Imaging to Predict Prognosis in Hepatocellular Carcinoma: Current and Future Perspectives.

The focus of hepatocellular carcinoma (HCC) research for many years has been on noninvasive diagnosis. Standardized systematic algorithms composed of combinations of precise features now serve as diagnostic imaging markers of HCC and constitute a major innovation for liver imaging. In clinical practice, the diagnosis of HCC is based primarily on imaging and secondarily on pathologic analysis if the imaging features are not specific. Whereas accurate diagnosis is essential, the next phase of innovation for HCC will likely encompass predictive and prognostic markers. HCC is a biologically heterogeneous malignancy because of complex molecular, pathologic, and patient-level factors that impact the outcomes of treatment. In recent years, there have been many advances in systemic therapy to augment and extend the existing large cache of local and regional options. However, the guideposts for treatment decisions are neither sophisticated nor individualized. This review provides an overview of prognosis in HCC from the patient to the imaging feature level with a focus on future directions toward more individualized treatment guidance.

NCCN Guidelines® Insights: Biliary Tract Cancers, Version 2.2023.

In 2023, the NCCN Guidelines for Hepatobiliary Cancers were divided into 2 separate guidelines: Hepatocellular Carcinoma and Biliary Tract Cancers. The NCCN Guidelines for Biliary Tract Cancers provide recommendations for the evaluation and comprehensive care of patients with gallbladder cancer, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma. The multidisciplinary panel of experts meets at least on an annual basis to review requests from internal and external entities as well as to evaluate new data on current and emerging therapies. These Guidelines Insights focus on some of the recent updates to the NCCN Guidelines for Biliary Tract Cancers as well as the newly published section on principles of molecular testing.

Profile and Predictors of Blood Tumor Mutational Burden in Advanced Hepatocellular Carcinoma.

Advanced hepatocellular carcinoma (HCC) is responsive to immune checkpoint inhibitors, but there are currently no known biomarkers to predict treatment benefit. Blood TMB (bTMB) estimation via circulating tumor DNA (ctDNA) profiling can provide a convenient means to estimate HCC TMB. Here we provide the first landscape of bTMB in advanced HCC using a commercially available next-generation sequencing assay, show that it is approximately three times as high as matched tissue TMB, and show that bTMB correlates with NAFLD cirrhosis etiology and the presence of genomic alterations in HTERT and TP53. These results lay the foundation for subsequent studies evaluating bTMB as an immune therapy predictive biomarker in HCC.

Comprehensive genomic landscape and precision therapeutic approach in biliary tract cancers.

Biliary tract cancers have dismal prognoses even when cytotoxic chemotherapy is administered. There is an unmet need to develop precision treatment approaches using comprehensive genomic profiling. A total of 121 patients with biliary tract cancers were analyzed for circulating-tumor DNA (ctDNA) and/or tissue-based tumor DNA (tissue-DNA) using clinical-grade next-generation sequencing: 71 patients (59%) had ctDNA; 90 (74%), tissue-DNA; and 40 (33%), both. Efficacy of targeted therapeutic approaches was assessed based upon ctDNA and tissue-DNA. At least one characterized alteration was detected in 76% of patients (54/71) for ctDNA [median, 2 (range, 0-9)] and 100% (90/90) for tissue-DNA [median, 4 (range, 1-9)]. Most common alterations occurred in TP53 (38%), KRAS (28%), and PIK3CA (14%) for ctDNA vs TP53 (44%), CDKN2A/B (33%) and KRAS (29%) for tissue-DNA. In 40 patients who had both ctDNA and tissue-DNA sequencing, overall concordance was higher between ctDNA and metastatic site tissue-DNA than between ctDNA and primary tumor DNA (78% vs 65% for TP53, 100% vs 74% for KRAS and 100% vs 87% for PIK3CA [But not statistical significance]). Among 80 patients who received systemic treatment, the molecularly matched therapeutic regimens based on genomic profiling showed a significantly longer progression-free survival (hazard ratio [95%confidence interval], 0.60 [0.37-0.99]. P = .047 [multivariate]) and higher disease control rate (61% vs 35%, P = .04) than unmatched regimens. Evaluation of ctDNA and tissue-DNA is feasible in biliary tract cancers.

