Management of Hepatocellular Carcinoma in 2024: The Multidisciplinary Paradigm in an Evolving Treatment Landscape.

Liver cancer is the third most common cause of cancer-related deaths worldwide, and hepatocellular carcinoma (HCC) makes up the majority of liver cancer cases. Despite the stabilization of incidence rates in recent years due to effective viral hepatitis treatments, as well as improved outcomes from early detection and treatment advances, the burden of HCC is anticipated to rise again due to increasing rates of metabolic dysfunction-associated steatotic liver disease and alcohol-related liver disease. The treatment landscape is evolving and requires a multidisciplinary approach, often involving multi-modal treatments that include surgical resection, transplantation, local regional therapies, and systemic treatments. The optimal approach to the care of the HCC patient requires a multidisciplinary team involving hepatology, medical oncology, diagnostic and interventional radiology, radiation oncology, and surgery. In order to determine which approach is best, an individualized treatment plan should consider the patient's liver function, functional status, comorbidities, cancer stage, and preferences. In this review, we provide an overview of the current treatment options and key trials that have revolutionized the management of HCC. We also discuss evolving treatment paradigms for the future.

Evaluation of tumor microenvironment and biomarkers of immune checkpoint inhibitor response in metastatic renal cell carcinoma.

BACKGROUND: Immunotherapy combinations including ipilimumab and nivolumab are now the standard of care for untreated metastatic renal cell carcinoma (mRCC). Biomarkers of response are lacking to predict patients who will have a favorable or unfavorable response to immunotherapy. This study aimed to use the OmniSeq transcriptome-based platform to develop biomarkers of response to immunotherapy. METHODS: Two cohorts of patients were retrospectively collected. These included an investigational cohort of patients with mRCC treated with immune checkpoint inhibitor therapy from five institutions, and a subsequent validation cohort of patients with mRCC treated with combination ipilimumab and nivolumab from two institutions (Duke Cancer Institute and Cleveland Clinic Taussig Cancer Center). Tissue-based RNA sequencing was performed using the OmniSeq Immune Report Card on banked specimens to identify gene signatures and immune checkpoints associated with differential clinical outcomes. A 5-gene expression panel was developed based on the investigational cohort and was subsequently evaluated in the validation cohort. Clinical outcomes including progression-free survival (PFS) and overall survival (OS) were extracted by retrospective chart review. Objective response rate (ORR) was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1. RESULTS: The initial investigation cohort identified 86 patients with mRCC who received nivolumab (80%, 69/86), ipilimumab/nivolumab (14%, 12/86), or pembrolizumab (6%, 5/86). A gene expression score was created using the top five genes found in responders versus non-responders (FOXP3, CCR4, KLRK1, ITK, TIGIT). The ORR in patients with high gene expression (GEhigh) on the 5-gene panel was 29% (14/48), compared with low gene expression (GElow) 3% (1/38, χ2 p=0.001). The validation cohort was comprised of 62 patients who received ipilimumab/nivolumab. There was no difference between GEhigh and GElow in terms of ORR (44% vs 38.5%), PFS (HR 1.5, 95% CI 0.58 to 3.89), or OS (HR 0.96, 95% CI 0.51 to 1.83). Similarly, no differences in ORR, PFS or OS were observed when patients were stratified by tumor mutational burden (high=top 20%), PD-L1 (programmed death-ligand 1) expression by immunohistochemistry or RNA expression, or CTLA-4 (cytotoxic T-lymphocytes-associated protein 4) RNA expression. The International Metastatic RCC Database Consortium (IMDC) risk score was prognostic for OS but not PFS. CONCLUSION: A 5-gene panel that was associated with improved ORR in a predominantly nivolumab monotherapy population of patients with mRCC was not predictive for radiographic response, PFS, or OS among patients with mRCC treated with ipilimumab and nivolumab.

Association of baseline neutrophil-to-eosinophil ratio with response to nivolumab plus ipilimumab in patients with metastatic renal cell carcinoma.

