Epigenetic alterations fuel brain metastasis via regulating inflammatory cascade.

Brain metastasis (BrM) is a major threat to the survival of melanoma, breast, and lung cancer patients. Circulating tumor cells (CTCs) cross the blood-brain barrier (BBB) and sustain in the brain microenvironment. Genetic mutations and epigenetic modifications have been found to be critical in controlling key aspects of cancer metastasis. Metastasizing cells confront inflammation and gradually adapt in the unique brain microenvironment. Currently, it is one of the major areas that has gained momentum. Researchers are interested in the factors that modulate neuroinflammation during BrM. We review here various epigenetic factors and mechanisms modulating neuroinflammation and how this helps CTCs to adapt and survive in the brain microenvironment. Since epigenetic changes could be modulated by targeting enzymes such as histone/DNA methyltransferase, deacetylases, acetyltransferases, and demethylases, we also summarize our current understanding of potential drugs targeting various aspects of epigenetic regulation in BrM.

Rethinking the chemokine cascade in brain metastasis: Preventive and therapeutic implications.

Brain metastasis (BrM) is one of the major causes of death in cancer patients and is associated with an estimated 10-40 % of total cancer cases. The survival rate of brain metastatic patients has not improved due to intratumor heterogeneity, the survival adaptations of brain homing metastatic cells, and the lack of understanding of underlying molecular mechanisms that limit the availability of effective therapies. The heterogeneous population of immune cells and tumor-initiating cells or cancer stem cells in the tumor microenvironment (TME) release various factors, such as chemokines that upon binding to their cognate receptors enhance tumor growth at primary sites and help tumor cells metastasize to the brain. Furthermore, brain metastatic sites have unique heterogeneous microenvironment that fuels cancer cells in establishing BrM. This review explores the crosstalk of chemokines with the heterogeneous TME during the progression of BrM and recognizes potential therapeutic approaches. We also discuss and summarize different targeted, immunotherapeutic, chemotherapeutic, and combinatorial strategies (with chemo-/immune- or targeted-therapies) to attenuate chemokines mediated BrM.

Open Payments Data Analysis of General and Fellowship-trained Surgeons Receiving Industry General Payments From 2016 to 2020: Payment Disparities and COVID-19 Pandemic Impact.

OBJECTIVE: To characterize industry nonresearch payments made to general and fellowship-trained surgeons between 2016 and 2020. BACKGROUND: The Centers for Medicare & Medicaid Services Open Payments Data (OPD) reports industry payments made to physicians related to drugs and medical devices. General payments are those not associated with research. METHODS: OPD data were queried for general and fellowship-trained surgeons who received general payments from 2016 to 2020. Payments' nature, amount, company, covered product, and location were collected. Surgeons' demographics, subspecialty, and leadership roles in hospitals, societies, and editorial boards were evaluated. RESULTS: From 2016 to 2020, 44,700 general and fellowship-trained surgeons were paid $535,425,543 in 1,440,850 general payments. The median payment was $29.18. The most frequent payments were for food and beverage (76.6%) and travel and lodging (15.6%); however, the highest dollar payments were for consulting fees ($93,128,401; 17.4%), education ($88,404,531; 16.5%), royalty or license ($87,471,238; 16.3%), and travel and lodging ($66,333,149; 12.4%). Five companies made half of all payments ($265,654,522; 49.6%): Intuitive Surgical ($128,517,411; 24%), Boston Scientific ($48,094,570; 9%), Edwards Lifesciences ($41,835,544, 7.8%), Medtronic Vascular ($33,607,136; 6.3%), and W. L. Gore & Associates ($16,626,371; 3.1%). Medical devices comprised 74.7% of payments ($399,897,217), followed by drugs and biologicals ($33,945,300; 6.3%). Texas, California, Florida, New York, and Pennsylvania received the most payments; however, the top dollar payments were in California ($65,702,579; 12.3%), Michigan ($52,990,904, 9.9%), Texas ($39,362,131; 7.4%), Maryland ($37,611,959; 7%), and Florida ($33,417,093, 6.2%). General surgery received the highest total payments ($245,031,174; 45.8%), followed by thoracic surgery ($167,806,514; 31.3%) and vascular surgery ($60,781,266; 11.4%). A total of 10,361 surgeons were paid >$5000, of which 1614 were women (15.6%); in this group, men received higher payments than women (means, $53,446 vs $22,571; P <0.001) and thoracic surgeons received highest payments (mean, $76,381; NS, P =0.14). A total of 120 surgeons were paid >$500,000 ($203,011,672; 38%)-5 non-Hispanic White (NHW) women (4.2%) and 82 NHW (68.3%), 24 Asian (20%), 7 Hispanic (5.8%), and 2 Black (1.7%) men; in this group, men received higher payments than women (means, $1,735,570 vs $684,224), and NHW men received payments double those of other men (means, $2,049,554 vs $955,368; NS, P =0.087). Among these 120 highly paid surgeons (>$500,000), 55 held hospital and departmental leadership roles, 30 were leaders in surgical societies, 27 authored clinical guidelines, and 16 served on journal editorial boards. During COVID-19, 2020 experienced half the number of payments than the preceding 3 years. CONCLUSIONS: General and fellowship-trained surgeons received substantial industry nonresearch payments. The highest-paid recipients were men. Further work is warranted in assessing how race, gender, and leadership roles influence the nature of industry payments and surgical practice. A significant decline in payments was observed early during the COVID-19 pandemic.

