Kevan L. Hartshorn’s research while affiliated with Boston Medical Center and other places

We present a distinctive case of solid pseudopapillary neoplasm as seen in a 44-year-old woman who presented with an abdominal mass but unremarkable labs with no elevation in any of the tumor markers. Her symptomatology ranged from typical symptoms suggestive of malignancy such as weight loss, lethargy, and anorexia to complaints like abdominal pain and jaundice. Prior to presenting at our center, she was given no hope or much in terms of treatment options. She was found to have a substantial mass over the body and tail of pancreas with characteristic and typical gross as well as histological features. Subsequently, she underwent a successful surgery and has found herself in remission since.

Simple Summary Hepatic and intrahepatic bile duct cancer is the sixth most frequently diagnosed cancer in the world. A total of 830,200 people died from liver cancer globally in 2020. It is estimated that hepatocellular carcinoma (HCC), an aggressive, primary malignant liver tumor, accounts for approximately 85% of all primary liver tumors. Despite the improvements in surveillance screening programs, the prevalence of HCC is expected to rise significantly over the coming decades. Beginning with the approval of sorafenib in 2007, there has been a monumental amount of progress attained in the management of advanced HCC with systemic therapies. Certain major gaps in therapy remain. This narrative review details the history, current landscape, and future directions of HCC systemic therapy. We hope this review will heighten interest in the field of HCC systemic therapies, provide a clear outline of the current data and strategy for treatment, and sensitize readers to new developments that are likely to emerge. Abstract We provide a comprehensive review of current approved systemic treatment strategies for advanced hepatocellular carcinoma (HCC), starting with the phase III clinical trial of sorafenib which was the first to definitively show a survival benefit. After this trial, there was an initial period of little progress. However, in recent years, an explosion of new agents and combinations of agents has resulted in a markedly improved outlook for patients. We then provide the authors’ current approach to therapy, i.e., “How We Treat HCC”. Promising future directions and important gaps in therapy that persist are finally reviewed. HCC is a highly prevalent cancer worldwide and the incidence is growing due not only to alcoholism, hepatitis B and C, but also to steatohepatitis. HCC, like renal cell carcinoma and melanoma, is a cancer largely resistant to chemotherapy but the advent of anti-angiogenic, targeted and immune therapies have improved survival for all of these cancers. We hope this review will heighten interest in the field of HCC therapies, provide a clear outline of the current data and strategy for treatment, and sensitize readers to new developments that are likely to emerge in the near future.

PurposeThe purpose of this study was to examine receipt of follow-up surveillance among sexual minority and heterosexual survivors and identify survivor-, physician-, and practice-level characteristics associated with follow-up surveillance.Methods An average of 3 years after their stage I–III colorectal cancer diagnosis, we recruited survivors from four cancer registries. A questionnaire, which queried about sexual orientation and other eligibility criteria, was mailed to all cancer survivors. Subsequently, 418 eligible survivors without recurrent disease participated in a telephone survey. Colorectal cancer–specific follow-up surveillance was defined as colonoscopy, carcinoembryonic antigen (CEA) test, or imaging test. We used logistic regression with forward selection to obtain models that best explained each follow-up test.ResultsAbout 10% of survivors received no follow-up surveillance, while 70% had colonoscopies. While survivors irrespective of sexual orientation received follow-up surveillance, sexual minority survivors had 3 times the odds of receiving imaging tests compared to heterosexual survivors. Having a designated provider of any specialty was most salient for the receipt of surveillance.Conclusions Sexual minority survivors’ greater receipt of imaging tests may indicate providers perceive them at greater risk for recurrence than heterosexual survivors. Future studies need to examine provider behaviors towards monitoring colorectal cancer survivors of diverse sexual orientations.Implications for Cancer SurvivorsGuidelines recommend surveillance of colorectal cancer survivors to improve survival. This study showed that having a designated provider for follow-up is most salient for the receipt of surveillance, most survivors receive surveillance, and sexual minority survivors had more imaging tests compared to heterosexual survivors.

People with disorders such as cancer, autoimmune disease, diabetes, or obesity often have metabolic dysregulation of cellular glycosylation and also have more severe influenza disease, a reduced immune response to the virus, and reduced vaccine efficacy. Since influenza viruses that infect such people do not show consistent genomic variations, it is generally assumed that the altered biology is mainly related to host factors.