BACKGROUND: The identification of biomarkers to select patients with metastatic renal cell carcinoma (mRCC) most likely to respond to combination immunotherapy (IO) is needed. We sought to investigate an association of the baseline neutrophil-to-eosinophil ratio (NER) with outcomes to nivolumab plus ipilimumab for patients with mRCC. METHODS: We performed a retrospective review of patients with clear cell mRCC treated with nivolumab plus ipilimumab from Vanderbilt-Ingram Cancer Center and Duke Cancer Institute. Patients with prior receipt of immunotherapy and those without available baseline complete blood count with differential were excluded. Patients were divided into groups by the median baseline NER and analyzed for overall survival (OS), progression free survival (PFS), and objective response rate (ORR). Patients were also divided by median baseline neutrophil-to-lymphocyte ratio (NLR) and analyzed for clinical outcome. Further analyses of patients above/below the median NER and NLR were performed in subgroups of IMDC intermediate/poor risk, IMDC favorable risk, and treatment naïve patients. RESULTS: A total of 110 patients were included: median age was 61 years and 75% were treatment naïve. The median NER (mNER) at baseline was 26.4. The ORR was 40% for patients with mNER (OR 2.39, p = 0.04). The median PFS for patients with mNER (HR 0.50, p < 0.01). Median OS was not reached (NR) for patients with mNER (HR 0.31, p < 0.01). The median NLR (mNLR) was 3.42. While patients with mNLR group. CONCLUSIONS: A lower baseline NER was associated with improved clinical outcomes (PFS, OS, and ORR) in patients with mRCC treated with nivolumab plus ipilimumab, and prospective validation of the baseline NER as a predictive biomarker for response to immunotherapy-based combinations in mRCC is warranted.

Clinical outcomes in patients with metastatic renal cell carcinoma and brain metastasis treated with ipilimumab and nivolumab.

The combination of ipilimumab plus nivolumab (I+N) has greatly improved outcomes in patients with intermediate or poor-risk untreated metastatic renal cell carcinoma (mRCC). However, little is known about the outcomes of patients with brain metastasis (BrM) treated with I+N. A search was performed to retrospectively identify all patients with mRCC treated with I+N in the Duke Cancer Institute and the Cleveland Clinic Taussig Cancer Center, followed by a chart review. Patients were included if they had BrM at the time of I+N initiation. Cohort characteristics are summarized with descriptive statistics. Kaplan-Meier method was used to estimate overall survival (OS) and global, intracranial, and extracranial progression-free survival (PFS) for the cohort and log rank test was used to compare OS and PFS between patient groups. Radiographic response was categorized by RECIST. Fisher's exact test was used to correlate patient factors with radiographic response. From October 2017 to December 2020, 19 patients with BrM received I+N for mRCC with a median follow-up time of 27.1 months (range 15.0-35.6). By International Metastatic RCC Database Consortium (IMDC) risk criteria, 16% had favorable, 58% had intermediate, and 26% had poor-risk disease. 68% were systemic therapy naïve, and 77% of patients had clear cell histology. 95% had received local CNS directed therapy with surgery, radiotherapy, or both. The objective response rate was 44% (0% complete response) with three of six patients treated in the second line or greater setting experiencing a partial response. The median PFS was 7.6 months (95% CI 5.6 to 14.9). The median extracranial PFS was 8.5 months (95% CI 5.6 to 19.7), and median intracranial PFS was 14.7 months (95% CI 7.2 to not reached). No variables assessed were significantly associated with radiographic response (gender, IMDC risk, presence of bone metastasis, line of therapy, or presence of immune related adverse events). In our retrospective cohort of patients with mRCC with BrM, I+N, in combination with CNS-directed local therapy, appears to have clinical efficacy as previously described with responses seen beyond the first-line setting. Further investigation is warranted in this population given exclusion from prior clinical trials.

A Multi-institutional, Retrospective Analysis of Patients with Metastatic Renal Cell Carcinoma to Bone Treated with Combination Ipilimumab and Nivolumab.