Age-related next-generation sequencing mutational analysis in 1196 melanomas.

BACKGROUND AND OBJECTIVES: Melanoma mutational burden is high and approximately 50% have oncogenic mutations in BRAF. We sought to evaluate age-related mutational differences in melanoma. METHODS: We analyzed melanoma samples in the Genomics Evidence Neoplasia Information Exchange database. Targetable mutations were identified using the Precision Oncology Knowledge Base (OncoKB). RESULTS: We found 1194 patients with a common set of 30 genes. The top mutated genes in patients <40 years old (y/o) (n = 98) were BRAF (59%), TP53 (31%), NRAS (17%), and PTEN (14%); in 40-59 y/o (n = 354) were BRAF (51%), NRAS (30%), TP53 (26%), and APC (13%); and in ≥60 y/o (n = 742) were BRAF (38%), NRAS (33%), TP53 (26%), and KDR (19%). BRAF mutations were almost mutually exclusive from NRAS mutations in <40 y/o (58/59). Mutational burden increased with age, with means of 2.39, 2.92, and 3.67 mutations per sample in patients <40, 40-59, and ≥60 y/o, respectively (p < 0.0001). There were 10 targetable mutations meeting OncoKB criteria for melanoma: BRAF (level 1), RET (level 1), KIT (level 2), NRAS (level 3A), TP53 (level 3A), and FGFR2, MET, PTEN, PIK3CA, and KRAS (level 4). CONCLUSIONS: Mutations in melanoma have age-related differences and demonstrates potential targetable mutations for personalized therapies.

Liquid biopsies to occult brain metastasis.

Brain metastasis (BrM) is a major problem associated with cancer-related mortality, and currently, no specific biomarkers are available in clinical settings for early detection. Liquid biopsy is widely accepted as a non-invasive method for diagnosing cancer and other diseases. We have reviewed the evidence that shows how the molecular alterations are involved in BrM, majorly from breast cancer (BC), lung cancer (LC), and melanoma, with an inception in how they can be employed for biomarker development. We discussed genetic and epigenetic changes that influence cancer cells to breach the blood-brain barrier (BBB) and help to establish metastatic lesions in the uniquely distinct brain microenvironment. Keeping abreast with the recent breakthroughs in the context of various biomolecules detections and identifications, the circulating tumor cells (CTC), cell-free nucleotides, non-coding RNAs, secretory proteins, and metabolites can be pursued in human body fluids such as blood, serum, cerebrospinal fluid (CSF), and urine to obtain potential candidates for biomarker development. The liquid biopsy-based biomarkers can overlay with current imaging techniques to amplify the signal viable for improving the early detection and treatments of occult BrM.

Surgical Management of Melanoma: Advances and Updates.