Mannose-binding lectins effectively inhibit most seasonal strains of influenza A virus and contribute to the innate host defense vs. these viruses. In contrast, pandemic IAV strains are largely resistant to these lectins, likely contributing to increased spread and worse outcomes. In this paper, we evaluated the inhibition of IAV by mannose-binding lectins of human, bacterial, and fungal origin to understand and possibly increase activity vs. the pandemic IAV. A modified version of the human surfactant protein D (SP-D) neck and carbohydrate recognition domain (NCRD) with combinatorial substitutions at the 325 and 343 positions, previously shown to inhibit pandemic H3N2 IAV in vitro and in vivo, and to inhibit pandemic H1N1 in vitro, failed to protect mice from pandemic H1N1 in vivo in the current study. We attempted a variety of maneuvers to improve the activity of the mutant NCRDs vs. the 2009 pandemic H1N1, including the formation of full-length SP-D molecules containing the mutant NCRD, cross-linking of NCRDs through the use of antibodies, combining SP-D or NCRDs with alpha-2-macroglobulin, and introducing an additional mutation to the double mutant NCRD. None of these substantially increased the antiviral activity for the pandemic H1N1. We also tested the activity of bacterial and algal mannose-binding lectins, cyanovirin, and griffithsin, against IAV. These had strong activity against seasonal IAV, which was largely retained against pandemic H1N1. We propose mechanisms to account for differences in activity of SP-D constructs against pandemic H3N2 and H1N1, and for differences in activity of cyanovirin vs. SP-D constructs.

Objective The purpose of this study was to determine the association of physical and psychological symptoms with health care utilization in sexual minority and heterosexual colorectal cancer survivors. Methods Four hundred eighteen colorectal cancer survivors who were in remission an average of 3 years after their diagnosis were surveyed about their non-emergency health care visits during the preceding 3 months. Survivors reported whether they had experienced any of 21 symptoms common among colorectal cancer survivors in the past week. The relation between having had two or more health care visits in the preceding 3 months and symptoms experienced was assessed using logistic regression, controlling for cancer registry, sexual orientation, sex, age, race/ethnicity, income, and comorbidities. Results Of the survivors, 12% reported no symptoms, while 12% reported six or more symptoms. Sexual minority survivors reported significantly more weight concerns and more health-related and general anxiety as well as worse body image than heterosexual survivors. Frequent worrying about weight and experiencing sore skin around the anal area or stoma were the two symptoms that significantly contributed towards explaining survivors’ increased health care utilization. Conclusion Weight concerns, which are more common among the heaviest survivors, may prompt survivors to seek help from health care providers, which may lead to more frequent visits. On the other hand, some symptoms, despite their prevalence, had no relationship with the frequency of health care visits, raising questions about whether survivors share these concerns with providers.

Background The purpose of this study was to examine the health‐related quality of life of sexual minority survivors in comparison with heterosexual survivors. Methods Four hundred eighty eligible survivors participated in a telephone survey that measured survivors' outcomes, which consisted of physical and mental quality of life and self‐rated fair or poor health. These survivors were diagnosed with stage I, II, or III colorectal cancer an average of 3 years before the survey and were recruited from 4 cancer registries. Using forward selection with generalized linear models or logistic regression models, the authors considered 4 domains—personal factors, environmental factors, health condition characteristics, and body function and structure—as correlates for each survivorship outcome. Results The authors found that unadjusted physical quality of life and self‐rated fair/poor health were similar for all survivors. Sexual minority survivors had poorer unadjusted mental quality of life in comparison with heterosexual survivors. After adjustments for covariates, this difference was no longer statistically significant. Three domains (personal factors, health condition characteristics, and body function and structure) explained colorectal cancer survivors' fair/poor health and 46% of the variance in physical quality of life, whereas 56% of the variance in mental quality of life was explained by personal factors, body function and structure, and environmental factors. Conclusions This study has identified modifiable factors that can be used to improve cancer survivors' quality of life and are, therefore, relevant to ongoing efforts to improve the survivorship experience.