BACKGROUND: Bone metastases (BM) in renal cell carcinoma (RCC) patients are associated with poor outcomes. There are limited published data on outcomes in these patients with immunotherapy agents. We present a multi-institutional, retrospective analysis of metastatic RCC patients with BM treated with ipilimumab and nivolumab (I + N). OBJECTIVE: Patient, tumor, and treatment-related variables were retrospectively collected from electronic medical records of patients with a histologically confirmed diagnosis of RCC and at least one radiographically confirmed BM prior to initiation of I + N. Best objective response was assessed by clinical chart review, imaging reports, and treating physician evaluation; progression-free survival (PFS) and overall survival (OS) were recorded as of 31 December 2020. Descriptive statistics were used to summarize patient characteristics and BM-related variables. Kaplan-Meier method and Mantel-Haenszel log-rank test were used to compare survival among groups. Cox regression univariable and multivariable models were used to correlate patient- and treatment-related variables to outcomes. RESULTS: Eighty patients with RCC and BM treated with I + N were identified. Patients were predominantly male and Caucasian presenting primarily with IMDC intermediate or poor-risk clear-cell RCC. Best response to I + N was progressive disease (46%), stable disease (28%), partial response (21%), and not evaluable (5%). Median PFS was 6.1 months (95% CI 3.8-8.9 months) with the majority of patients (65%) discontinuing I + N due to disease progression. Median OS was 25.6 months (95% CI 14.9-NA) with median follow-up of 25.2 months. A multivariable regression model for PFS showed several variables to be significantly associated with worse PFS including female gender [p = 0.02; hazard ratio (HR) 2.16; 95% CI 1.14-4.12], metastases to other sites (p = 0.006; HR 2.12; 95% CI 1.24-3.62) and presence of BM to ribs (p = 0.0007; HR 2.61; 95% CI 1.50-4.52). A multivariable Cox model of OS showed no prior radiation therapy to BM (p = 0.02; HR 2.17; 95% CI 1.13-4.17) and presence of liver metastases (p = 0.0006; HR 3.19; 95% CI 1.65-6.19) to be significantly associated with worse OS. CONCLUSION: RCC patients with ≥ 1 BM who received I + N therapy had a relatively low response rate, PFS, and OS. Strategies to improve outcomes in this subset of patients are needed.

Combination antiangiogenic tyrosine kinase inhibition and anti-PD1 immunotherapy in metastatic renal cell carcinoma: A retrospective analysis of safety, tolerance, and clinical outcomes.

INTRODUCTION: Two separate antiangiogenic tyrosine kinase inhibitors (TKIs) and immunotherapy (IO) combinations are FDA-approved as front-line treatment for metastatic renal cell carcinoma (mRCC). Little is known about off-protocol and post-front-line experience with combination TKI-IO approaches. METHODS: We conducted a retrospective analysis of mRCC patients who received combination TKI-IO post-first-line therapy between November 2015 and January 2019 at MD Anderson Cancer Center and Duke Cancer Institute. Chart review detailed patient characteristics, treatments, toxicity, and survival. Independent radiologists, blinded to clinical data, assessed best radiographic response using RECIST v1.1. RESULTS: We identified 48 mRCC patients for inclusion: median age 65 years, 75.0% clear cell histology, 68.8% IMDC intermediate risk, and median two prior systemic therapies. TKI-IO combinations included nivolumab-cabozantinib (N +C; 24 patients), nivolumab-pazopanib (N+P; 13), nivolumab-axitinib (6), nivolumab-lenvatinib (2), and nivolumab-ipilimumab-cabozantinib (3). The median progression-free survival was 11.6 months and the median overall survival was not reached. Response data were available in 45 patients: complete response (CR; n = 3, 6.7%), partial response (PR; 20, 44.4%), stable disease (SD; 19, 42.2%), and progressive disease (3, 6.7%). Overall response rate was 51% and disease control rate (CR+PR+SD) was 93%. Only one patient had a grade ≥3 adverse event. CONCLUSION: To our knowledge, this is the first case series reporting off-label use of combination TKI-IO for mRCC. TKI-IO combinations, particularly N+P and N+C, are well tolerated and efficacious. Although further prospective research is essential, slow disease progression on IO or TKI monotherapy may be safely controlled with addition of either TKI or IO.

Metastatic Hormone-Sensitive Prostate Cancer: A Review of the Current Treatment Landscape.