PURPOSE OF REVIEW: To review and update surgeons about the evolving complexities in the surgical management of melanoma including lymph node staging and treatment. RECENT FINDINGS: Primary resection with adequate margins continues to be the standard of care for localized cutaneous melanoma. Sentinel lymph node biopsy is confirmed to be a powerful tool due to its prognostic value and informative guidance for adjuvant treatments and surveillance. Due to the lack of benefit in melanoma-specific survival and distant metastasis-free survival, completion lymph node dissection is not performed routinely after a positive sentinel lymph node biopsy. Neoadjuvant systemic treatment approaches for advanced loco-regional disease show promise in phase I and II clinical trial data, and phase III studies. The surgical management of cutaneous melanoma continues to evolve with further de-escalation of the extent of excision of primary melanomas and the management of lymph node disease.

Changing Trends in Industry Funding for Surgical Oncologists.

BACKGROUND: With reductions in public funding, alternate research funding is essential to surgical oncologists (SOs). We aimed to examine current trends in industry funding of SOs. METHODS: Society of Surgical Oncology surgeons were identified and matched with board certification and years in practice. Departmental and hospital data were evaluated, and industry payments from 2013 to 2017 were matched with the Open Payment Data. RESULTS: Of the 1670 SOs identified, 922 (55%) had academic positions: 588 (64%) males and 334 (36%) females. Between 2013 and 2017, research payments totaling $46,596,706 were made to 162 SOs (17.5%): $40,774,716 (87%) for research related to drugs and clinical trials, compared with $5,194,199 (11%) for surgical devices (p = 0.018). Funding correlated with academic leadership and years in practice (p = 0.0001 and p = 0.0037). Massachusetts ($9,060,976), Texas ($7,656,228), and New York ($4,210,864) received the most funding, whereas Utah ($1,533,166/SO), Massachusetts ($1,294,425/SO), and Oregon ($1,241,702/SO) received the highest average payments per SO. The majority of funding was from Novartis ($16,045,608), Amgen ($6,810,832), and Merck ($3,758,299), for an oncolytic vaccine (talimogene laherparepvec, $5,939,007), a BRAF inhibitor (dabrafenib, $5,727,309), and a KIT inhibitor (imatinib, $4,323,586). Male SOs received funding more frequently than females (120/588 [20%] vs. 42/334 [12.6%]; p = 0.0027). Males also received more general payments (travel/lodging, food/beverage, consulting/speaker fees): $48,830 vs. $11,867 per male and female, respectively (p = 0.0001). CONCLUSIONS: The majority of industry research payments to SOs are related to novel pharmaceuticals, which highlights the expanding influence SOs play in systemic therapies. Industry payments are influenced by location, gender, and academic leadership.

Surrogate indicators of quality are associated with survival following surgical treatment for hepatocellular carcinoma.

INTRODUCTION: Quality/core measures have been collected for over 10 years. Studies have demonstrated hospital performance is related to postoperative outcomes. We hypothesize that hospital quality measures are associated with long-term survival following surgical resection for hepatocellular carcinoma (HCC). METHODS: The National Cancer Data Base was queried for all HCC cases. Individual hospitals were deidentified. Quality markers were defined as hospital-specific median length of stay (LOS), 30-day mortality rate and readmit rate. A Cox regression stratified by stage estimated survival. To minimize confounding, a landmark analysis was estimated for patients that survived greater than 30 days. RESULTS: A total of 16 202 HCC patients underwent surgical resection and 996 (6.1%) died within 30 days following surgery. Calculated by unique hospital, median 30-day death rate was 4.6% (interquartile range [IQR]: 1.2% to 7.6%). Thirty-day readmit rate was 2.6% (IQR: 0% to 5.9%) and median LOS was 8.0 days (IQR: 6.5 to 9.2). In the multivariate Cox regression, 30-day death rate (hazard ratio [HR], 1.89; 95% confidence interval [CI]: 1.32 to 2.71) and longer LOS (HR, 1.02; 95% CI: 1.01 to 1.02) were associated with worse survival. Higher 30-day readmission rate was associated with improved survival (HR, 0.61; 95% CI, 0.38 to 0.97). CONCLUSIONS: Hospital-level surrogate markers of surgical quality appear to be significantly associated with HCC survival following resection. Patients treated in higher 30-day mortality centers, experienced worse outcomes. Individual hospitals should critically review disease-specific outcomes following resection to identify areas for improvement.

