Liver Volume Research Articles

Mathematical Model of Insulin-like growth factor-1 estimating its cause in human bone cancer arises due to liver cancer

The insulin-like growth factor-1 (IGF-1) is a peptide hormone that is regulated by growth hormone and secreted in the liver; its prime role is to regulate the growth and proliferation of the bone cell. Our study results relate to the cause of bone cancer due to high IGF-1 levels in liver metastatic conditions. Liver cancer increases the liver volume which further increases IGF-1 secretion to a toxic level, which in turn causes uncontrolled bone cell proliferation and maturation thus leading to bone cancer. Thus, the mathematical model was designed to explain the kinetics of IGF-1 from the liver to bone and mathematically simplified using the ordinary differential equation, and IGF-1 concentration was estimated in the normal and cancerous state. The mathematical simulation was done using a high throughput technique using MATLAB (version R2020a). The model parameter condition due to liver cancer is considered as an increase in liver volume (vL), The initial mass of IGF-1(x01), and the varying rate constants (kP, kL, ke1, and ke2). The graphical results represent the volume of the liver and synthesis of IGF-1 increases with varying abnormal rate constants giving the estimation of an increase in IGF-1 concentration in plasma, and more IGF-1 deposits over the bone to a toxic level.

Phase 1 Trial of SPECT-Guided Liver-Directed Ablative Radiotherapy for Patients with Low Functional Liver Volume

Traditional liver dose constraints specify that a critical volume of 700 cc of non-tumor liver should be spared from receiving a hepatotoxic dose. We evaluated the safety of liver-directed ablative radiotherapy for patients with hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), or liver metastases (LM) with Child-Pugh (CP) A5 liver function at baseline and with low functional liver volume as estimated by Tc-99m sulfur colloid single photon emission computed tomography (SPECT). We hypothesized that functional liver image guidance with SPECT would allow safe delivery of ablative radiotherapy in patients with limited liver volume. A phase 1 trial with a 3+3 design was conducted to evaluate the safety of comprehensive ablative radiotherapy to the liver disease using escalating functional non-target liver radiation dose constraints. Eligibility criteria included (1) a diagnosis of HCC, iCCA, or LM, (2) prior treatment with irinotecan or oxaliplatin chemotherapy or liver resection, and (3) a minimum functional liver volume of 400 cc as estimated by SPECT using a threshold of 40% maximum intensity. Patients with CP >A5 liver function, prior liver-directed radiotherapy, or prior Yttrium-90 therapy were excluded. The prescription dose was 67.5-75 Gy in 15 fractions or 75-100 Gy in 25 fractions. The volumetric dose constraint for functional non-target liver receiving <24 Gy for 15 fractions or <27 Gy for 25 fractions was determined by the dose level of trial enrollment: level 0 was ≥400 cc and level +1 was ≥300 cc. A level -1 was included if needed. We used standard 15 and 25 fraction dose constraints for other organs at risk. The following dose limiting toxicities (DLTs) were assessed within 6-8 weeks of completing radiotherapy: Grade 3 hypoalbuminemia, increase in INR, increase in bilirubin, or ascites, or Grade 4 hepatic failure or any radiation-related toxicity. Twelve patients enrolled between February 2016 and June 2022. The median (range) GTV was 36 (2-651) cc. The median CT anatomical non-tumor liver volume was 1584 (764-2699) cc, and the median SPECT functional liver volume was 1117 (570-1928) cc, with a Pearson correlation coefficient of 0.98 (p<0.001). The median non-target SPECT functional liver volume below the volumetric dose constraint was 684 (429-1244) cc. None of the 3 patients treated in dose level 0, and none of the 9 patients treated in dose level +1 experienced any DLTs. The 1-year in-treatment-field control rate was 55%, and 1-year overall survival was 71%. Ablative radiotherapy can be safely delivered using functional SPECT image guidance, which enables sparing lower volumes of functional liver than traditionally accepted in patients with CP A5 liver function. Further evaluation with a phase 2 study is warranted.

The Effect of Deep Inspiration Breath-Hold Technique on Right Coronary Artery, Heart, and Liver Doses in Right Breast Cancer Radiotherapy

The deep inspiration breath-hold (DIBH) approach has been thoroughly researched with the aim of reducing radiation exposures to normal tissues in breast cancer patients. Although heart and lung toxicity are widely addressed in many literature, radiation-associated liver toxicity and dose constraints for the right coronary artery (RCA) are not well studied in relation to breast radiotherapy. Additionally, very few studies have investigated the relationship between doses to cardiac substructures. This study aimed to determine the effect of the DIBH technique on the right coronary artery (RCA) region, cardiac substructures, and liver dose in right breast cancer irradiation. Between January 2022 and December 2022, thirty-five right breast cancer patients who previously received breast-surgery underwent computed tomography (CT) simulation with both free-breathing (FB) and DIBH techniques. Patients were contoured by a radiation oncologist on the scans using the Treatment Planning System. For cardiac substructures, reference atlas contours were used for accurate delineation and to reduce inter-observer variation. Each patient underwent two treatment plans for both the DIBH and FB datasets. The plan comprised the FB and DIBH techniques, and the doses to the cardiac substructures, ipsilateral lung, RCA region, and liver were compared using a two-tailed paired t-test. Radiotherapy was delivered with a Linac with the prescription dose of 50 Gy in 25 fractions. For both FB and DIBH irradiation groups, the mean radiation doses to the ipsilateral lung, heart, and RCA region in patients with FB and DIBH techniques were; 14.67 Gy, 2.33 Gy, 4.88 Gy and 12.05 Gy, 1.34 Gy and 3.29 Gy respectively. The mean radiation doses to the cardiac substructures; for the left ventricle, right ventricle, left atrium, and right atrium for the FB were 1.08 Gy, 1.79 Gy, 4.11 Gy, and for DIBH, 0.49 Gy, 1.49 Gy, 0.95 Gy, and 2.61 Gy, respectively. For the DIBH group, the liver maximum dose (p<0.01), right lung mean dose (p = 0.001), heart maximum dose (p = 0.009), RCA mean dose (p = 0.020), RCA maximum dose (p = 0.008), RCA V5 dose (p = 0.035), right atrium maximum dose (p = 0.009) and right ventricle mean dose (p = 0.040) were significantly lower than in patients treated in the non-gated group. DIBH resulted in considerable displacement of the liver away from the high-dose target region, such that the volume of liver in the high-dose region was reduced. Additionally, the use of the DIBH technique in right breast cancer irradiation effectively reduces the radiation doses to the cardiac substructures, such as the left ventricle, right ventricle, left atrium, right atrium, RCA region, and lungs. DIBH could lead to substantial sparing of these structures with the right breast cancer radiotherapy. Future prospective studies are required to determine whether improvements to dose-distribution will translate into improved toxicity outcomes.

