls (n = 4) using artificial vagina, diluted to 20, 15, 10 and 5 million spermatozoa/0.25 ml, and cryopreserved. The results revealed that total motility (%), progressive motility (%) and rapid motility (%), straight linear velocity (µm/s), straightness (%) reduced significantly (p < 0.05) when semen was diluted to 5 million sperm concentration. Among the various sperm function attributes, proportions of live spermatozoa, acrosome intact spermatozoa, hypo-osmotic swelling responsive spermatozoa and non-capacitated spermatozoa reduced (p < 0.05) in 5 million spermatozoa, and the proportions of moribund spermatozoa, dead spermatozoa, live acrosome reacted spermatozoa, dead acrosome intact spermatozoa, capacitated spermatozoa and spermatozoa with lipid peroxidation increased significantly (p < 0.05) when semen was diluted from 20 to 5 million. However, the over-dilution of semen did not affect slow motility, dead acrosome reacted spermatozoa, sperm protamine deficiency and spermatozoa with lipid peroxidation. In conclusion, the over dilution of semen affected sperm motion and functional attributes of frozen-thawed bull semen.

Degree of reduction in normal liver complication probability from free-breathing to breath-hold liver SBRT: a dose-escalation strategy using radiation dose-volume effect.

Introduction. This study aimed to analyze the degree of reduction in normal liver complication probability (NTCP) from free-breathing (FB) to breath-hold (BH) liver SBRT. The effect of the radiation dose-volume on the mean liver dose (MLD) was also analyzed due to dose prescription, normal liver volume (NLV), and PTV.Materials and Methods. Thirty-three stereotactic body radiation therapy (SBRT) cases of hepatocellular carcinoma were selected, retrospectively. For FB, the treatments were planned on average intensity projection scan (CTavg), and patient-specific internal target volume (ITV) margins were applied. To simulate the BH treatment, computed tomography (CT) scan correspond to the 40%-50% of the respiratory cycle (CT40%-50%) was chosen, and an appropriate intrafraction margin of 2 mm, 1.5 mm, and 1.5 mm were given in craniocaudal (CC), superior-inferior (SI), and lateral direction to generate the final iGTV. As per RTOG 1112, all organs at risk (OAR's) were considered during the optimization of treatment plans. NTCP was calculated using LKB fractionated model. Multivariate regression analysis was performed to see the effect of EQD2Gy, NLV, and PTV on MLD2Gy.Results.A significant dosimetric difference was observed in the normal liver (liver-ITV/iGTV). A reduction of 1.7% in NTCP was observed from FB to BH technique. The leverage of dose escalation is more in BH because MLD2Gycorresponds to 5%, 10%, 20%, and 50% NTCP was 0.099 Gy, 0.41 Gy, 1.21 Gy, and 3.432 Gy more in BH as compared to FB technique. In MVRA, the major factor which was attributed to a change in MLD2Gyis EQD2Gy. Conclusion. From FB to BH technique, a significant reduction in NTCP was observed. The dose prescription is a major factor attributed to the change in MLD2Gy. Advances in knowledge: If feasible, prefer BH treatment either for tumor dose escalation or for the reduction in NTCP.

Dosimetric impact of contrast-enhanced 4d computed tomography for stereotactic body radiation therapy of hepatocelluar carcinoma.

BACKGROUND: A purpose of the study was to investigate the dosimetric impact of contrast media on dose calculation using average 4D contrast-enhanced computed tomography (4D-CECT) and delayed 4D-CT (d4D-CT) images caused by CT simulation contrast agents for stereotactic body radiation therapy (SBRT) of liver cases. MATERIALS AND METHODS: Fifteen patients of liver SBRT treated using the volumetric modulated arc therapy (VMAT) technique were selected retrospectively. 4D-CECT, and d4D-CT were acquired with the Anzai gating system and GE CT. For all patients, gross target volume (GTV) was contoured on the ten phases after rigid registration of both the contrast and delayed scans and merged to generate internal target volume (ITV) on average CT images. Region of interest (ROI) was drawn on contrast images and then copied to the delayed images after rigid registration of two average CT datasets. The treatment plans were generated for contrast enhanced average CT, delayed average CT and contrast enhanced average CT with electron density of the heart overridden. RESULTS: No significant dosimetric difference was observed in plans parameters (mean HU value of the liver, total monitor units, total control points, degree of modulation and average segment area) except mean HU value of the aorta amongst the three arms. All the OARs were evaluated and resulted in statistically insignificant variation (p > 0.05) using one way ANOVA analysis. CONCLUSIONS: Contrast enhanced 4D-CT is advantageous in accurate delineation of tumors and assessing accurate ITV. The treatment plans generated on average 4D-CECT and average d4D-CT have a clinically insignificant effect on dosimetric parameters.