Commission on Cancer Facility Type is Associated with Overall Survival in Patients with Gastric Adenocarcinoma in the United States.

BACKGROUND: In the United States, "high-volume" centers for gastric cancer treat significantly fewer cases per year compared with centers in Asia. Factors associated with oncologic outcomes, aside from volume, are poorly understood. METHODS: Patients with gastric adenocarcinoma between 2004 and 2015 were analyzed in the NCDB cohort. Commission on Cancer facility types were classified as either Academic/Research Programs (ARP) or Non-Academic Programs (NAP). Factors associated with treatment at facility type were assessed by logistic regression. Overall survival was compared between facility types by Cox proportional hazard models. RESULTS: Thirty-nine percent of patients were treated at ARPs. In multivariable analysis, patients treated at ARPs were younger, healthier (Charlson-Deyo score), and had lower AJCC stage. Treatment at an ARP was associated with superior median OS compared with treatment at a NAP (17.3 months vs. 11.1 months, respectively, P < 0.001,) and in each stage of disease. Treatment of stages II and III patients at ARPs increased over time. Among patients with stages II and III disease, adherence to therapy guidelines was higher and postoperative mortality was lower at ARPs. CONCLUSION: Although patients at ARPs tend to have favorable characteristics, superior overall survival may also be due to better adherence to therapy guidelines and capacity to rescue after surgical complications.

Hepatobiliary Cancers, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Guidelines for Hepatobiliary Cancers focus on the screening, diagnosis, staging, treatment, and management of hepatocellular carcinoma (HCC), gallbladder cancer, and cancer of the bile ducts (intrahepatic and extrahepatic cholangiocarcinoma). Due to the multiple modalities that can be used to treat the disease and the complications that can arise from comorbid liver dysfunction, a multidisciplinary evaluation is essential for determining an optimal treatment strategy. A multidisciplinary team should include hepatologists, diagnostic radiologists, interventional radiologists, surgeons, medical oncologists, and pathologists with hepatobiliary cancer expertise. In addition to surgery, transplant, and intra-arterial therapies, there have been great advances in the systemic treatment of HCC. Until recently, sorafenib was the only systemic therapy option for patients with advanced HCC. In 2020, the combination of atezolizumab and bevacizumab became the first regimen to show superior survival to sorafenib, gaining it FDA approval as a new frontline standard regimen for unresectable or metastatic HCC. This article discusses the NCCN Guidelines recommendations for HCC.

Pathologic, Molecular, and Prognostic Radiologic Features of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a malignancy with variable biologic aggressiveness based on the tumor grade, presence or absence of vascular invasion, and pathologic and molecular classification. Knowledge and understanding of the prognostic implications of different pathologic and molecular phenotypes of HCC are emerging, with therapeutics that promise to provide improved outcomes in what otherwise remains a lethal cancer. Imaging has a central role in diagnosis of HCC. However, to date, the imaging algorithms do not incorporate prognostic features or subclassification of HCC according to its biologic aggressiveness. Emerging data suggest that some imaging features and further radiologic, pathologic, or radiologic-molecular phenotypes may allow prediction of the prognosis of patients with HCC. An invited commentary by Bashir is available online. Online supplemental material is available for this article. ©RSNA, 2021.