Liver Regeneration Following Radiation Therapy in Hepatocellular Carcinoma Patients: Insights from Functional Liver Imaging

A critical need for hepatocellular carcinoma (HCC) patients is understanding how the liver recovers following radiation therapy (RT). While liver regeneration after hepatic resection has been well-studied, liver recovery following RT is less understood. We have previously studied 99mTc-sulphur colloid (SC) single photon emission tomography (SPECT)/CT to spatially and quantitatively analyze liver function. The purpose of this study was to assess both volumetric and functional liver changes following RT. Patients with HCC had liver function assessed with SC SPECT/CT before and after definitive RT. Patients received 30-67.5 Gy in 4-15 fractions. Anatomic and functional liver metrics were assessed before and after treatment. The anatomic liver volume (ALV) was drawn on CT imaging. Liver function was measured as the functional volume encompassing 30% of maximum uptake (FLV) and mean liver-to-spleen uptake ratio (L/S). Changes in liver size and function were compared to clinical characteristics, including Child-Pugh (CP) score. Parametric t-tests were used to analyze the data. Of 23 evaluable patients (proton RT, n = 16 or photon RT, n = 7), 15 patients had CP-A5/6, 7 had CP-B7/8, and 1 had CP-C10 scores. The mean interval of SC SPECT was 67 days following RT (range, 44 to 113 days). The mean PTV was 272 cc (range 22-802 cc). Regarding baseline liver status, mean pre-treatment ALV was 1584 cc (range 810-2749 cc) with no significant difference in ALV between CP-A and B/C patients (p = 0.285). Pre-treatment mean liver function as assessed with L/S was 1.06 ± 0.43 with significantly greater function in CP-A compared to CP-B/C patients (1.27 vs 0.66, respectively, p<0.001). Mean pre-treatment FLV was 1351 ± 430.8 cc with no significant difference in FLV between CP-A and B/C patients (1422 ± 441 cc vs 1220 ± 436 cc, respectively, p = 0.31). When evaluating change following RT, the mean change in ALV was 0.9% (range, -29% to 23%) with no significant difference between CP-A and CP-B/C patients (-1.5% vs 5.4%, respectively, p = 0.19). In contrast, change in liver function following RT was larger; mean change in FLV was -20% (range, -55% to 33%) and mean change in L/S was -16% (range, -66% to 105%). While change in FLV was not significantly different between CP-A and CP-B/C patients, CP-B/C patients had significantly greater decline in mean liver function (L/S) than CP-A patients (-40 ± 18% vs -3.6 ± 36%, respectively, p = 0.018). There was no association between change in liver volume and change in L/S, p = 0.543. Functional liver imaging metrics reveal different information about the potential functional reserve of irradiated livers compared to anatomic measurements. These data imply that functional liver imaging may more accurately assess the regenerative potential of irradiated and non-irradiated volumes of liver, which may be useful in clinical scenarios where assessment of the function of future liver remnants become critical.

Compensatory Enlargement of the Liver after Proton Beam Therapy for Hepatocellular Carcinoma

Charged particle therapy (CPT) has been applied as a safe and effective treatment option for hepatocellular carcinoma (HCC). Although most HCC patients have cirrhosis, favorable treatment outcome has been achieved with CPT preserving liver function. After proton beam therapy (PBT) for patients with HCC, the liver volume in the non-irradiated area is often enlarged. Here, we evaluated whether enlargement of the non-irradiated liver affects preserving hepatic function and prognosis in HCC patients treated with PBT. Among consecutive patients with HCC treated with PBT between April 2011 and July 2017, we retrospectively identified patients who fulfilled the following criteria: (i) receiving PBT to the right hepatic lobe, (ii) the left lateral segment was not irradiated, (iii) no local treatment was performed for liver within 12 months after PBT, and (iv) the albumin-bilirubin (ALBI) score was evaluable at 12 months after PBT. The left lateral segment was defined as the non-irradiated region and measured by contrast-enhanced CT just before and 3 months after PBT. ALBI scores just before and 12 months after PBT were compared to evaluate changes of hepatic function. Overall survival rate was estimated using the Kaplan-Meier method, and differences in survival between subgroups were examined using the log-rank test. The ALBI scores were compared using the Wilcoxon signed-rank test. We identified 40 patients (male/female = 32/8). The median age at the start date of PBT was 72 (range, 54-87) years. The prescribed dose was 66.0-76.0 Gy (relative biological effectiveness) delivered in 10-38 fractions. The median follow-up was 61 (range, 12-126) months. The 5-year overall survival rates were 79.0% (95% CI: 60.4-100.0%) in the larger enlargement group (n = 16, enlarged volume of non-irradiated region 3 months after PBT ≥75 cm3) and 53.7% (95% CI: 36.0-79.9%) in the smaller enlargement group (n = 24, as above, <75 cm3), respectively (p = 0.21). The median ALBI scores just before and 12 months after PBT were -3.14 (95% CI: -3.22- (-2.53)) and -2.74 (95% CI: -3.07- (-2.42)) in the larger enlargement group (p = 0.09), and -2.91 (95% CI: -3.15- (-2.40)) and -2.59 (95% CI: -2.74- (-2.12)) in the smaller enlargement group (p = 0.006), respectively. Our study suggests that larger enlargement of the non-irradiated liver after PBT is related to well-preserved liver function at 1 year and modestly associated with a favorable prognosis.