PURPOSE: In recent years, the treatment options for metastatic hormone-sensitive prostate cancer (mHSPC) have expanded significantly. In addition to androgen deprivation therapy, the systemic treatments now include docetaxel, abiraterone, enzalutamide, and apalutamide. Radiation to the primary is also an option for select low-volume patients. METHODS: We conducted a review of the pivotal trials that have changed the practice of mHSPC. RESULTS: We describe an overview of the trials that investigated docetaxel (CHAARTED and STAMPEDE-Docetaxel), abiraterone (LATTITUDE and STAMPEDE-Abiraterone), enzalutamide (ARCHES, ENZAMET), apalutamide (TITAN), and radiation to the primary (STAMPEDE-Radiation). DISCUSSION: The treatment of mHSPC is a complex topic, and treatment choice should be individualized. Patient preferences, cost, volume of disease, and side effect profiles are important in determining which option is the best for an individual patient.

Can I Get a Multidisciplinary Consult, Please? Systemic Immunotherapy and the Timing of Cytoreductive Nephrectomy.

Patient selection is critical to determine who benefits from initial cytoreductive nephrectomy and who benefits from initial systemic treatment. Cytoreductive nephrectomy can no longer be considered a one-size-fits-all approach. Multidisciplinary evaluation is key.

MRI predictors of tumor-positive margins after breast-conserving surgery.

PURPOSE: The purpose of this study is to identify predictors of tumor-positive surgical margins after breast-conserving surgery on dynamic contrast-enhanced (DCE) MRI. MATERIALS AND METHODS: We conducted a retrospective study of consecutive women who underwent DCE MRI before breast-conserving surgery from 2005 to 2014. Patient demographics, indication for surgery, MRI findings, biopsy pathology results, and surgical outcomes were reviewed. The unpaired t-test and chi-square test were used to compare the positive and negative margins groups. RESULTS: 554 women (mean age, 56; range, 26-90) underwent DCE MRI before 575 breast-conserving surgeries for invasive carcinoma (n = 473) or ductal carcinoma in situ (DCIS) (n = 102). Positive margins requiring re-excision occurred in 19.7% (93/473) of surgeries for invasive carcinoma and 31.4% (32/102) of surgeries for DCIS. For invasive carcinoma surgeries, positive margins were more common when MRI demonstrated the finding of non-mass enhancement (NME) rather than the finding of enhancing mass (33.8% [22/65] versus 16.9% [61/360], p < 0.01). Tumor size on MRI was significantly larger in the positive margins group (2.5 cm versus 1.9 cm, p < 0.001). Positive margins were more common with invasive lobular rather than invasive ductal histology at core biopsy (38.3% [18/47] versus 16.0% [56/350], p < 0.001). For DCIS surgeries, there were no significant differences in positive margin rates related to MRI features. CONCLUSION: For invasive carcinoma surgeries, positive margins are associated with NME on MRI, larger tumor size on MRI, and lobular histology at core biopsy. These findings may be used to predict which patients are at risk for positive margins after breast-conserving surgery.

Predictors of Physical and Functional Loss in Advanced-Stage Lung Cancer Patients Receiving Platinum Chemotherapy.

INTRODUCTION: Muscle wasting has detrimental effects, including increased mortality. Identifying patients at risk can guide treatment efforts. METHODS: POWER 1 and 2 were randomized, double-blind, placebo-controlled, multinational phase III trials that studied 600 patients with lung cancer at the start of chemotherapy; the studies' aim was to assess the efficacy of enobosarm on prevention and treatment of muscle loss. We performed a secondary analysis restricted to the control group, using a cumulative logit model for ordinal outcome to determine which baseline characteristics predicted physical and functional loss during chemotherapy. RESULTS: In all, 53% of patients had loss of lean body mass and 49% had loss of stair climb power (SCP) at day 84 of treatment. Of the 322 patients who received placebo, 232 with observable outcome and baseline covariates were included for lean body mass analysis and 236 for SCP analysis. More advanced disease predicted a higher probability of greater physical loss (OR = 1.96; 95% confidence interval [CI]: 1.14-3.36). Three factors predicted higher probability of SCP loss: taxane chemotherapy (OR = 1.73; 95% CI: 1.06-2.83), tobacco use before chemotherapy (OR = 2.15, 95% CI: 1.10-4.18), and SCP at baseline (OR = 1.01, 95% CI: 1.004-1.015). Higher body mass index was a protective factor for functional loss (OR = 0.85; 95% CI: 0.73-0.98). A higher Eastern Cooperative Oncology Group Performance Status trended toward being predictive of greater probability of both physical loss (0.767) and functional loss (0.070), but the results were not statistically significant. CONCLUSIONS: Approximately 50% of patients with advanced lung cancer who were undergoing chemotherapy had ongoing loss of muscle mass and muscle function. Advanced stage predicted physical loss. Tobacco use and taxane chemotherapy predicted functional loss. Body mass index was a protective factor for functional loss. We identified predictors of physical and functional loss that could be used as therapeutic targets or to guide treatment efforts.