Current management of succinate dehydrogenase-deficient gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) are increasingly recognized as having diverse biology. With the development of tyrosine kinase inhibitors molecularly matched to oncogenic KIT and PDGFRA mutations, GISTs have become a quintessential model for precision oncology. However, about 5-10% of GIST lack these driver mutations and are deficient in succinate dehydrogenase (SDH), an enzyme that converts succinate to fumarate. SDH deficiency leads to accumulation of succinate, an oncometabolite that promotes tumorigenesis. SDH-deficient GISTs are clinically unique in that they generally affect younger patients and are associated with GIST-paraganglioma hereditary syndrome, also known as Carney-Stratakis Syndrome. SDH-deficient GISTs are generally resistant to tyrosine-kinase inhibitors, the standard treatment for advanced or metastatic GIST. Thus, surgical resection is the mainstay of treatment for localized disease, but recurrence is common. Clinical trials are currently underway investigating systemic agents for treatment of advanced SDH-deficient GIST. However, further studies are warranted to improve our understanding of SDH-deficient GIST disease biology, natural history, surgical approaches, and novel therapeutics.

Loss of the PTCH1 tumor suppressor defines a new subset of plexiform fibromyxoma.

BACKGROUND: Plexiform fibromyxoma (PF) is a rare gastric tumor often confused with gastrointestinal stromal tumor. These so-called "benign" tumors often present with upper GI bleeding and gastric outlet obstruction. It was recently demonstrated that approximately one-third of PF have activation of the GLI1 oncogene, a transcription factor in the hedgehog (Hh) pathway, via a MALAT1-GLI1 fusion protein or GLI1 up-regulation. Despite this discovery, the biology of most PFs remains unknown. METHODS: Next generation sequencing (NGS) was performed on formalin-fixed paraffin-embedded (FFPE) samples of PF specimens collected from three institutions (UCSD, NCI and OHSU). Fresh frozen tissue from one tumor was utilized for in vitro assays, including quantitative RT-PCR and cell viability assays following drug treatment. RESULTS: Eight patients with PF were identified and 5 patients' tumors were analyzed by NGS. An index case had a mono-allelic PTCH1 deletion of exons 15-24 and a second case, identified in a validation cohort, also had a PTCH1 gene loss associated with a suspected long-range chromosome 9 deletion. Building on the role of Hh signaling in PF, PTCH1, a tumor suppressor protein, functions upstream of GLI1. Loss of PTCH1 induces GLI1 activation and downstream gene transcription. Utilizing fresh tissue from the index PF case, RT-qPCR analysis demonstrated expression of Hh pathway components, SMO and GLI1, as well as GLI1 transcriptional targets, CCND1 and HHIP. In turn, short-term in vitro treatment with a Hh pathway inhibitor, sonidegib, resulted in dose-dependent cell killing. CONCLUSIONS: For the first time, we report a novel association between PTCH1 inactivation and the development of plexiform fibromyxoma. Hh pathway inhibition with SMO antagonists may represent a target to study for treating a subset of plexiform fibromyxomas.

Frequent rectal gastrointestinal stromal tumor recurrences in the imatinib era: Retrospective analysis of an International Patient Registry.

INTRODUCTION: Rectal gastrointestinal stromal tumor (GIST) is rare and comprises about 3% of GIST. METHODS: Registry data was collected by the Life Raft Group June 1976 to November 2017. All patients had a histologic GIST diagnosis. Demographic, clinicopathologic, and clinical outcome data were patient reported. Recurrence-free survival (RFS) was analyzed using the Kaplan-Meier method and Cox regression analysis. RESULTS: Of 1798 patients in the database, 48 had localized rectal GIST (2.7%). Patients were frequently male (58.3%) and non-Hispanic whites (58.3%). Median age at diagnosis was 52 years. Most patients (77%) were diagnosed in the imatinib era (2001 to current). Over half (54.2%) of the cohort had mutation testing and all profiled tumors possessed KIT mutations (exon 9: 7.7%, exon 11: 88.5%, and exon 13: 3.8%). Most evaluable patients (26/28; 92.9%) had high-risk disease (modified NIH criteria) and nearly all patients (95.8%) received imatinib. Median follow-up was 8.8 years (range, 0.3-30.7) and overall RFS was 8.0 years (95% CI, 2.9-13.1). Thirty-two percent (12/37) of patients in the post-imatinib era developed recurrent disease. Diagnosis in the imatinib era was associated with improved RFS (HR = 0.22, 95% CI, 0.08-0.62; P = .004) in the multivariable model. CONCLUSION: We find that disease recurrence remains prevalent in one-third of patients treated during the imatinib-era.