Predictive Value of Tumor Volume on Local Control in Hepatocellular Carcinoma Treated with Image Guided Hypofractionated Radiation Treatment

External beam radiation treatment (EBRT) is an important local treatment in liver-confined hepatocellular carcinoma (HCC) patients who are not candidates for curative therapy. EBRT dose, technique and prognostic factors are evolving. We hypothesized that tumor volume to liver volume ratio can be a predictor of local control (LC) in patients treated with hypo-fractionated radiation (HFRT) in HCC MATERIALS/METHODS: We retrospectively reviewed 50 patients of HCC treated with HFRT at our institution. HFRT schedule was chosen such that the radiation dose to the remaining liver and other organs at risk (OAR) met the standard dosimetric constraints. Image guided techniques were used for motion management, internal target volume (ITV) and planning target volume (PTV) delineation. Tumor to Liver Ratio (TLR) was defined as ratio of PTV volume to whole liver volume. TLR ≤ 0.3 was considered as low volume disease and TLR > 0.3 was considered as high-volume disease. The radiation dose ranged from 45 Gy to 67.5 Gy in 5 - 15 fractions. The biologically equivalent dose (BED) for tumor ranged from 58.5 Gy10 to 100 Gy10. Local control (LC) was evaluated by Kaplan-Meier analysis, with log-rank test for groups stratified as per TLR. Multivariate Cox regression analysis was performed to identify additional prognostic factors. The mean duration of follow-up was 24 months. The median age was 69 years (range 50 - 90) and 76% were males. 32 patients had CP-A class cirrhosis while 17 had CP-B and 1 had CP-C class. BCLC stage A, B, C and D was seen in 2, 14, 33 and 2 patients, respectively. Portal vein thrombosis was present in 9 patients and prior trans-arterial chemo embolization (TACE) was done in 23 patients. The median volume of PTV was 551 cc (range 52 - 1990 cc). The TLR ranged from 0.04 - 0.67 with a median of 0.29. The median BED radiation dose was 78.4 Gy10 (range - 58.5 Gy10 to 100 Gy10). Nine patients had local recurrence with overall LC rate of 82%. The LC was better in low volume tumors, with the TLR cut-off of 0.3 as a significant factor associated with LC (p = 0.007). The 1-year actuarial LC with TLR ≤ 0.3 was 88% as compared 61% in TLR of > 0.3 (p = 0.007). BED ≥60 Gy10 was associated with better 1 year LC as compared to BED < 60 Gy10 (89% vs 62%; p = 0.11). ALBI grade 1 was associated with better 1 year LC as compared to ALBI grade 2 (80% versus 75%; p = 0.40). On multivariate analysis, high volume disease and TLR >0.3 were significant prognostic factor for LC. HFRT has good 1-year local control of 82% in carefully selected unresectable HCC. Radiation with BED greater than 60 Gy10 and ALBI grade 1 showed a trend towards better LC. Smaller tumors had better LC with a PTV to liver ratio (TLR) of < 0.3. This information can help in identifying the poor responders, intensifying the radiation treatment and adding additional therapy to improve the oncological outcomes.

Intratumoral Dose Escalation Using Lattice Radiotherapy for Hepatocellular Carcinoma with Unfavorable Size and Location