Exploring the Genomic Landscape of Hepatobiliary Cancers to Establish a Novel Molecular Classification System.

Taxonomy of hepatobiliary cancer (HBC) categorizes tumors by location or histopathology (tissue of origin, TO). Tumors originating from different TOs can also be grouped by overlapping genomic alterations (GA) into molecular subtypes (MS). The aim of this study was to create novel HBC MSs. Next-generation sequencing (NGS) data from the AACR-GENIE database were used to examine the genomic landscape of HBCs. Machine learning and gene enrichment analysis identified MSs and their oncogenomic pathways. Descriptive statistics were used to compare subtypes and their associations with clinical and molecular variables. Integrative analyses generated three MSs with different oncogenomic pathways independent of TO (n = 324; p < 0.05). HC-1 "hyper-mutated-proliferative state" MS had rapidly dividing cells susceptible to chemotherapy; HC-2 "adaptive stem cell-cellular senescence" MS had epigenomic alterations to evade immune system and treatment-resistant mechanisms; HC-3 "metabolic-stress pathway" MS had metabolic alterations. The discovery of HBC MSs is the initial step in cancer taxonomy evolution and the incorporation of genomic profiling into the TNM system. The goal is the development of a precision oncology machine learning algorithm to guide treatment planning and improve HBC outcomes. Future studies should validate findings of this study, incorporate clinical outcomes, and compare the MS classification to the AJCC 8th staging system.

Merkel cell carcinoma: 30-year experience from a single institution.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare cutaneous malignancy. Few single-institution series have been reported. METHODS: Review of MCC patients treated at our institution between 1980 and 2010. Patient, tumor, and treatment variables were analyzed to determine MCC-specific outcomes. RESULTS: We identified 161 patients with MCC. There was a 2.5-fold increase in cases over the last decade. Median length of follow-up was 36 months. Stage at diagnosis was I in 35 %, II in 21 %, IIIa in 12 %, IIIb in 23 %, and IV in 9 %. The 5-year MCC-specific survival rates were 87, 63, 42, and 0 % for stages I, II, III, and IV, respectively. Death from the disease occurred in 10 % of patients with T1 and in 50 % with larger lesions. One-third of patients presented with nodal disease. Sentinel lymph node biopsy (SLNB) identified micrometastases in 9 out of 27 (33 %) early-stage patients. Recurrence developed in 56 % of SLNB-positive and 39 % of SLNB-negative patients. Half of patients recurred after a median time of 9 months. Proportions of first recurrence location were distant (52 %), nodal (27 %), and local (21 %). Adjuvant treatments did not improve recurrence or survival rates. One-third of patients died of the disease. CONCLUSIONS: SLNB identifies micrometastasis in one-third of early-stage patients. Negative SLNB may predict for improved but not necessarily favorable outcome. Initial tumor size and clinical nodal disease predict for poor outcome. High recurrence rates warrant the development of more effective adjuvant therapies, and better markers of recurrence and treatment response for MCC are needed.

Disparities in the impact of the AJCC 8th edition staging system on differentiated thyroid cancer outcomes.

BACKGROUND: The impact of AJCC8 among self-reported racial/ethnic groups on differentiated thyroid cancer (DTC) outcomes is unknown. METHODS: Multivariate-regression evaluated the association between AJCC7 to AJCC8 stage change and race/ethnicity in patients with DTC in the NCDB. Cox-proportional-regression evaluated whether AJCC7 to AJCC8 stage change affects overall survival (OS) differently based on reported race/ethnicity. RESULTS: After adjusting for confounders, Hispanics and Asian-Pacific-Islanders (APIs) were 27% and 12% less likely to be down-staged compared to white-non-Hispanics (WNHs) (p < 0.001); black-non-Hispanics (BNHs) had no significant down-staging difference. Down-staged patients had an increased risk of death compared to patients with unchanged staging, regardless of race/ethnicity. However, based on two-way interaction, the magnitude of this negative change on survival from down-staging was only different between WNHs (HR = 2.64) and BNHs (HR = 1.77), (p = 0.04). CONCLUSIONS: Outcome disparities persist among self-reported racial/ethnic groups with AJCC8. Down-staged patients across all racial/ethnic groups had decreased survival compared to those with unchanged stage, with the least impact in BNHs.

