Utilization of Immunotherapy as a Neoadjuvant Therapy for Liver Transplant Recipients with Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) is widely recognized as the predominant type of primary liver malignancy. Orthotopic liver transplantation (OLT) has emerged as a highly effective treatment option for unresectable HCC. Immunotherapies as neoadjuvant options are now being actively investigated in the transplant oncology era to enhance outcomes in patients with HCC. Here, we report our experience with patients with HCC who had received Immune Checkpoint Inhibitors (ICPI) prior to curative OLT. Methods: This was a retrospective cohort that included patients with HCC who received ICPI prior to OLT at a single institution from January 2019 to August 2023. Graft rejection was assessed and reported along with the type of ICPI, malignancy treated, and the timing of ICPI in association with OLT. Results: During this cohort period, six patients with HCC underwent OLT after neoadjuvant ICPI. All patients were male with a median age of 61 (interquartile range: 59-64) years at OLT. Etiology associated with HCC was viral (N = 4) or Non-alcoholic steatohepatitis, NASH (N = 2). Tumor focality was multifocal (N = 4) and unifocal (N = 2). Lymphovascular invasion was identified in four patients. No perineural invasion was identified in any of the patients. All patients received ICPI including atezolizumab/bevacizumab (N = 4), nivolumab/ipilimumab (N = 1), and nivolumab as monotherapy (N = 1). All patients received either single or combined liver-directed/locoregional therapy, including transarterial chemoembolization (TACE), Yttrium-90 (Y90), stereotactic body radiotherapy (SBRT), and radiofrequency ablation (RFA). The median washout period was 5 months. All patients responded to ICPI and achieved a safe and successful OLT. All patients received tacrolimus plus mycophenolate as immunosuppressant (IS) therapy post-OLT and one patient received prednisone as additional IS. No patient had clinical evidence of rejection. Conclusions: This cohort emphasizes the success of tumor downstaging by ICPI for OLT when employed as the neoadjuvant therapy strategy. In addition, this study illustrated the importance of timing for the administration of ICPI before OLT. Given the lack of conclusive evidence in this therapeutic area, we believe that our study lays the groundwork for prospective trials to further examine the impact of ICPI prior to OLT.

Endotype evaluation of Hispanic/Latinx-American patients with chronic rhinosinusitis with nasal polyps.

KEY POINTS: Hispanic-American patients with chronic rhinosinusitis with nasal polyps have a comparable level of tissue eosinophilia compared to their Caucasian counterparts in the United States. Mixed inflammation involving both neutrophils and eosinophils is more common in this population compared to Caucasians. Findings from this study may indicate that Hispanic-American patients have a unique endotype or endotypes that deserves further investigation.

Aggressive Cutaneous Squamous Cell Carcinoma of the Head and Neck: A Review.

Non-melanoma skin cancer of the head and neck (NMSCHN) is one of the most common malignancies worldwide, and its incidence is growing at a significant rate. It has been found to be aggressive in its spread and has the capacity to metastasize to regional lymph nodes. Cutaneous squamous cell carcinoma (cSCC) has a considerably high mortality rate. It has remarkable characteristics: diameter >2 cm, depth >5 mm, high recurrence, perineural invasion, and locoregional metastases. Aggressive cSCC lesions most commonly metastasize to the parotid gland. Also, immunocompromised patients have a higher risk of developing this aggressive cancer along with the worst prognostic outcomes. It is very important to discuss and assess the risk factors, prognostic factors, and outcomes of patients with cSCC, which will give clinicians future directives for making modifications to their treatment plans. The successful treatment of aggressive cSCC of the head and neck includes early detection and diagnosis, surgery alone or adjuvant chemotherapy, and radiotherapy as required. Multimodal therapy options should be considered by clinicians for better outcomes of aggressive cSCC of the head and neck.

Combined Hepatocellular Neuroendocrine Carcinoma: A Rare Tumor.

Neuroendocrine tumors originate from neuroendocrine cells primarily located in the gastrointestinal tract. These tumors often metastasize to the liver. Primary hepatic neuroendocrine carcinomas are uncommon, and combined hepatocellular neuroendocrine carcinomas are exceedingly rare. There is a lack of data on the management of these rare tumors. Most cases have very poor prognosis secondary to aggressive behavior of the neuroendocrine tumor component. It is important for clinicians to be aware of this rare carcinoma to allow for early diagnosis and optimize potential treatment options.