Stereotactic body radiation therapy (SBRT) is a standard of care for unresectable hepatocellular carcinoma (HCC). However, its safe delivery is limited by tumor size and adjacent organs-at-risk (OARs). RTOG 1112 showed a survival benefit with local control in advanced HCC, but median dose was limited to 35 Gy in 5 fractions due to OARs. Here, we demonstrate the dosimetric feasibility of lattice radiation therapy (LRT) for dose escalation in advanced HCC. Five-fraction volumetric arc-based (VMAT) LRT plans were generated using a customized Python v3.6 script. For each combination of peak/valley doses and sphere size and spacing, a bounding box was generated around the gross tumor volume (GTV) and divided into equal segments in the x, y, and z planes. Individual spheres were constructed for a given parameter set and those fully encompassed within the target contracted by 2 cm were used to create peak dose targets with values of 30, 40, or 50 Gy. Valley dose target volumes over a range of 2 to 45 Gy were generated by subtracting an 8 mm expansion of the peak dose spheres from the overall target volume. Multi-criteria optimization (MCO) was applied to generate a final plan. The planning target volume (PTV) was a 5-mm uniform expansion from the GTV. All plans were generated at maximum inspiration on 4D-CT. OAR parameters were compared against a standard 5-fraction SBRT plan using Wilcoxon signed-rank testing. GTV and PTV measured 593 (23%) and 804 (32%) cm3, respectively, of a total liver volume of 2525 cm3. The minimum distance of GTV from stomach and duodenum was 6 mm and 2 mm, respectively. Plans were evaluated as per RTOG 1112 with stepwise reduction from a maximum PTV dose of 50 Gy based upon ability to meet mean liver dose (MLD, defined as liver-GTV) constraints; the 30 Gy threshold was the highest achievable. Of 7 eligible LRT plans, 5 with ablative 50 Gy peak doses were analyzed. Associated valley doses were 15 or 20 Gy. Median values of mean GTV and PTV doses for these plans were 36.2 (IQR, 34.6 - 37.8) and 32.9 (IQR, 31.3 - 33.4) Gy, respectively. A median of 12.4% (IQR, 7.4 - 28.4) of the GTV received a dose of 50 Gy. Median doses to 0.5 cc of stomach and duodenum were 16.7 Gy (range, 15.6 - 19.6) and 14.4 Gy (range, 12.3 - 23.9), respectively. The median value for MLD was 13.9 Gy (range, 13.6 to 14.8) and the median volume of normal liver spared 15 Gy was 1114 cm3 (range, 969 to 1154). These hepatic parameters were significantly decreased compared to a standard 30 Gy SBRT plan (18.1 Gy and 611.3 cc spared, p = 0.043 for both) which did not meet constraints. Dose escalation of advanced HCC using LRT is dosimetrically feasible. Though mean target doses remained limited by MLD, LRT allowed delivery of ablative dose to 12.4% of the GTV while meeting critical OAR constraints. Intratumoral dose-escalation may improve local control in advanced HCC patients.

Dosimetric Analysis of Patients Treated with Stereotactic Body Radiation Therapy for Malignant Portal Vein Tumor Thrombosis Using MRI-Guided vs. CT-Guided Linear Accelerator

The use of MRI-guided linear accelerators (MRI-LINAC) for radiation therapy has allowed for increased treatment precision and real-time tumor tracking. We hypothesized that the use of an MRI-LINAC, recently acquired by our institution, would allow us to treat malignant portal vein tumor thromboses (PVTT) closer to the origin of the portal vein with similar doses to the liver and nearby GI organs and with similar treatment toxicities compared to patients treated using a CT-guided linear accelerator (CT-LINAC). We retrospectively assessed patients who received SBRT for treatment of PVTT within the UVA health system using the electronic medical record. We contoured the origin of the portal vein on the simulation scans (MRI or CT) for each patient. The shortest distance from the GTV to the portal vein origin and to organs at risk (OAR; duodenum, stomach or "other intestine") were measured. The PTV, volume of the liver receiving less than 18 Gy during treatment, and the Dmax to the portal vein origin and OAR were determined. The means for each variable were then compared between CT-LINAC and MRI-LINAC using independent samples t-tests. Treatment toxicities were graded using CTCAE version 5.0 guidelines. All plans met institutional dose constraints for SBRT. A total of 6 patients treated on CT-LINAC and 3 patients treated on MRI-LINAC were identified (mean dose CT 37.7 Gy [range 21-50] in 2-5 fractions; MRI 48.3 Gy [range 45-50] in 5 fractions). The GTV was significantly closer to the portal vein origin in the MRI-LINAC group (mean CT 92.75 mm ± 45.89; MRI 32.00 mm ± 29.46; p = 0.04). The GTV trended towards being closer to OAR in the MRI-LINAC group (mean CT 43.81 mm ± 37.09; MRI 4.36 mm ± 1.85; p = 0.059). The Dmax to both the portal vein origin (mean CT 0.58 Gy ± 0.33; MRI 22.49 Gy ±24.16; p = 0.024) and OAR (mean CT 13.38 Gy ± 5.98; MRI 36.23 Gy ± 5.38; p = <0.001) was significantly higher in the MRI-LINAC group. The PTV (mean CT 152.11 cc ± 169.94; MRI 122.47 cc ± 114.65; p = 0.398) or volume of liver receiving less than 18 Gy during treatment (mean CT 1287.87 cc ± 285.20; MRI 1743.88 cc ±961.94 = 3; p = 0.147) were not significantly different between the two groups. No patients in either the MRI-LINAC or CT-LINAC group reported acute toxicities greater than Grade 1. We found that patients with PVTT treated with MRI-LINAC SBRT at our institution were more likely to have central tumors near dose-limiting OAR. However, due to superior tumor delineation and dynamic tumor tracking, these patients were able to be treated without decreasing treatment dose or increasing acute GI toxicity compared to patients treated with CT-LINAC. A larger sample size and longer follow-up period is warranted to corroborate these initial findings.

Deep-Learning Based Auto-Segmentation for Liver Yttrium-90 Selective Internal Radiation Therapy