Metastatic melanoma patients' sensitivity to ipilimumab cannot be predicted by tumor characteristics.

Immune checkpoint inhibitors have dramatically changed the prognosis for patients with metastatic melanoma. However, not all patients respond to therapy and toxicities can be severe leaving need for reliable clinical predictive markers. METHODS: We examined primary tumor characteristics including ulceration, BRAF mutation status, and Breslow depth in patients who subsequently developed stage IV disease and were treated with ipilimumab at 3 institutions. Patients in this study were not treated on clinical trials. To investigate the relationship between patient characteristics at the time of diagnosis and survival following melanoma diagnosis we utilized Cox proportional hazards models, accounting for delayed entry into the study cohort. Cox models estimate the age and institution adjusted hazard ratios for risk of death. RESULTS: Of patients (n=385) treated with ipilimumab for stage IV melanoma, 302 met inclusion criteria. The complete response to ipilimumab was 5%, partial response was 13%, 18% had stable disease, 62% had progressive disease, and 5 unknown. The median overall survival rate was 2.03 years [95% confidence interval (CI): 0.13, 3.05]. Primary tumor Breslow depth, lymphovascular invasion, BRAF status, and ulceration did not predict sensitivity to ipilimumab. In this study patient cohort, BRAF mutation (adjusted hazard ratio: 1.43, 95% CI: 0.98, 2.07) and presence of ulceration (adjusted hazard ratio: 1.47, 95% CI: 0.95, 2.26) contributed to an increased risk of death. CONCLUSIONS: The presence of ulceration did not correlate with sensitivity to ipilimumab. Ulceration of the primary tumor and a BRAF mutation were moderately associated with worse survival in patients with metastatic melanoma treated with ipilimumab.

Architectural Distortion on Mammography: Correlation With Pathologic Outcomes and Predictors of Malignancy.

OBJECTIVE: The objective of our study was to determine the risk of malignancy associated with architectural distortion and to evaluate the imaging and clinical features that may contribute to the prediction of malignancy in the setting of architectural distortion. MATERIALS AND METHODS: We performed a retrospective review of architectural distortion cases from January 1, 2004, to December 31, 2013. Imaging findings and pathology outcomes were reviewed. RESULTS: Over the 10-year study period, architectural distortion that was considered to be suspicious for or highly suggestive of malignancy was present in 435 of 231,051 (0.2%) mammographic examinations. Cases were excluded if the main finding described was a mass with an associated feature of architectural distortion (n = 62) or if no pathology results were available (n = 4). Two hundred seventy-five cases of invasive adenocarcinoma or ductal carcinoma in situ (DCIS) were identified; the positive predictive value (PPV) was therefore 74.5% (275/369). DCIS alone was identified in only 4.1% (15/369). The most common benign finding on pathology was a radial scar or complex sclerosing lesion (27/369, 7.3%). Architectural distortion was less likely to represent malignancy on screening mammography than on diagnostic mammography (67.0% vs 83.1%, respectively; p < 0.001). Architectural distortion without a sonographic correlate was less likely to represent malignancy than architectural distortion with a correlate (27.9% vs 82.9%, respectively; p < 0.001). There was no statistically significant difference in the malignancy rate between pure architectural distortion and architectural distortion with calcifications or asymmetries (73.0% vs 78.8%; p = 0.26). CONCLUSION: The PPV of architectural distortion for malignancy is 74.5%. Architectural distortion is less likely to represent malignancy if detected on screening mammography than on diagnostic mammography or if there is no sonographic correlate.

Exploring intended infant feeding decisions among low-income women.