Impact of dose heterogeneity in target on TCP and NTCP for various radiobiological models in liver SBRT: different isodose prescription strategy.

INTRODUCTION: The impact of dose heterogeneity within the tumor on TCP and NTCP was studied using various radiobiological models. The effect of the degree of heterogeneity index (HI) on TCP was also analyzed. MATERIALS AND METHODS: Thirty-seven pre-treated liver SBRT cases were included in this study. Two different kinds of treatment techniques were employed. In both arms, the prescribed dose was received by 95% of the PTV. Initially, the inhomogeneous treatment plans (IHTP) were made in which the spatial change of dose within the PTV was high and the maximum dose within the PTV can go up to 160%. Subsequently, in another arm, homogeneous treatment plans (HTP) were generated in which PTV was covered with the same prescription isodose and the maximum dose can go up to 120%. As per RTOG 1112, all organs at risk (OAR's) were considered while optimization of the treatment plans. TCP was calculated using the Niemierko and Poisson model. NTCP was calculated using the Niemierko and LKB fractionated model. RESULTS: For the IHTP, TCP was decreasing as 'a' value decreased in the Niemierko model whereas, for HTP, TCP was found to be the same. NTCP of the normal liver was less in IHTP as compared to HTP, and the Niemierko model overestimates the NTCP as compared to LKB fractionated model. NTCP for all other OAR's was <1% in both kinds of treatment plans. CONCLUSION: IHTP is found to be clinically better than HTP because NTCP of the normal liver was significantly less and TCP was more for certain 'a' values of the Niemierko model and the Poisson model. There is not any effect of HI on TCP was observed. Advances in knowledge: IHTP could be used clinically because of the dose-escalation and subsequently, leads to an increase in the TCP.

Interplay effect modeling in stereotactic body radiotherapy treatment of liver cancer using volumetric modulated arc therapy.

To model the interplay effect and minimize it by a selection of optimum parameters value using a predictive model for SBRT of liver cancers. Ten cases of liver tumors treated with the VMAT technique were selected retrospectively. The dosimetric error due to the interplay effect was measured with a micro ionization chamber (0.015cm3) in a Quasar phantom simulating the moving tumor. The interplay effect dependent parameter's viz. patient breaths per minute, the amplitude of respiration, fractional dose (FD), plan complexity due to different energies (Relative degree of modulation), degree of modulation due to a different level of dose optimization constraints, and dose rate (DR) were measured. For the predictive model, mathematical equations were modeled in python from 300 combinations of proposed parameters using multivariate regression analysis. It was observed that the dose variation reduced from -8.44% to -5.16% for change in the BPM values from 7 to 31 and similarly for amplitude, the dose variation reduced from -9.44% to -4.93% for change in amplitude value from 16 mm to 2 mm. The DR and FD have a prominent effect with R2 values of 0.990 and 0.880 respectively. The calculated mean square errors of equations excluding amplitude for the predictive model were 0.90 and 0.82 whereas those for equations excluding BPM were 1.31 and 1.41 for 6 MV and 10 MV beams respectively. The values of the parameters can be prospectively optimized by the use of the predictive model according to clinical situations, so dose variation can be minimized.

Supplementing extender with anandamide enhances quality of low sperm doses during cryopreservation in bulls.

The present study explored the effect of anandamide supplementation in the extender on quality of low sperm doses during cryopreservation in Sahiwal bulls. Each fresh semen sample was split into eight aliquots (I, II, III, IV, V, VI, VII and VIII). The aliquots I, II, III and IV were taken as control and diluted to 20, 15, 10 and 5 million spermatozoa/0.25 ml respectively. The aliquots V, VI, VII and VIII were diluted with extender (supplemented with anandamide at 1 µM/ml of extender) to 20, 15, 10 and 5 million spermatozoa/0.25 ml respectively. This was followed by filling of diluted semen into French mini straws, equilibrated at 4°C of 4 hr and cryopreserved. The results revealed that the proportions of motile spermatozoa, live spermatozoa and live acrosome intact spermatozoa were significantly (p < .05) higher in all anandamide-treated sperm doses compared to control. The proportions of moribund spermatozoa, dead acrosome intact spermatozoa and capacitated spermatozoa were significantly (p < .05) reduced in all anandamide-treated sperm doses compared to control, with no difference in proportion of dead acrosome-reacted spermatozoa. In conclusion, anandamide supplementation in the extender increases the post-thaw quality of low sperm doses during cryopreservation in bulls.

Dosimetric comparison of dynamic conformal arc integrated with segment shape optimization and variable dose rate versus volumetric modulated arc therapy for liver SBRT.