In resin Yttrium-90 (Y-90) selective internal radiation therapy (SIRT), liver volume sizes are needed for Y-90 activity calculations using the body-surface-area method, which are obtained from contours that are manually delineated in 3D images. The aim was to apply a deep-learning based auto-segmentation method for liver delineation for Y-90 SIRT. A deep-learning-based liver segmentation method was applied using the U-Net3D architecture, which is a 3D convolutional neural network (CNN) extended from the original 2D U-Net architecture for 3D objects in medical imaging. The segmentation model was trained on the Liver Tumor Segmentation (LiTS) dataset. The training data set contained 130 CT scans, and the test data set contained 70 CT scans. The model was deployed in the clinic using DICOM communication. Auto-segmentation of liver in the CT images of 18 SIRT patients was studied. The CT images were exported from clinical database to the segmentation model's DICOM location, where a monitoring software detected the incoming data and automatically ran the liver segmentation. The results were then returned to the original DICOM location where the CT images were stored. Auto-segmented liver contours were compared with physician manually-delineated contours. Dice similarity coefficient (DSC), mean distance to agreement (MDA), ratio of volume (RV), and ratio of activity (RA, ratio of activity calculated using an auto-segmented liver contour to the accurate activity calculated using a manually-delineated contour), were assessed. DSC, MDA, and RV are 0.942±0.014 (range: 0.908-0.959), 1.902±0.503 mm (range: 1.043-2.956 mm), and 0.988±0.039 (range: 0.901-1.045), respectively. RA is 1.001±0.003 (range: 0.993-1.007), which indicates that the activities calculated using the auto-segmented liver contours are close to the accurate activities. The segmentation model was able to successfully identify and segment livers in the CT images, and provide accurate and reliable results. The proposed method is beneficial for clinical use as it can process large amounts of data quickly and efficiently, and can be easily deployed in a clinical environment using DICOM communication.

Statistical Analysis to Determine the Predictors of Liver Segmental Hypertrophy Observed Post-Radiotherapy

Prediction of liver segment hypertrophy based on radiotherapy (RT) dose is crucial for maximizing functional liver volume and avoiding hepatic failure after RT. We determined predictors associated with liver hypertrophy with stratification based on induction chemo (IC) and tumor location. RT planning, CT images, and 3-month-followup CTs were analyzed from 148 patients who underwent RT for primary or metastatic liver cancers. A nnUNet based model was trained (train/test = 160/40 CTs) to contour the liver segments (1, 2, 3, 4, 5-8) with accuracy assessed using Dice Similarity Coefficients (DSC). 52 features corresponding to segments 1, 2, 3, 2+3, 4, 5-8, were collected including equivalent dose to 2Gy fractions metrics-mean dose (Dmean), dose received by 95% of the volume (D95), volume spared from x gy (Vx), cancer type, tumor location, and IC status. Descriptive statistics were reported as percentage of segments showing hypertrophy under all stratification. Predictors were compared with 6 response variables using Chi-squared/Fisher-Exact test (CST/FET) and logistic regression (LR) for categorical and numerical predictors. The nnUNet model had an average DSC of 0.91 across all segments. Overall, segments 1, 4, and 5-8 showed hypertrophy in 35% of cases, and segments 2, 3 and 2+3 showed hypertrophy in 45-49% of patients. Stratification based on tumor location resulted in segment 2+3 hypertrophy in 66% of patients when the tumor was in segments 5-8. For bilobed tumors, segment 2+3 hypertrophy was observed in 34% of patients. CST/FET showed that tumor location, IC, and tumor type were significant predictors of segment 5-8 hypertrophy. Tumor location was also a significant predictor of segments 3 and 2+3 hypertrophy. In LR analysis, all segment-based dose metrics were significant predictors of segment hypertrophy except Dmean in segment 4, and D95 in segment 2 and 4. Overall, the strongest association was obtained for V35 significantly predicting for each segment hypertrophy. The mean dose for segments with hypertrophy was significantly lower (range: 15-30 Gy) than segments with atrophy (p<0.01), except for segment 4 where the mean dose was 10Gy lower but did not reach significance. IC impacts the threshold mean dose that leads to hypertrophy, with more toxic drugs reducing the mean dose threshold. Tumor location and IC significantly impact the response of segments to RT. Dose volume metrics are strong predictors of volumetric response with segment volume spared from 35 Gy being the strongest predictor.

Role of Stereotactic Body Radiation Therapy in Portal Vein Tumor Thrombosis in Hepatocellular Carcinoma: A Prospective Single Institute Experience

Patients diagnosed with Hepatocellular carcinoma (HCC) complicated with portal vein tumor thrombosis (PVTT) have a limited number of treatment options available and are associated with an overall poor prognosis. With the recent developments in the field of radiation therapy, the role of radiotherapy particularly Stereotactic Body radiotherapy (SBRT) has increased as a loco-regional therapy for HCC. This study was planned to evaluate the role of SBRT in Locally advanced HCC complicated with PVTT and its role as loco-regional therapy. We conducted a prospective study that included patients diagnosed with HCC complicated with PVTT Child-Turcotte Pugh (CTP) Class A/B with a maximum score of 7, diagnosed on triple phase Contrast-Enhanced - MRI unsuitable for other ablative procedures. Patients with Bilirubin levels > 4 mg/dl, active Hepatitis, CTP score >7, normal liver volume <700cc or history of prior radiotherapy were excluded from the study. Patients underwent a contrast enhanced 4D-CT simulation with abdominal compression and were planned for SBRT using VMAT technique. Patients were followed-up as per Institute protocol. CECT or MRI for a radiological response was done for response assessment using mRECIST criteria version 1.1. A baseline MRI was done at one-month post-SBRT to understand any RT changes in the liver and to differentiate from tumor progression during the response assessment at three months. A total of 22 patients with HCC were recruited and received SBRT to PVTT, with a dosage between 30-42 Gy over 6 fractions treated on alternate days. Patients were assessed post-treatment with triphasic CE-MRI every 3 months as per institute protocol. Five patients had achieved Complete response in form of Portal vein recanalization. Three patients had Partial response to the treatment. Seven patients maintained stable disease status whereas six patients had disease progression during the entire course of treatment. The response rate (CR+PR) to treatment was 36.3% at the time of analysis. The Overall Response rate (CR+PR+SD) was 69%. No grade 3 or 4 toxicities were observed and treatment was tolerated well by patients. Kaplan-Meier method was applied to calculate the survival probability at various follow-up intervals. The median time for overall survival was 25 months ((95% CI: 15-35). Out of the 22 subjects included in the study, 6 patients died. There was a 78% survival probability at 12 months and a 68% survival probability at 18 months of follow-up. This prospective single-arm study demonstrated the vital role of SBRT in the treatment of Hepatocellular carcinoma with Portal vein tumor thrombosis and its efficacy in terms of achieving excellent local control with relatively lesser toxicities compared with existing treatment modalities. Patients have shown benefit post-treatment in terms of thrombus reduction and restoration of Portal vein flow making them suitable for further treatment like Resection or TACE.