A Novel PRKAR1B-BRAF Fusion in Gastrointestinal Stromal Tumor Guides Adjuvant Treatment Decision-Making During Pregnancy.

Gastrointestinal stromal tumors (GISTs) are rare in pregnancy, with only 11 reported cases. Adjuvant imatinib therapy, which targets the most common driver mutations in GIST (KIT and PDGFRA), is recommended for patients with high-risk GIST, but it has known teratogenicity in the first trimester. A 34-year-old G3P2 woman underwent exploratory laparotomy at 16 weeks' gestation for a presumed adnexal mass. Surgical findings included normal adnexa and a 14-cm solid small bowel mass. The mass was resected en bloc with a segment of jejunum followed by a primary anastomosis. Histopathology and genomic analyses demonstrated a GIST with high-risk features but lack of KIT/PDGFRA mutations and identified the presence of a previously unreported, pathogenic PRKAR1B-BRAF gene fusion. Given her tumor profile, adjuvant therapy with imatinib was not recommended. GIST is rare in pregnancy, but can masquerade as an adnexal mass in women of childbearing age. Because neoadjuvant/adjuvant imatinib has risks of teratogenicity, tumor molecular profiling is critical as we identified a previously unreported gene fusion of PRKAR1B with BRAF that is predicted to be imatinib-resistant. In this case, testing provided the rationale for not offering adjuvant imatinib to avoid unnecessary toxicity to the patient and fetus.

FGFR1 and NTRK3 actionable alterations in "Wild-Type" gastrointestinal stromal tumors.

BACKGROUND: About 10-15% of adult, and most pediatric, gastrointestinal stromal tumors (GIST) lack mutations in KIT, PDGFRA, SDHx, or RAS pathway components (KRAS, BRAF, NF1). The identification of additional mutated genes in this rare subset of tumors can have important clinical benefit to identify altered biological pathways and select targeted therapies. METHODS: We performed comprehensive genomic profiling (CGP) for coding regions in more than 300 cancer-related genes of 186 GISTs to assess for their somatic alterations. RESULTS: We identified 24 GIST lacking alterations in the canonical KIT/PDGFRA/RAS pathways, including 12 without SDHx alterations. These 24 patients were mostly adults (96%). The tumors had a 46% rate of nodal metastases. These 24 GIST were more commonly mutated at 7 genes: ARID1B, ATR, FGFR1, LTK, SUFU, PARK2 and ZNF217. Two tumors harbored FGFR1 gene fusions (FGFR1-HOOK3, FGFR1-TACC1) and one harbored an ETV6-NTRK3 fusion that responded to TRK inhibition. In an independent sample set, we identified 5 GIST cases lacking alterations in the KIT/PDGFRA/SDHx/RAS pathways, including two additional cases with FGFR1-TACC1 and ETV6-NTRK3 fusions. CONCLUSIONS: Using patient demographics, tumor characteristics, and CGP, we show that GIST lacking alterations in canonical genes occur in younger patients, frequently metastasize to lymph nodes, and most contain deleterious genomic alterations, including gene fusions involving FGFR1 and NTRK3. If confirmed in larger series, routine testing for these translocations may be indicated for this subset of GIST. Moreover, these findings can be used to guide personalized treatments for patients with GIST. Trial registration NCT 02576431. Registered October 12, 2015.

Increased risk of additional cancers among patients with gastrointestinal stromal tumors: A population-based study.