Hepatocellular Carcinoma Recurrence as Isolated Adrenal Metastasis.

Hepatocellular carcinoma is the sixth most common cancer in the Western world. The most frequent sites of metastasis are lungs, lymph nodes, and bones. Risk factors for extrahepatic metastasis are advanced intrahepatic lesions, vascular invasion, elevated tumor markers, and viral hepatitis. Isolated metachronous adrenal metastasis occurring after liver transplantation is exceedingly rare.

Survival following liver transplantation for locally advanced, unresectable intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (iCCA) has previously been considered a contraindication to liver transplantation (LT). However, recent series showed favorable outcomes for LT after neoadjuvant therapy. Our center developed a protocol for neoadjuvant therapy and LT for patients with locally advanced, unresectable iCCA in 2010. Patients undergoing LT were required to demonstrate disease stability for 6 months on neoadjuvant therapy with no extrahepatic disease. During the study period, 32 patients were listed for LT and 18 patients underwent LT. For transplanted patients, the median number of iCCA tumors was 2, and the median cumulative tumor diameter was 10.4 cm. Patients receiving LT had an overall survival at 1-, 3-, and 5-years of 100%, 71%, and 57%. Recurrences occurred in seven patients and were treated with systemic therapy and resection. The study population had a higher than expected proportion of patients with genetic alterations in fibroblast growth factor receptor (FGFR) and DNA damage repair pathways. These data support LT as a treatment for highly selected patients with locally advanced, unresectable iCCA. Further studies to identify criteria for LT in iCCA and factors predicting survival are warranted.

Expanding the clinicopathological spectrum of succinate dehydrogenase-deficient renal cell carcinoma with a focus on variant morphologies: a study of 62 new tumors in 59 patients.

Most succinate dehydrogenase (SDH)-deficient renal cell carcinomas (RCCs) demonstrate stereotypical morphology characterized by bland eosinophilic cells with frequent intracytoplasmic inclusions. However, variant morphologic features have been increasingly recognized. We therefore sought to investigate the incidence and characteristics of SDH-deficient RCC with variant morphologies. We studied a multi-institutional cohort of 62 new SDH-deficient RCCs from 59 patients. The median age at presentation was 39 years (range 19-80), with a slight male predominance (M:F = 1.6:1). A relevant family history was reported in 9 patients (15%). Multifocal or bilateral tumors were identified radiologically in 5 patients (8%). Typical morphology was present at least focally in 59 tumors (95%). Variant morphologies were seen in 13 (21%) and included high-grade nuclear features and various combinations of papillary, solid, and tubular architecture. Necrosis was present in 13 tumors, 7 of which showed variant morphology. All 62 tumors demonstrated loss of SDHB expression by immunohistochemistry. None showed loss of SDHA expression. Germline SDH mutations were reported in all 18 patients for whom the results of testing were known. Among patients for whom follow-up data was available, metastatic disease was reported in 9 cases, 8 of whom had necrosis and/or variant morphology in their primary tumor. Three patients died of disease. In conclusion, variant morphologies and high-grade nuclear features occur in a subset of SDH-deficient RCCs and are associated with more aggressive behavior. We therefore recommend grading all SDH-deficient RCCs and emphasize the need for a low threshold for performing SDHB immunohistochemistry in any difficult to classify renal tumor, particularly if occurring at a younger age.

Optic Perineuritis Distinguishing Arteritic Ischaemic from Amiodarone-Associated Optic Neuropathy.

Giant cell arteritis (GCA) is a common medium to large vessel vasculitis of the elderly that can lead to permanent vision loss. Neuroimaging in GCA may reveal optic nerve sheath enhancement, which is a cardinal finding of optic perineuritis (OPN). The clinical manifestations of GCA can mimic that of other ocular disorders including amiodarone-associated optic neuropathy (AAON). We report a case of biopsy-proven GCA in a patient initially suspected to have AAON. This patient presented with bilateral optic disc oedema in conjunction with subacute predominately monocular vision loss and enhancement of the corresponding optic nerve sheath on neuroimaging. Clinicians should recognise that clinical and neuroimaging findings of GCA can mimic a variety of ocular and orbital pathologies including idiopathic OPN and AAON.