Dose Volume and Liver Function Test Relationship following Radiotheraphy for Right Breast Cancer: A Multicenter Study.

The liver is a critical organ at risk during right breast radiotherapy (RT). Liver function tests (LFTs) such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT) serve as biochemical markers for hepatobiliary damage. In this multicenter cross-sectional study, the effects of liver dose-volume on changes in LFTs pre- and post-RT in patients treated for right breast cancer were evaluated. Between January 2019 and November 2022, data from 100 patients who underwent adjuvant right breast RT across three centers were retrospectively assessed. Target volumes and normal structures were contoured per the RTOG atlas. Patients were treated with a total dose of 50 Gy in 25 fractions to the CTV, followed by a boost to the tumor bed where indicated. The percentage change in LFT values in the first two weeks post-RT was calculated. Statistics were analyzed with SPSS version 22 software, with significance set at p < 0.05. Statistical correlation between liver doses (in cGy) and the volume receiving specific doses (Vx in cc) on the change in LFTs were analyzed using Kolmogorov-Smirnov, Mann-Whitney U test. The median age among the 100 patients was 56 (range: 29-79). Breast-conserving surgery was performed on 75% of the patients. The most common T and N stages were T1 (53%) and N0 (53%), respectively. None of the patients had distant metastasis or simultaneous systemic treatment with RT. A total of 67% of the treatments utilized the IMRT technique and 33% VMAT. The median CTV volume was 802 cc (range: 214-2724 cc). A median boost dose of 10 Gy (range: 10-16 Gy) was applied to 28% of the patients with electrons and 51% with IMRT/VMAT. The median liver volume was 1423 cc (range: 825-2312 cc). Statistical analyses were conducted on a subset of 57 patients for whom all three LFT values were available both pre- and post-RT. In this group, the median values for AST, ALT, and GGT increased up to 15% post-RT compared to pre-RT, and a median liver Dmean below 208 cGy was found significant. While many factors can influence LFT values, during RT planning, attention to liver doses and subsequent regular LFT checks are crucial. Due to factors such as anatomical positioning, planning technique, and breast posture, the liver can receive varying doses during right breast irradiation. Protecting patients from liver toxicity secondary to RT is valuable, especially in breast cancer patients with a long-life expectancy. Our study found that, even in the absence of any systemic treatment or risk factors, there was an average increase of nearly 15% in enzymes, indicating acute liver damage post-RT compared with pre-RT. Attention to liver doses during RT planning and regular follow-up with LFTs is essential.

Post Living Donor Liver Transplantation Small-for-size Syndrome: Definitions, Timelines, Biochemical, and Clinical Factors for Diagnosis: Guidelines From the ILTS-iLDLT-LTSI Consensus Conference.

When a partial liver graft is unable to meet the demands of the recipient, a clinical phenomenon, small-for-size syndrome (SFSS), may ensue. Clear definition, diagnosis, and management are needed to optimize transplant outcomes. A Consensus Scientific committee (106 members from 21 countries) performed an extensive literature review on specific aspects of SFSS, recommendations underwent blinded review by an independent panel, and discussion/voting on the recommendations occurred at the Consensus Conference. The ideal graft-to-recipient weight ratio of ≥0.8% (or graft volume standard liver volume ratio of ≥40%) is recommended. It is also recommended to measure portal pressure or portal blood flow during living donor liver transplantation and maintain a postreperfusion portal pressure of <15 mm Hg and/or portal blood flow of <250 mL/min/100 g graft weight to optimize outcomes. The typical time point to diagnose SFSS is the postoperative day 7 to facilitate treatment and intervention. An objective 3-grade stratification of severity for protocolized management of SFSS is proposed. The proposed grading system based on clinical and biochemical factors will help clinicians in the early identification of patients at risk of developing SFSS and institute timely therapeutic measures. The validity of this newly created grading system should be evaluated in future prospective studies.

Higher need for polycystic liver disease therapy in female patients: Sex-specific association between liver volume and need for therapy.

Prognostic tools or biomarkers are urgently needed in polycystic liver disease (PLD) to monitor disease progression and evaluate treatment outcomes. Total liver volume (TLV) is currently used to assess cross-sectional disease severity, and female patients typically have larger livers than males. Therefore, this study explores the sex-specific association between TLV and volume-reducing therapy (VRT). In this prospective cohort study, we included patients with PLD from European treatment centers. We explored sex-specific differences in the association between baseline TLV and initiation of volume-reducing therapy and determined the cumulative incidence rates of volume-reducing therapy in our cohort.We included 358 patients, of whom 157 (43.9%) received treatment. Treated patients had a higher baseline TLV (median TLV 2.16 vs. 4.34 liter, p < 0.001), were more frequently female (69.7% vs. 89.8%, p < 0.001), and had a higher risk of liver events (HR 4.381, p < 0.001). The cumulative volume-reducing therapy rate at 1 year of follow-up was 21.0% for females compared to 9.1% for males. Baseline TLV was associated with volume-reducing therapy, and there was an interaction with sex (HR females 1.202, p < 0.001; HR males 1.790, p < 0.001; at 1.5l). Baseline TLV is strongly associated with volume-reducing therapy initiation at follow-up in patients with PLD, with sex-specific differences in this association. Disease staging systems should use TLV to predict the need for future volume-reducing therapy in PLD separately for males and females.