Is surgical resection superior to transplantation in the treatment of hepatocellular carcinoma?

OBJECTIVE: To compare outcomes for patients with hepatocellular carcinoma (HCC) treated with either liver resection or transplantation. METHODS: A retrospective, single-institution analysis of 413 HCC patients from 1999 to 2009. RESULTS: A total of 413 patients with HCC underwent surgical resection (n = 106) and transplantation (n = 270) or were listed without receiving transplantation (n = 37). Excluding transplanted patients with incidental tumors (n = 50), 257 patients with suspected HCC were listed with the intent to transplant (ITT). The median diameter of the largest tumor by radiography was 6.0 cm in resected, 3.0 cm in transplanted, and 3.4 cm in the listed-but-not-transplanted patients. Median time to transplant was 48 days. Recurrence rates were 19.8% for resection and 12.1% for all ITT patients. Overall, patient survival for resection versus ITT patients was similar (5-year survival of 53.0% vs 52.0%, not significant). However, for HCC patients with model end-stage liver disease (MELD) scores less than 10 and who radiologically met Milan or UCSF (University of California, San Francisco) criteria, 1-year and 5-year survival rates were significantly improved in resected patients. For patients with MELD score less than 10 and who met Milan criteria, 1-year and 5-year survival were 92.0% and 63.0% for resection (n = 26) versus 83.0% and 41.0% for ITT (n = 73, P = 0.036). For those with MELD score less than 10 and met UCSF criteria, 1-year and 5-year survival was 94.0% and 62.0% for resection (n = 33) versus 81.0% and 40.0% for ITT (n = 78, P = 0.027). CONCLUSIONS: Among known HCC patients with preserved liver function, resection was associated with superior patient survival versus transplantation. These results suggest that surgical resection should remain the first line therapy for patients with HCC and compensated liver function who are candidates for resection.

Prognostic Impact and Utility of Immunoprofiling in the Selection of Patients with Colorectal Peritoneal Carcinomatosis for Cytoreductive Surgery (CRS) and Heated Intraperitoneal Chemotherapy (HIPEC).

BACKGROUND: Recent studies have shown an association in non-metastatic colorectal cancer between patient survival and immunoprofiling (expression of CD3, CD4, CD8, CD45, and FOXP3 T cells at the invasive margin (IM) and the tumor center (TC)) regardless of stage. Patients with peritoneal carcinomatosis have a dismal prognosis, but survival can be significantly improved in selected patients who undergo cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). However, current patient selection for CRS/HIPEC is suboptimal. The purpose of this study is to evaluate immune profiles of patients with peritoneal carcinomatosis and their correlation with overall survival (OS). METHODS: The study cohort included patients from a prospectively maintained database of adults with colorectal peritoneal carcinomatosis who underwent CRS/HIPEC. Immunohistochemistry (IHC) using antibodies to CD3, CD4, CD8, CD45RO, and FOXP3 T cells was performed. IHC image density was calculated using ImageJ software, and an immunoscore was determined. RESULTS: Eighty tumors were evaluated from 66 patients. These included 14 primary sites and 66 metastatic sites. R0/R1 resection was achieved in 44 (66.7%) patients. Known prognostic factors including resection status (HR 1.99, p = 0.004) and lymph node status (HR 3.49, p = 0.002) were associated with overall survival. On multivariate analysis, increased CD3/CD4 IM (HR 0.54, p = 0.03) ratio positively was associated with improved OS. DISCUSSION: This is the first study to assess the utility of subtypes of T cells as prognostic markers in patients with colorectal peritoneal carcinomatosis, which may play a role in patients with low-volume disease. Further studies into immune mechanisms may improve patient selection for cytoreductive surgery and HIPEC as well as provide novel pathways for effective immunotherapy.

Csf1r or Mer inhibition delays liver regeneration via suppression of Kupffer cells.

