Correlation of tumor microenvironment from biopsy and resection specimens in untreated colorectal cancer patients: a surprising lack of agreement.

BACKGROUND: Colorectal cancer (CRC) tumor microenvironment (TME) characteristics, such as tumor infiltrating lymphocyte (TIL) densities and PD-L1 status, are predictive of recurrence, disease-free survival, and overall survival. In many malignancies, TME characteristics are also predictive of response to immunotherapy. As window of opportunity studies using neoadjuvant immunotherapy become more common and treatment guidelines incorporate TME features, accurate assessment of the pre-treatment TME using the biopsy specimen is critical. However, no study has thoroughly evaluated the correlation between the TMEs of the biopsy and resection specimens. METHODS: We conducted a retrospective analysis of patients with stage I-III CRC with matched biopsy and resection specimens. CD3+, CD4+, CD8+, and FoxP3+ lymphocyte populations at the center of tumor (CT) and invasive margin (IM) and tumor PD-L1 status in the biopsy and resection specimens were evaluated. TIL populations were compared using Mann-Whitney U tests or Student's t tests and correlated using Pearson r. RESULTS: CD3+ and CD4+ densities were significantly higher in the CT of the biopsy relative to the resection specimen Comparing biopsy and resection specimens, no TIL population at either the CT or IM had a correlation coefficient > 0.5. Determining PD-L1 status based on biopsy tissue resulted in a sensitivity of 37.1%, specificity of 81.4%, and accuracy of 61.5%. CONCLUSIONS: These findings demonstrate significant discordance between the TME of the biopsy and resection specimens. Caution should be used when basing treatment decisions on pre-treatment endoscopic biopsy findings and when interpreting changes in the TME between pre-treatment biopsy and resection specimens after neoadjuvant therapy.

Effect of Topical Garlic on Wound Healing and Scarring: A Clinical Trial.

BACKGROUND: Historically, garlic containing compounds have been used on wounds to improve healing and ward off infection. Researchers have tested many of these ancient ointments, discovering that garlic is a common ingredient in those that are effective. OBJECTIVE: To determine the efficacy of topical garlic on surgical wounds compared with Vaseline by analysis of visual analog scales and digital photograph analysis. MATERIALS AND METHODS: Seventeen patients with 2 skin excisions applied a 30% garlic ointment to one surgical wound and Vaseline to the other surgical wound twice daily. They were followed up at 2 weeks and 4 weeks post-op. Digital photographs were taken of the sites, and wound visual analog scales were filled out by the patient and the physician. RESULTS: Patients and the onsite physician stated the garlic site healed better in 59% and 65% of the wounds, respectively, at 2 weeks. At 4 weeks, the patients and the onsite physician stated the garlic site healed better in 76% and 88% of wounds, respectively. Digital photograph analysis revealed less erythema at the garlic sites (p-value = .02). CONCLUSION: Surgical wounds treated with 30% garlic ointment healed with more cosmetically appealing scars than the Vaseline-treated sites.

Predictive value of basal cell carcinoma biopsies with negative margins: A retrospective cohort study.

BACKGROUND: Pathology reports of basal cell carcinoma (BCC) biopsies often contain comments of positive or negative margins, with only 1%-2% of the margin evaluated. The negative predictive value (NPV) of biopsy margin status on residual BCC is unknown. OBJECTIVE: The purpose of this study was to determine the NPV of BCC biopsy margin status on the absence of residual BCC in the corresponding excision. METHODS: From our institution's archives, we collected BCC biopsies with negative margin readings that had subsequent excisions. For excisions read as negative for residual BCC, the excision blocks were sectioned at 150-µm intervals until exhausted. RESULTS: We collected 143 cases that met criteria; 34 (24%) were found to contain residual BCC in the corresponding excision leading to a NPV of 76%; in 31 of 34 (91%) of these cases, the residual histologic subtype was superficial. LIMITATIONS: Our sectioning technique did not evaluate 100% of the excision specimens. CONCLUSION: Negative margins in a BCC biopsy are a poor predictor of residual disease in the patient. We recommend that clinicians treat these lesions, and that pathologists who comment on margin status of BCC biopsies consider adding a caveat to reflect these findings.