Nonalcoholic Fatty Liver Disease after Liver Transplant.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease in the world. The rising prevalence of nonalcoholic steatohepatitis (NASH) has led to a 170% increase in NASH cirrhosis as the listing indication for liver transplantation from 2004 to 2013. As of 2018, NASH has overtaken hepatitis C as an indication for liver transplantation in the USA. After liver transplantation, the allograft often develops recurrent NAFLD among patients with known NASH cirrhosis. In addition to recurrent disease, de novo NAFLD has been reported in patients with other indications for liver transplantation. In this review, we will discuss the risk factors associated with recurrent and de novo NAFLD, natural course of the disease, and management strategies after liver transplantation.

Metastatic colorectal carcinoma to the right atrium: a case report and review of the literature.

BACKGROUND: Cardiac metastasis due to colon cancer is extraordinarily uncommon. Given the rarity of diagnosis, there is paucity of evidence and hence, no established guidelines for evaluation or clinical management strategy. CLINICAL PRESENTATION: We present the case of a 59 year old male with a previously treated colonic carcinoma who presented with new onset exertional dyspnea. He was noted to be having a right atrial mass on an echocardiogram performed at his cardiologist's office. Further workup with CT angiogram of the chest confirmed a right atrial mass measuring 4.0 cm. Serum CEA was normal. Biopsies of the right atrial mass demonstrated metastatic moderately differentiated colonic adenocarcinoma. Mismatch repair protein expression analysis by immunohistochemistry showed no loss of MLH1, MSH2, MSH6 or PMS2 expression. Next generation sequencing for RAS and BRAF mutations was negative. Patient received treatment with FOLFIRINOX/ bevacizumab with noted reduction in size of mass. CONCLUSION: To the best of our knowledge, this is the first report of next generation sequencing results available on a biopsy of metastatic colorectal cancer to the heart with the largest literature review of 31 reported cases of metastatic colorectal cancer to the heart. It will help direct clinical management and also adds evidence to the potential efficacy of treatment of this rare aggressive disease with chemotherapy in combination with VEGF inhibitors.

An imageomics and multi-network based deep learning model for risk assessment of liver transplantation for hepatocellular cancer.

INTRODUCTION: Liver transplantation (LT) is an effective treatment for hepatocellular carcinoma (HCC), the most common type of primary liver cancer. Patients with small HCC (<5 cm) are given priority over others for transplantation due to clinical allocation policies based on tumor size. Attempting to shift from the prevalent paradigm that successful transplantation and longer disease-free survival can only be achieved in patients with small HCC to expanding the transplantation option to patients with HCC of the highest tumor burden (>5 cm), we developed a convergent artificial intelligence (AI) model that combines transient clinical data with quantitative histologic and radiomic features for more objective risk assessment of liver transplantation for HCC patients. METHODS: Patients who received a LT for HCC between 2008-2019 were eligible for inclusion in the analysis. All patients with post-LT recurrence were included, and those without recurrence were randomly selected for inclusion in the deep learning model. Pre- and post-transplant magnetic resonance imaging (MRI) scans and reports were compressed using CapsNet networks and natural language processing, respectively, as input for a multiple feature radial basis function network. We applied a histological image analysis algorithm to detect pathologic areas of interest from explant tissue of patients who recurred. The multilayer perceptron was designed as a feed-forward, supervised neural network topology, with the final assessment of recurrence risk. We used area under the curve (AUC) and F-1 score to assess the predictability of different network combinations. RESULTS: A total of 109 patients were included (87 in the training group, 22 in the testing group), of which 20 were positive for cancer recurrence. Seven models (AUC; F-1 score) were generated, including clinical features only (0.55; 0.52), magnetic resonance imaging (MRI) only (0.64; 0.61), pathological images only (0.64; 0.61), MRI plus pathology (0.68; 0.65), MRI plus clinical (0.78, 0.75), pathology plus clinical (0.77; 0.73), and a combination of clinical, MRI, and pathology features (0.87; 0.84). The final combined model showed 80 % recall and 89 % precision. The total accuracy of the implemented model was 82 %. CONCLUSION: We validated that the deep learning model combining clinical features and multi-scale histopathologic and radiomic image features can be used to discover risk factors for recurrence beyond tumor size and biomarker analysis. Such a predictive, convergent AI model has the potential to alter the LT allocation system for HCC patients and expand the transplantation treatment option to patients with HCC of the highest tumor burden.

Pleomorphic giant cell carcinoma of prostate: Rare tumor with unique clinicopathological, immunohistochemical, and molecular features.