Baseline [18F]FDG PET features are associated with survival and toxicity in patients treated with CAR T cells for large B cell lymphoma.

Chimeric antigen receptor (CAR) T cells have established themselves as an effective treatment for refractory or relapsed large B cell lymphoma (LBCL). Recently, the sDmax, which corresponds to the distance separating the two farthest lesions standardized by the patient's body surface area, has appeared as a prognostic factor in LBCL. This study aimed to identify [18F]FDG-PET biomarkers associated with prognosis and predictive of adverse events in patients treated with CAR T cells. Patients were retrospectively included from two different university hospitals. They were being treated with CAR T cells for LBCL and underwent [18F]FDG-PET just before CAR T cell infusion. Lesions were segmented semi-automatically with a threshold of 41% of the maximal uptake. In addition to clinico-biological features, sDmax, total metabolic tumor volume (TMTV), SUVmax, and uptake intensity of healthy lymphoid organs and liver were collected. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The occurrence of adverse events, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), was reported. Fifty-six patients were included. The median follow-up was 9.7 months. Multivariate analysis showed that TMTV (cut-off of 36 mL) was an independent prognostic factor for PFS (p < 0.001) and that sDmax (cut-off of 0.15 m-1) was an independent prognostic factor for OS (p = 0.008). Concerning the occurrence of adverse events, a C-reactive protein level > 35 mg/L (p = 0.006) and a liver SUVmean > 2.5 (p = 0.027) before CAR T cells were associated with grade 2 to 4 CRS and a spleen SUVmean > 1.9 with grade 2 to 4 ICANS. TMTV and sDmax had independent prognostic values, respectively, on PFS and OS. Regarding adverse events, the mean liver and spleen uptakes were associated with the occurrence of grade 2 to 4 CRS and ICANS, respectively. Integrating these biomarkers into the clinical workflow could be useful for early adaptation of patients management.

Liver triacylglycerol accumulation but not postprandial lipemia is reduced by a skim milk powder diet in male rats

Increases in postprandial lipids are linked to the development of cardiometabolic and fatty liver disease. Prior work has suggested that dairy possesses beneficial cardiometabolic effects and thus the aim of the current investigation was to test the hypotheses that the habitual consumption of dairy, in the form of skim milk powder (SMP), would protect against increases in circulating lipids and liver lipid accumulation following an oral fat challenge in rats. Male rats were fed either a semipurified low-fat control diet with casein or a diet with an equivalent amount of protein (∼13% kcal) provided through skim milk powder (SMP) for 6 weeks (n = 40/group). Rats were then given an oral gavage of palm oil (5 mL/kg body weight) or an equivalent volume of water, and serum and liver were harvested 90 minutes or 4 hours after. Rats fed the SMP diet gained less weight than controls but there were no differences in glucose tolerance between groups. The fat gavage increased serum lipids in both diet groups, whereas there was a main effect of the fat challenge to increase, and the SMP diet, to decrease liver triacylglycerol accumulation. The percentage of saturated and monounsaturated fatty acids and the protein content/activity of lipogenic enzymes were reduced in livers from SMP-fed rats, whereas the percentage of polyunsaturated fatty acids was increased. In summary, we provide evidence that SMP consumption, although not protecting against postprandial lipemia, markedly attenuates triacylglycerol accumulation and the relative amount of saturated and monounsaturated fatty acids in the liver.

Essential updates 2021/2022: Update in surgical strategy for perihilar cholangiocarcinoma.

Resection is the only potential curative treatment for perihilar cholangiocarcinoma (PHC); however, complete resection is often technically challenging due to the anatomical location. Various innovative approaches and procedures were invented to circumvent this limitation but the rates of postoperative morbidity (20%-78%) and mortality (2%-15%) are still high. In patients diagnosed with resectable PHC, deliberate and coordinated preoperative workup and optimization of the patient and future liver remnant are crucial. Biliary drainage is recommended to relieve obstructive jaundice and optimize the clinical condition before liver resection. Biliary drainage for PHC can be performed either by endoscopic biliary drainage or percutaneous transhepatic biliary drainage. To date there is no consensus about which method is preferred. The volumetric assessment of the future remnant liver volume and optimization mainly using portal vein embolization is the gold standard in the management of the risk to develop post hepatectomy liver failure. The improvement of systemic chemotherapy has contributed to prolong the survival not only in patients with unresectable PHC but also in patients undergoing curative surgery. In this article, we review the literature and discuss the current surgical treatment of PHC.

The spleen as a possible source of serine protease inhibitors and migrating monocytes required for liver regeneration after 70% resection in mice.