Neutrophils participate in the early phase of the innate response to uncomplicated influenza A virus (IAV) infection but also are a major component in later stages of severe IAV or COVID 19 infection where neutrophil extracellular traps (NETs) and associated cell free histones are highly pro-inflammatory. It is likely that IAV interacts with histones during infection. We show that histone H4 binds to IAV and aggregates viral particles. In addition, histone H4 markedly potentiates IAV induced neutrophil respiratory burst responses. Prior studies have shown reactive oxidants to be detrimental during severe IAV infection. C reactive protein (CRP) and surfactant protein D (SP-D) rise during IAV infection. We now show that both of these innate immune proteins bind to histone H4 and significantly down regulate respiratory burst and other responses to histone H4. Isolated constructs composed only of the neck and carbohydrate recognition domain of SP-D also bind to histone H4 and partially limit neutrophil responses to it. These studies indicate that complexes formed of histones and IAV are a potent neutrophil activating stimulus. This finding could account for excess inflammation during IAV or other severe viral infections. The ability of CRP and SP-D to bind to histone H4 may be part of a protective response against excessive inflammation in vivo.

Purpose Camptothecin (CPT) analogues topotecan and irinotecan specifically target topoisomerase I (topoI), and are used to treat colorectal, gastric and pancreatic cancer. Patient response rate for this class of drug varies from 10-30% and there is no predictive biomarker for patient stratification by response. Based on our understanding of CPT drug resistance mechanisms, we developed an IHC-based predictive test (P-topoI-Dx) to stratify the responder versus non-responder patient populations. Patients and mthods The retrospective validation studies included a training set of (n=79) and a validation cohort (n=27) of gastric cancer (GC) patients, and eight cohorts of colorectal cancer (CRC) patient tissue (n=176). Progression-free survival for 6 months was considered positive response to CPT-based therapy. FFPE slides were immunohistochemically stained with anti-phosphospecific topoI-Serine10 (topoI-pS10), quantitated and analyzed statistically. Results We determined a threshold of 35% percent positive staining as offering optimal test characteristics in GC. The GC (n=79) training set demonstrated 76.6% (64-86) sensitivity; 68.8% (41-88) specificity; positive predictive value (PPV) 92.5% (81-98); and negative predictive value (NPV) 42.3% (24-62). The GC validation set (n=27) demonstrated 82.4% (56-95) sensitivity and 70.0% (35-92) specificity. Estimated PPV and NPV were 82.4% (56-95) and 70.0% (35-92) respectively. In the CRC validation set (n=176), the 40% threshold demonstrated 87.5% (78-94) sensitivity; 70.0% (59-79) specificity; PPV 70.7% (61-79) and NPV 87.0 % (77-93). Conclusion The analysis of retrospective data from patients (n=275) provides clinical validity to our P-topoI-Dx IHC test to identify the individuals who are more likely to respond to topoI inhibitors.

Innate immunity is vital for the early control of influenza A virus (IAV) infection. Serum amyloid A (SAA1) is an acute phase reactant produced in the liver and lung that rises dramatically during IAV infection. The potential role of SAA1 in host defense against IAV is unknown. SAA1 has been reported to directly activate neutrophils and to recruit them to the lung during infectious and inflammatory processes. Neutrophils are the most abundant cell recruited to the lung in the early phase of IAV infection. There are different forms and preparations of SAA1 that have found to have different effects on phagocyte responses, through various receptors. In this paper, we test the direct effects of various preparations of serum derived or recombinant SAA on IAV and how it modulates the interactions of IAV with neutrophils. All SAA preparations bound to IAV in vitro but caused minimal hemagglutination inhibition or viral aggregation. The human serum‐derived SAA1 or the complex of SAA1 with HDL did have IAV neutralizing activity in vitro, whereas the recombinant SAA1 preparations did not. We found that different SAA preparations also had markedly different effects on neutrophil functions, with E. coli‐derived SAA1 triggering some responses in neutrophils on its own or in presence of IAV whereas mammalian cell‐derived SAA1 did not. This discrepancy could be explained by the reported contamination of the former preparation with bacterial components. Of interest, however, serum SAA alone, serum SAA complexed with HDL, or HDL alone potentiated some neutrophil responses to IAV. Our results suggest that SAA may play some role in host response to IAV, but further work needs to be done to clarify the role of different variants of SAA alone or complexed with HDL. Serum amyloid a protein (SAA) bound to and inhibited influenza virus infectivity, but SAA free of bacterial products did not alter neutrophil responses.