BACKGROUND: Most gastrointestinal stromal tumors (GISTs) are considered nonhereditary or sporadic. However, single-institution studies suggest that GIST patients develop additional malignancies at increased frequencies. It was hypothesized that greater insight could be gained into possible associations between GISTs and other malignancies with a national cancer database inquiry. METHODS: Patients diagnosed with GISTs (2001-2011) in the Surveillance, Epidemiology, and End Results database were included. Standardized prevalence ratios (SPRs) and standardized incidence ratios (SIRs) were used to quantify cancer risks incurred by GIST patients before and after GIST diagnoses, respectively, in comparison with the general US population. RESULTS: There were 6112 GIST patients, and 1047 (17.1%) had additional cancers. There were significant increases in overall cancer rates: 44% (SPR, 1.44) before the GIST diagnosis and 66% (SIR, 1.66) after the GIST diagnosis. Malignancies with significantly increased occurrence both before and after diagnoses included other sarcomas (SPR, 5.24; SIR, 4.02), neuroendocrine-carcinoid tumors (SPR, 3.56; SIR, 4.79), non-Hodgkin lymphoma (SPR, 1.69; SIR, 1.76), and colorectal adenocarcinoma (SPR, 1.51; SIR, 2.16). Esophageal adenocarcinoma (SPR, 12.0), bladder adenocarcinoma (SPR, 7.51), melanoma (SPR, 1.46), and prostate adenocarcinoma (SPR, 1.20) were significantly more common only before the GIST diagnosis. Ovarian carcinoma (SIR, 8.72), small intestine adenocarcinoma (SIR, 5.89), papillary thyroid cancer (SIR, 5.16), renal cell carcinoma (SIR, 4.46), hepatobiliary adenocarcinoma (SIR, 3.10), gastric adenocarcinoma (SIR, 2.70), pancreatic adenocarcinoma (SIR, 2.03), uterine adenocarcinoma (SIR, 1.96), non-small cell lung cancer (SIR, 1.74), and transitional cell carcinoma of the bladder (SIR, 1.65) were significantly more common only after the GIST diagnosis. CONCLUSIONS: This is the first population-based study to characterize the associations and temporal relations between GISTs and other cancers by both site and histological type. These associations may carry important clinical implications for future cancer screening and treatment strategies.

Gastrointestinal stromal tumors in the setting of multiple tumor syndromes.

PURPOSE OF REVIEW: Knowledge related to gastrointestinal stromal tumor (GIST) in the setting of nonhereditary and hereditary multiple tumor syndromes continues to expand. This review describes associations between sporadic GIST and second malignancies, as well as new contributions to our knowledge about hereditary GIST multiple tumor syndromes. RECENT FINDINGS: Sporadic GIST patients have increased risk of developing synchronous/metachronous cancers, including nonhematologic and hematologic malignancies. Data suggest these associations are nonrandom, more prevalent in men and increase with age. New adrenal tumors have also been associated with nonhereditary Carney's triad. Meanwhile, understanding of the molecular basis of heritable GIST syndromes has improved. Several new familial GIST kindreds have been reported, including those with germline KIT and PDGFRα mutations. Knowledge about succinate dehydrogenase (SDH) deficiency and mutations in hereditary GIST syndromes has expanded. It is now known that neurofibromatosis-1-associated GISTs are SDHB-positive, whereas Carney-Stratakis syndrome-associated GISTs are SDHB-deficient with underlying germline mutations in SDH subunits A-D. SUMMARY: Recognition and early diagnosis of GIST syndromes allows for improved comprehensive medical care. With additional understanding of the molecular pathogenesis of GIST multiple tumor syndromes, we can refine our screening programs and management of these patients and their families.

Cabozantinib plus atezolizumab in previously untreated advanced hepatocellular carcinoma and previously treated gastric cancer and gastroesophageal junction adenocarcinoma: results from two expansion cohorts of a multicentre, open-label, phase 1b trial (COSMIC-021).