Pleomorphic giant cell carcinoma (PGCC) of the prostate is a rare entity categorized as a variant of prostatic acinar adenocarcinoma in the 2016 World Health Organization (WHO) classification system. PGCC differs from conventional prostatic adenocarcinoma by having bizarre, markedly enlarged, and pleomorphic cells. It differs from high grade urothelial carcinoma by negativity for urothelial differentiation markers, and can be distinguished from sarcomatoid carcinoma by lack of spindle cells. Including two new cases described herein, there have been 51 cases of prostate PGCC reported in the English literature. Clinical features shared by cases of prostate PGCC include poor prognosis, occurrence in older patients, and frequent association with prior therapy. Pathologic features common to cases of prostate PGCC include admixture with a high-grade conventional prostate carcinoma component and absent or reduced expression of prostate differentiation markers. More recent studies have begun to elucidate the molecular characteristics of PGCC, detecting specific mutations and chromosomal translocations, and showing evidence of a high degree of molecular instability in these tumors. We report novel findings in two cases of PGCC including a PIK3CA p.His1047Arg mutation not previously described. One of our cases is the first to clearly demonstrate chronological loss of prostate markers during dedifferentiation from prior conventional prostate carcinoma to PGCC. Herein, we present our two new cases and comprehensively review the literature on all reported cases of PGCC with critical commentary on findings in cases of this rare tumor.

Seminal vesicle invasion combined with extraprostatic extension is associated with higher frequency of biochemical recurrence and lymph node metastasis than seminal vesicle invasion alone: Proposal for further pT3 prostate cancer subclassification.

The 8th edition of the American Joint Committee on Cancer (AJCC) TNM staging system subdivides prostatic pT3 tumors into pT3a, which includes cases with extraprostatic extension (EPE) and pT3b, which is defined by the presence of seminal vesicle invasion (SVI) with or without EPE. Yet, it is not established whether combined SVI and EPE impart a worse prognosis compared to SVI alone. We studied a cohort of 69 prostatectomy patients with SVI with or without EPE. Patient age at the time of radical prostatectomy was documented and Gleason score and presence or absence of EPE and/or SVI were determined. Biochemical recurrence (BCR) was defined as a PSA rise >0.2 ng/mL. The frequency of BCR was 33.9% in cases with combined EPE and SVI versus 12.5% in cases with SVI alone (relative risk = 2.71). An additional cohort of 88 patients also showed a higher frequency of lymph node metastasis of 29% in patients with combined SVI and EPE at the time of radical prostatectomy versus a 10% frequency of lymph node metastasis in patients with SVI alone (relative risk = 2.9). Based on our data, we propose further subdividing pT3 prostate cancers into three groups: EPE alone (pT3a), SVI alone (pT3b), and combined EPE and SVI (pT3c). This classification system would more accurately identify patients with pT3 prostate cancer who are more likely to experience worse outcomes and provide clinicians with additional information to aid in follow-up and postoperative treatment decisions.

Hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cell carcinoma: Morphological appraisal with a comprehensive review of differential diagnoses.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant syndrome wherein affected individuals are at risk for the development of cutaneous leiomyomas, early-onset multiple uterine leiomyomas, and an aggressive subtype of renal cell cancer. HLRCC is caused by germline mutations in the fumarate hydratase (FH) gene, which inactivates the enzyme and alters the function of the tricarboxylic acid/Krebs cycle. This article reviews the hitherto described morphologic features of HLRCC-associated renal cell carcinoma (RCC) and outlines the differential diagnosis and ancillary use of immunohistochemistry and molecular diagnostics for these tumors. The morphologic spectrum of HLRCC-associated RCC is wide and histologic features, including tumor cells with prominent nucleoli, perinucleolar halos, and multiple architectural patterns within the same tumor, which are suggestive of this diagnosis. FH immunohistochemistry in conjunction with genetic counseling and germline FH testing are the important parameters for detection of this entity. These kidney tumors warrant prompt treatment as even smaller sized lesions can demonstrate aggressive behavior and systemic oncologic treatment in metastatic disease should, if possible, be part of a clinical trial. Screening procedures in HLRCC families should preferably be evaluated in large cohorts.