Introduction: The role of the immune system in liver repair is fundamentally complex and most likely involves the spleen. The close connection between the two organs via the portal vein enables delivery of splenic cytokines and living cells to the liver. This study evaluates expression of inflammation-related genes and assesses the dynamics of monocyte-macrophage and lymphocyte populations of the spleen during the recovery from 70% hepatectomy in mice. Methods: The study used the established mouse model of 70% liver volume resection. The animals were sacrificed 24h, 72h or 7days post-intervention and splenic tissues were collected for analysis: Clariom™ S transcriptomic assay, immunohistochemistry for proliferation marker Ki-67 and macrophage markers, and flow cytometry for lymphocyte and macrophage markers. Results: The loss and regeneration of 70% liver volume affected the cytological architecture and gene expression profiles of the spleen. The tests revealed significant reduction in cell counts for Ki-67+ cells and CD115+ macrophages on day 1, Ly6C + cells on days 1, 3 and 7, and CD3+CD8+ cytotoxic lymphocytes on day 7. The transcriptomic analysis revealed significant activation of protease inhibitor genes Serpina3n, Stfa2 and Stfa2l1 and decreased expression of cell cycle regulatory genes on day 1, mirrored by inverse dynamics observed on day 7. Discussion and conclusion: Splenic homeostasis is significantly affected by massive loss in liver volume. High levels of protease inhibitors indicated by increased expression of corresponding genes on day 1 may play an anti-inflammatory role upon reaching the regenerating liver via the portal vein. Leukocyte populations of the spleen react by a slow-down in proliferation. A transient decrease in the local CD115+ and Ly6C+ cell counts may indicate migration of splenic monocytes-macrophages to the liver.

Comparison between CT volumetry, technetium99m galactosyl-serum-albumin scintigraphy, and gadoxetic-acid-enhanced MRI to estimate the liver fibrosis stage in preoperative patients.

To compare the efficacy of computed tomography volumetry (CTV), technetium99m galactosyl-serum-albumin (99mTc-GSA) scintigraphy, and gadolinium-ethoxybenzyl-diethylenetriamine-pentaacetic-acid-enhanced MRI (EOB-MRI) in estimating the liver fibrosis (LF) stage in patients undergoing liver resection. This retrospective study included 91 consecutive patients who had undergone preoperative dynamic CT and 99mTc-GSA scintigraphy. EOB-MRI was performed in 76 patients. CTV was used to measure the total liver volume (TLV), spleen volume (SV), normalised to the body surface area (BSA), and liver-to-spleen volume ratio (TLV/SV). 99mTc-GSA scintigraphy provided LHL15, HH15, and GSA indices. The liver-to-spleen ratio (LSR) was calculated in the hepatobiliary phase of EOB-MRI. Hyaluronic acid and type 4 collagen levels were measured in 65 patients.Logistic regression and receiver operating characteristic (ROC) analyses were performed to identify useful parameters for estimating the LF stage and laboratory data. According to the multivariable logistic regression analysis, SV/BSA (odds ratio [OR], 1.01; 95% confidence interval [CI], 1.003-1.02; p = 0.011), LSR (OR, 0.06; 95%CI, 0.004-0.70; p = 0.026), and hyaluronic acid (OR, 1.01; 95%CI, 1.001-1.02; p = 0.024) were independent variables for severe LF (F3-4). Combined SV/BSA, LSR, and hyaluronic acid correctly estimated severe LF, with an AUC of 0.91, which was significantly larger than the AUCs of the GSA index (AUC = 0.84), SV/BSA (AUC = 0.83), or LSR (AUC = 0.75) alone. Combined CTV, EOB-MRI, and hyaluronic acid analyses improved the estimation accuracy of severe LF compared to CTV, EOB-MRI, or 99mTc-GSA scintigraphy individually. The combined analysis of spleen volume on CT volumetry, liver-to-spleen ratio on gadolinium-ethoxybenzyl-diethylenetriamine-pentaacetic-acid-enhanced MRI, and hyaluronic acid can identify severe liver fibrosis associated with a high risk of liver failure after hepatectomy and recurrence in patients with hepatocellular carcinoma. • Spleen volume of CT volumetry normalised to the body surface area, liver-to-spleen ratio of EOB-MRI, and hyaluronic acid were independent variables for liver fibrosis. • CT volumetry and EOB-MRI enable the detection of severe liver fibrosis, which may correlate with post-hepatectomy liver failure and complications. • Combined CT volumetry, gadolinium-ethoxybenzyl-diethylenetriamine-pentaacetic-acid-enhanced MRI (EOB-MRI), and hyaluronic acid analyses improved the estimation of severe liver fibrosis compared to technetium99m galactosyl-serum-albumin scintigraphy.

Is an intraoperative liver function assessment possible? Application of the 13C-methacetin-breath-test during major liver resections – a pilot study

BackgroundAs prevention of posthepatectomy-liver-failure is crucial, there is need of dynamic assessment of liver function, even intraoperatively. 13C-methacetin-breath-test estimates the organ's microsomal functional capacity. This is its first intraoperative evaluation in major liver surgery. Methods30 patients planed for resection of ≥3 liver segments, between March-November 2019, were prospectively enrolled in this “single-center”, pilot study. Using the 13C-methacetin-breath-test, liver function was assessed four times: preoperatively, intraoperatively before and after resection and postoperatively. The resulted maximum-liver-function-capacity (LiMAx)-values and delta-over-baseline (DOB)-curves were compared, further analyzed and correlated to respective liver volumes. ResultsThe intraoperative LiMAx-values before resection were mostly lower than the preoperative ones (-11.3% ± 28%). The intraoperative measurements after resection resulted to mostly higher values than the postoperative ones (42.35% ± 46.19%). Pharmacokinetically, an interference between the two intraoperative tests was observed. There was no strong correlation between residual liver volume and function with a percentual residual-LiMAx mostly lower than the percentual residual volume (-17.7% ± 4.1%). ConclusionsIntraoperative application of the 13C-methacetin-breath-test during major liver resections seems to deliver lower values than the standard preoperative test. As multiple intraoperative tests interfere significantly to each other, a single intraoperative measurement is suggested. Multicentric standardized measurements could define the “normal” range for intraoperative measurements and control their predictive value.