Background: Cabozantinib is approved for previously treated advanced hepatocellular carcinoma (aHCC) and has been investigated in gastric cancer (GC) and gastroesophageal junction adenocarcinoma (GEJ). Atezolizumab plus bevacizumab is approved for unresectable or metastatic HCC untreated with prior systemic therapy. We evaluated efficacy and safety of cabozantinib plus atezolizumab in aHCC previously untreated with systemic anticancer therapy or previously treated GC/GEJ. Methods: COSMIC-021 (ClinicalTrials.gov, NCT03170960) is an open-label, phase 1b study in solid tumours with a dose-escalation stage followed by tumour-specific expansion cohorts, including aHCC (cohort 14) and GC/GEJ (cohort 15). Eligible patients were aged ≥18 years with measurable locally advanced, metastatic, or recurrent disease per RECIST version 1.1. Patients received oral cabozantinib 40 mg daily and intravenous atezolizumab 1200 mg once every 3 weeks until progressive disease or unacceptable toxicity. The primary endpoint was investigator-assessed objective response rate per RECIST version 1.1. Findings: Patients were screened between February 14, 2019, and May 7, 2020, and 61 (30 aHCC, 31 GC/GEJ) were enrolled and received at least one dose of study treatment. Median duration of follow-up was 31.2 months (IQR 28.5-32.7) for aHCC and 30.4 months (28.7-31.9) for GC/GEJ. Objective response rate was 13% (4/30, 95% CI 4-31) for aHCC and 0% (95% CI 0-11) for GC/GEJ. Six (20%) aHCC patients and three (10%) GC/GEJ patients had treatment-related adverse events resulting in discontinuation of either study drug. Interpretation: Cabozantinib plus atezolizumab had clinical activity with a manageable safety profile in aHCC previously untreated with systemic anticancer therapy. Clinical activity of cabozantinib plus atezolizumab was minimal in previously treated GC/GEJ. Funding: Exelixis, Inc., Alameda, CA, USA.

Molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma.

Atezolizumab (anti-programmed death-ligand 1 (PD-L1)) and bevacizumab (anti-vascular endothelial growth factor (VEGF)) combination therapy has become the new standard of care in patients with unresectable hepatocellular carcinoma. However, potential predictive biomarkers and mechanisms of response and resistance remain less well understood. We report integrated molecular analyses of tumor samples from 358 patients with hepatocellular carcinoma (HCC) enrolled in the GO30140 phase 1b or IMbrave150 phase 3 trial and treated with atezolizumab combined with bevacizumab, atezolizumab alone or sorafenib (multikinase inhibitor). Pre-existing immunity (high expression of CD274, T-effector signature and intratumoral CD8+ T cell density) was associated with better clinical outcomes with the combination. Reduced clinical benefit was associated with high regulatory T cell (Treg) to effector T cell (Teff) ratio and expression of oncofetal genes (GPC3, AFP). Improved outcomes from the combination versus atezolizumab alone were associated with high expression of VEGF Receptor 2 (KDR), Tregs and myeloid inflammation signatures. These findings were further validated by analyses of paired pre- and post-treatment biopsies, in situ analyses and in vivo mouse models. Our study identified key molecular correlates of the combination therapy and highlighted that anti-VEGF might synergize with anti-PD-L1 by targeting angiogenesis, Treg proliferation and myeloid cell inflammation.

Establishment of Patient-Derived Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumor Models for Predicting Therapeutic Response.