INTRODUCTION: Murine Kupffer cells (KCs) comprise CD11bhi and F4/80hi subsets. Tissue-resident macrophages are known to express the tyrosine kinase receptors colony-stimulating factor 1 receptor (Csf1r) and Mer. However, the expression of Csf1r and Mer on KC subsets and the importance of these tyrosine kinases during liver regeneration (LR) are unknown. METHODS: KCs from wild-type and Csf1r-GFP mice were characterized by flow cytometry. Partial hepatectomy (PH) was performed in mice treated with clodronate liposomes, a Csf1r small molecule inhibitor or depleting antibody, or a small molecule Mer inhibitor. Sera and livers were analyzed. The function of sorted KC subsets was tested in vitro. RESULTS: Mer was specifically expressed on tissue-resident F4/80hi KCs, 55% of which also expressed Csf1r. Mer+Csf1r+ and Mer+Csf1r- KCs had distinct expression of macrophage markers. Csf1r inhibition in mice reduced F4/80hi KCs by approximately 50%, but did not affect CD11bhi KCs. Clodronate liposomes depleted F4/80hi KCs, but also altered levels of other intrahepatic leukocytes. Csf1r inhibition delayed LR, as demonstrated by a 20% reduction in liver-to-body weight ratios 7 days after PH. At 36h after PH, Csf1r inhibition increased serum ALT and histological liver injury, and decreased liver cell proliferation. A small molecule inhibitor of Mer did not alter the percentage of KCs or their proliferation and just modestly delayed LR. In vitro, Csf1r or Mer inhibition did not decrease KC viability, but did attenuate their cytokine response to stimulation. CONCLUSIONS: F4/80hi KCs are Mer+ and can be subdivided based on Csf1r expression. Csf1r or Mer inhibition each reduces KC cytokine production and delays LR.

Left Shoulder Fungating Mass in a 46-Year-Old Man.

A 46-year-old man presented with a left shoulder mass. He reported limited shoulder movements and denied other symptoms. What is your diagnosis?

Left Axilla Adenocarcinoma of Unknown Origin.

A 76-year-old woman presents with a palpable left axillary mass, yet no breast lesions are found. What is your diagnosis?

Wnt/ß-catenin Signaling Contributes to Tumor Malignancy and Is Targetable in Gastrointestinal Stromal Tumor.

Gastrointestinal stromal tumor (GIST) is the most common type of sarcoma and usually harbors either a KIT or PDGFRA mutation. However, the molecular basis for tumor malignancy is not well defined. Although the Wnt/ß-catenin signaling pathway is important in a variety of cancers, its role in GIST is uncertain. Through analysis of nearly 150 human GIST specimens, we found that some human GISTs expressed ß-catenin and contained active, dephosphorylated nuclear ß-catenin. Furthermore, advanced human GISTs expressed reduced levels of the Wnt antagonist DKK4. Accordingly, in human GIST T1 cells, Wnt stimulation increased ß-catenin-mediated transcriptional activity in a reporter assay as well as transcription of the downstream target genes Axin2 and CCND1 In contrast, DKK4 overexpression in GIST T1 cells reduced Wnt/ß-catenin signaling. In addition, we showed that nuclear ß-catenin stability was partially regulated by the E3 ligase COP1, as demonstrated with coimmunoprecipitation and COP1 knockdown. Three molecular inhibitors of the Wnt/ß-catenin pathway demonstrated antitumor efficacy in various GIST models, both in vitro and in vivo Notably, the tankyrase inhibitor G007-LK alone had substantial activity against tumors of genetically engineered KitV558Δ/+ mice, and the effect was increased by the addition of the Kit inhibitor imatinib mesylate. Collectively, our findings demonstrate that Wnt/ß-catenin signaling is a novel therapeutic target for selected untreated or imatinib-resistant GISTs. Mol Cancer Ther; 16(9); 1954-66. ©2017 AACR.

Ganglioneuroma of the pancreas in a 4-year-old girl.

Ganglioneuroma (GN) is the uncommon, benign representative of the peripheral neuroblastic tumours (PNTs), which arise from primitive sympathetic ganglion cells. PNTs comprise one of the most common groups of neoplastic diseases in infants and children, but its occurrence in the pancreas is rare. We report a 4-year-old girl with GN of the pancreas requiring pancreaticoduodenectomy as a definitive therapy and with a great outcome, and we review the published literature.