Outcomes of Liver Transplantation for Hepatocellular Carcinoma Beyond the University of California San Francisco Criteria: A Single-center Experience.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary malignant liver tumor. Currently, liver transplantation may be the optimal treatment for HCC in cirrhotic patients. Patient selection is currently based on tumor size. We developed a program to offer liver transplantation to selected patients with HCC outside of traditional criteria. METHODS: Retrospective review for patients transplanted with HCC between April 2008 and June 2017. Patients were grouped by tumor size according to Milan, University of California San Francisco (UCSF), and outside UCSF criteria. Patient demographics, laboratory values, and outcomes were compared. Patients radiographically outside Milan criteria were selected based on tumor control with locoregional therapy (LRT) and 9 months of stability from LRT. α-fetoprotein values were not exclusionary. RESULTS: Two hundred twenty HCC patients were transplanted, 138 inside Milan, 23 inside UCSF, and 59 beyond UCSF criteria. Patient survival was equivalent at 1, 3, or 5 years despite pathologic tumor size. Waiting time to transplantation was not significantly different at an average of 344 days. In patients outside UCSF, tumor recurrence was equivalent to Milan and UCSF criteria recipients who waited >9 months from LRT. Although tumor recurrence was more likely in outside of UCSF patients (3% versus 9% versus 15%; P = 0.02), recurrence-free survival only trended toward significance among the groups (P = 0.053). CONCLUSIONS: Selective patients outside of traditional size criteria can be effectively transplanted with equivalent survival to patients with smaller tumors, even when pathologic tumor burden is considered. Tumor stability over time can be used to help select patients for transplantation.

Clinically Significant Enhancement of Voriconazole Efficacy by Moxifloxacin and Gentamicin in Fungal Keratitis.

PURPOSE: To report the effect of topical antibiotics moxifloxacin 0.3% and gentamicin 0.3% on the clinical efficacy of topical antifungal agent voriconazole 1% in cases of culture- or biopsy-proven fungal keratitis. METHODS: Two cases of fungal keratitis in which the addition of topical moxifloxacin or moxifloxacin and gentamicin led to an improved clinical response to topical voriconazole were reviewed retrospectively. RESULTS: One patient with clinical resistance of his fungal keratitis to both topical voriconazole and natamycin had resolution of his keratitis with the addition of topical moxifloxacin and gentamicin to voriconazole. One patient who had a poor response to topical voriconazole had a dramatic response to the increase of the voriconazole regimen and addition of moxifloxacin. CONCLUSIONS: In a subset of patients with fungal keratitis, the addition of topical moxifloxacin 0.3% or moxifloxacin 0.3% and gentamicin 0.3% may enhance the therapeutic effect of topical voriconazole 1%.

Yield, Techniques, and Complications of Transvitreal and Transscleral Biopsies in Small Uveal Melanoma.

Importance: Intraoperative adequacy check of biopsy samples can lead to a higher biopsy yield rate, and subsequent genomic analysis can provide patients with valuable prognostic information. Objectives: To examine the yield rates for transscleral and transvitreal fine-needle aspiration biopsies of small uveal melanoma less than 3.6 mm in apical height and to discuss techniques that would maximize yield rates and minimize complications. Design, Setting, and Participants: A retrospective, consecutive observational case series was conducted from January 29, 2013, to May 23, 2017, at Retina Consultants of Houston and Houston Methodist Hospital among 44 patients with uveal melanoma of the ciliary body or choroid. Interventions or Exposures: Fine-needle aspiration biopsy and intraoperative histopathologic analysis prior to iodine 125 brachytherapy. Main Outcomes and Measures: Tumor locations and dimensions were identified by histopathologic analysis and B-scan ultrasonography. Either transscleral or transvitreal biopsy was performed for tumors anterior to the equator and posterior to the equator, respectively. Biopsy specimens were checked for adequacy intraoperatively. Specimens were examined using hematoxylin-eosin, double immunostain with human melanoma black 45 and Ki67, and gene expression profile. Results: A total of 44 patients were included in the study, with a mean (SD) age of 63.3 (12.7) years (21 men [47.7%]; 23 women [52.3%]). Median tumor height was 2.7 mm (interquartile range, 2.3- 2.9 mm). Forty of 44 biopsy samples (90.9%; 95% CI, 82.4%-99.4%) yielded adequate cells for gene expression profile analysis. Transscleral and transvitreal yield rates were 11 of 11 (100%) and 29 of 33 (87.9%), respectively. Most localized vitreous hemorrhages were resolved by 3 months. There was a moderate association between localized vitreous hemorrhage and transvitreal biopsy method, for which the phi value was -0.526 (95% CI, -0.712 to -0.157; P < .001). Conclusions and Relevance: These findings suggest intraoperative adequacy evaluation of fine-needle aspiration biopsy specimens leads to high yield and is more informative for patients.