PURPOSE: The aim is a dosimetric comparison of dynamic conformal arc integrated with the segment shape optimization and variable dose rate (DCA_SSO_VDR) versus VMAT for liver SBRT and interaction of various treatment plan quality indices with PTV and degree of modulation (DoM) for both techniques. MATERIAL: Twenty-five patients of liver SBRT treated using the VMAT technique were selected. DCA_SSO_VDR treatment plans were also generated for all patients in Monaco TPS using the same objective constraint template and treatment planning parameters as used for the VMAT technique. For comparison purpose, organs at risk (OARs) doses and treatment plans quality indices, such as maximum dose of PTV (Dmax%), mean dose of PTV (Dmean%), maximum dose at 2 cm in any direction from the PTV (D2cm%), total monitor units (MU's), gradient index R50%, degree of modulation (DoM), conformity index (CI), homogeneity index (HI), and healthy tissue mean dose (HTMD), were compared. RESULTS: Significant dosimetric differences were observed in several OARs doses and lowered in VMAT plans. The D2cm%, R50%, CI, HI and HTMD are dosimetrically inferior in DCA_SSO_VDR plans. The higher DoM results in poor dose gradient and better dose gradient for DCA_SSO_VDR and VMAT treatment plans, respectively. CONCLUSIONS: For liver SBRT, DCA_SSO_VDR treatment plans are neither dosimetrically superior nor better alternative to the VMAT delivery technique. A reduction of 69.75% MU was observed in DCA_SSO_VDR treatment plans. For the large size of PTV and high DoM, DCA_SSO_VDR treatment plans result in poorer quality.

Derivative-based gamma index: a novel methodology for stringent patient-specific quality assurance in the stereotactic treatment planning of liver cancer.

Objective:The development of a stringent derivative-based gamma (DBG) index for patient-specific QA in stereotactic radiotherapy treatment planning (SRTP) to account for the spatial change in dose.Methods:Twenty-five patients of liver SBRT were selected retrospectively for this study. Deliberately, two different kinds of treatment planning approaches were used for each patient. Firstly, the treatment plans were generated using a conventional treatment planning (CTP) approach in which the target was covered with a homogeneous dose along with the nominal dose fall-off around the treatment field. Subsequently, the other treatment plans were generated using an SRTP approach with the intent of heterogeneous dose within the target region along with a steeper dose gradient outside the treatment field as much as possible. For both kinds of treatment plans, two dimensional (2D) conventional gamma (CG) and DBG analysis were performed using the 2D ion chamber array and radiochromic film.Results:Difference in the DBG index was statistically significant whereas, for CG analysis, the difference in CG index was insignificant for both types of treatment plans (CTP and SRTP). A significant positive correlation was observed between the difference in the DBG index and the difference in HI for high gamma criteria.Conclusion:The DBG evaluation is found to be more rigorous, and sensitive to the only SRTP. The proposed method could be opted-in the routine clinical practice in addition to CG.Advances in knowledge:DBG is more sensitive to detect the spatial change of dose, especially in high dose gradient regions.

Effect of cholesterol loaded cyclodextrin supplementation on tyrosine phosphorylation and apoptosis like changes in frozen thawed Hariana bull spermatozoa.

The beneficial effects of cholesterol loaded cyclodextrin (CLC) addition were evaluated in cryopreserved bull semen. Forty ejaculates were collected from Hariana bulls (n = 4), pooled and divided into 4 aliquots. All the aliquots were initially diluted in to egg yolk tris citrate and supplemented with CLC @ 0.5 mg (Group-II), 1.0 mg (G-III) and 2.0 mg (G-IV) CLC/120 × 106 spermatozoa or without CLC (G-I) that served as control. Extended semen was cryopreserved at -196 °C for 24 h. Seminal attributes like motility, viability, cryocapacitation like changes, tyrosine phosphorylation, apoptosis like changes in terms of mitochondrial transmembrane potential and DNA integrity were evaluated after equilibration and thawing. Results showed a significant increase in the motility, viability and acrosome intact spermatozoa in Group II as compared to other three groups. Further, the proportion of spermatozoa showing capacitation and acrosome reaction was also decreased (P < 0.05) significantly in Group II as compared to Group I, III, and IV. Immunoblot demonstrated a 32 kDa (p32) protein showing differential variation in the band intensity in all the four groups being lower in Group II. Further, the immunolocalization study revealed positive immune reactivity for tyrosine phosphorylated proteins at middle piece and neck (high fluorescence), post-acrosomal region (medium fluorescence), and principal piece (low fluorescence) of spermatozoa. Addition of CLC significantly increased (P < 0.05) the percentage of spermatozoa showing high transmembrane mitochondrial potential, and also, CLC @ 0.5 mg/120 × 106 in semen extender significantly decreased (P < 0.05) spermatozoa showing fragmented DNA after thawing as compared to control. Results of the present study indicate beneficial effects of CLC supplementation on cryodamage of spermatozoa by reducing the cryocapacitation and apoptosis like changes.