PURPOSE: Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract, with mutant succinate dehydrogenase (SDH) subunits (A-D) comprising less than 7.5% (i.e., 150-200/year) of new cases annually in the United States. Contrary to GISTs harboring KIT or PDGFRA mutations, SDH-mutant GISTs affect adolescents/young adults, often metastasize, and are frequently resistant to tyrosine kinase inhibitors (TKI). Lack of human models for any SDH-mutant tumors, including GIST, has limited molecular characterization and drug discovery. EXPERIMENTAL DESIGN: We describe methods for establishing novel patient-derived SDH-mutant (mSDH) GIST models and interrogated the efficacy of temozolomide on these tumor models in vitro and in clinical trials of patients with mSDH GIST. RESULTS: Molecular and metabolic characterization of our patient-derived mSDH GIST models revealed that these models recapitulate the transcriptional and metabolic hallmarks of parent tumors and SDH deficiency. We further demonstrate that temozolomide elicits DNA damage and apoptosis in our mSDH GIST models. Translating our in vitro discovery to the clinic, a cohort of patients with SDH-mutant GIST treated with temozolomide (n = 5) demonstrated a 40% objective response rate and 100% disease control rate, suggesting that temozolomide represents a promising therapy for this subset of GIST. CONCLUSIONS: We report the first methods to establish patient-derived mSDH tumor models, which can be readily employed for understanding patient-specific tumor biology and treatment strategies. We also demonstrate that temozolomide is effective in patients with mSDH GIST who are refractory to existing chemotherapeutic drugs (namely, TKIs) in clinic for GISTs, bringing a promising treatment option for these patients to clinic.See related commentary by Blakely et al., p. 3.

Molecular phylogeny of Pholadoidea Lamarck, 1809 supports a single origin for xylotrophy (wood feeding) and xylotrophic bacterial endosymbiosis in Bivalvia.

The ability to consume wood as food (xylotrophy) is unusual among animals. In terrestrial environments, termites and other xylotrophic insects are the principle wood consumers while in marine environments wood-boring bivalves fulfill this role. However, the evolutionary origin of wood feeding in bivalves has remained largely unexplored. Here we provide data indicating that xylotrophy has arisen just once in Bivalvia in a single wood-feeding bivalve lineage that subsequently diversified into distinct shallow- and deep-water branches, both of which have been broadly successful in colonizing the world's oceans. These data also suggest that the appearance of this remarkable life habit was approximately coincident with the acquisition of bacterial endosymbionts. Here we generate a robust phylogeny for xylotrophic bivalves and related species based on sequences of small and large subunit nuclear rRNA genes. We then trace the distribution among the modern taxa of morphological characters and character states associated with xylotrophy and xylotrepesis (wood-boring) and use a parsimony-based method to infer their ancestral states. Based on these ancestral state reconstructions we propose a set of plausible hypotheses describing the evolution of symbiotic xylotrophy in Bivalvia. Within this context, we reinterpret one of the most remarkable progressions in bivalve evolution, the transformation of the "typical" myoid body plan to create a unique lineage of worm-like, tube-forming, wood-feeding clams. The well-supported phylogeny presented here is inconsistent with most taxonomic treatments for xylotrophic bivalves, indicating that the bivalve family Pholadidae and the subfamilies Teredininae and Bankiinae of the family Teredinidae are non-monophyletic, and that the principle traits used for their taxonomic diagnosis are phylogenetically misleading.

Rescue liver re-transplantation after graft loss due to severe rejection in the setting of pre-transplant nivolumab therapy.

Immune checkpoint inhibitors (ICI) have been used to treat hepatocellular carcinoma (HCC) since 2017. The safety of ICIs in the setting of solid organ transplantation remains controversial. When used in the post-transplant setting, ICIs have been associated with high allograft rejection rates, but there are few published reports on the use of ICIs prior to transplant. We present the first reported case of rescue liver re-transplantation after loss of the first allograft due to severe acute rejection with extensive hepatic necrosis in the setting of pre-transplant ICI therapy with the PD-1 inhibitor nivolumab. It is likely that the durable immune response triggered by nivolumab contributes to graft rejection, therefore extreme caution should be taken when using ICIs before transplant until further investigation has been conducted on their safety in the pre-transplant setting.