BACKGROUND: Low-income women have the lowest rates of breastfeeding in the United States. Greater understanding of factors that predict intention to feed artificial breastmilk substitute is needed to inform the design and timing of interventions to promote breastfeeding among vulnerable women. This study aimed to identify demographic and reproductive characteristics and other factors associated with intent to feed artificial breastmilk substitute among low-income women. MATERIALS AND METHODS: Data from 520 low-income women interviewed at 24-41 weeks of gestation during enrollment in a prenatal breastfeeding education intervention study were analyzed. Participant characteristics, reasons for feeding decision, and sources and types of information received were compared among women intending to feed only artificial breastmilk substitute and other women. RESULTS: Most participants (95%) had already chosen an infant feeding method at the time of interview. There were no differences in plans to return to work by feeding plan. Women reporting intention to feed only artificial breastmilk substitute were less likely to report receiving information about the benefits of breastfeeding, how to breastfeed, and pumps and were more likely to cite personal preference and convenience as reasons for their decision. Women were more likely to intend to feed artificial breastmilk substitute if they had a previous live birth or had not breastfed a child, including the most recent. CONCLUSIONS: These findings suggest breastfeeding promotion should target women early and include sensitive, effective ways to promote breastfeeding among women who have not previously successfully breastfed. Breastfeeding history should be elicited, and plans to pump should be supported prenatally.

Online screening and referral for postpartum depression: an exploratory study.

The fear and stigma associated with postpartum depression (PPD) is a major challenge in the treatment of this disease. Our goal is to develop innovative methods of screening women for the symptoms of PPD to facilitate referral and treatment. This study explores the efficacy of the Internet in reaching out to postpartum women in the convenience and privacy of their own homes, particularly those in rural and underserved areas. An exploratory study design was used to explore the feasibility and acceptability of online screening for PPD with postpartum women in the first 2-3 months after delivery (N = 18). In the first phase, a focus group was conducted with a small group of postpartum women; the second phase consisted of individual interviews of postpartum women in their homes; and in phase three, 10 women participated in the on-line screening intervention. PPD was measured using an online version of the Edinburgh Postnatal Depression Scale (EPDS) a well-established instrument with reported alpha reliabilities (0.81-0.88) across studies and concurrent validity demonstrated using the gold standard, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for depression interview. Qualitative data collected from all the participants were also analyzed. The sample included women age 18-29; 70 % White/Caucasian, 50 % low income, and the majority living in rural areas. The EPDS scores ranged from 0 to 13 (mean 8.0; SD 4.76). Participants described the online PPD screening process as easy, straightforward and personalized and provided additional suggestions for improvement.

Mapping of the snuffbox and cubital vessels for percutaneous arterial venous fistula (pAVF) in dialysis patients.

PURPOSE: Report on the anatomic qualification of the snuffbox radial artery (SBRA) and proximal radial artery (PRA) for pAVF.
 METHODS: Retrospective analysis of upper extremity mapping in 64 limbs in 55 dialysis patients was performed. The radial artery was assessed for diameter, patency, flow and proximity to the adjacent vein to SBRA and PRA. Sites qualified for pAVF on a binary basis when the in situ radial artery and adjacent vein were straight, parallel, greater than 2 mm in diameter and within 1.5 mm of each other. Effect of age, sex, diabetes, systolic blood pressure and obesity were assessed with logistic regression. Mean, median and frequency distribution of vessel diameter and distance were analyzed.
 RESULTS: Radial artery sites were qualified for pAVF in 47.6% (30/63) at the SBRA and 87.9% (29/33) at the PRA. SBRA sites were disqualified for vessel size in 36.4% (12/33 overall, usually vein 11/12), distance in 24% (8/33) and both 36.4% (12/33). All (4/4) PRA sites were disqualified for vessel size alone. The adjacent vein was the median vein or cephalic vein for the SBRA, and the perforating vein or vena comitans for the PRA. Effects of age, sex, diabetes, systolic blood pressure, obesity and prior fistula did not attain statistical significance.
 CONCLUSIONS: Most dialysis patients meet the anatomic requirements for pAVF in the SBRA or PRA. Vessel size is the most common limiting variable followed by distance between vessels.