Mechanism of Action of Topical Garlic on Wound Healing.

BACKGROUND: Allicin, the active component of garlic, has been shown to have antimicrobial and anti-inflammatory properties. Garlic has also been used historically by many cultures to heal wounds. Several animal studies have shown that garlic extracts increase the rate of wound healing and decrease the rate of infection. OBJECTIVE: Fibroblasts play a key role in wound healing. Here we hypothesize that fibroblasts are being activated by allicin, leading to more organized and rapid wound repair. MATERIALS AND METHODS: Six rats were each given 2 surgical wounds. One side was treated with a 30% garlic ointment while the other was treated with Vaseline for two weeks. A biopsy was taken from each scar site and histopathology with Immunohistochemistry was performed to quantify the number of fibroblasts and proliferating fibroblasts in each site. RESULTS: The wound biopsies had more proliferating fibroblasts in the scars treated with the 30% garlic ointment than in the scars treated with Vaseline with a p-value of 0.0175 at two weeks post op and 0.081 at 6 week post op. CONCLUSION: This data tells us that allicin is acting on fibroblasts as there were more proliferating fibroblasts in the garlic treated sites than in the other sites.

A Case of Metastatic Chromophobe Renal Cell Carcinoma Masked as Suspected Hepatic Abscesses.

Background: Characterizing multiple hepatic lesions on cross-sectional imaging, particularly differentiating abscesses from metastatic lesions, can be challenging. Case Presentation: A male aged 53 years with a history of chromophobe renal cell carcinoma presented with fevers and abdominal pain and was found to have multiple hepatic lesions concerning for hepatic abscesses. The lesions initially evaded diagnosis on imaging, laboratory tests, and biopsy, but ultimately were determined to be a rare case of metastatic chromophobe renal cell carcinoma of the liver. Conclusions: The finding of multiple new liver lesions on imaging during a febrile illness is concerning for hepatic abscess or malignancy, which can be difficult to diagnose with imaging alone. Differentiation between infectious and neoplastic etiologies may require additional imaging and/or tissue sampling.

Autoimmune gastritis as an unexpected cause of diarrhea in a young adult with type I diabetes: a case report.

BACKGROUND: Type 1 diabetes mellitus (T1DM) is a lifelong diagnosis that involves immune-mediated damage of pancreatic beta cells and subsequent hyperglycemia, manifesting as: polyuria, polydipsia, polyphagia, and weight loss. Treatment of type 1 diabetes centers on insulin administration to replace or supplement the body's own insulin with the goal of achieving euglycemia and preventing or minimizing complications. Patients with T1DM are at risk for developing other autoimmune conditions, most commonly thyroid or celiac disease. CASE PRESENTATION: A 20-year-old African American female with T1DM was referred by her endocrinologist to pediatric gastroenterology for 2 months of nocturnal, non-bloody diarrhea, left lower quadrant pain, and nausea; she was also being followed by neurology for complaints of lower extremity paresthesias and pain. The patient's initial lab-workup was remarkable for a low total Immunoglobulin A (IgA) level of < 6.7 mg/dL. As IgA deficiency is associated with an increased risk of celiac disease, the patient underwent upper and lower endoscopy, which was grossly unremarkable; however, histology revealed a pattern consistent with autoimmune gastritis. Subsequent serum evaluation was remarkable for an elevated fasting gastrin level and an elevated parietal cell antibody level without macrocytic anemia, iron deficiency, or vitamin B12 depletion. The patient was diagnosed with autoimmune gastritis (AIG) and subsequently initiated on parenteral B12 supplementation therapy with improvement in her neurologic and gastrointestinal symptoms. CONCLUSION: This case illustrates the importance of recognition of red flag findings in a patient with known autoimmune disease. Following well-established health maintenance recommendations for individuals with T1DM ensures that common comorbidities will be detected. Autoimmune gastritis, while a rarer pathology in the pediatric population, deserves consideration in patients with pre-existing autoimmune conditions and new gastrointestinal or neurologic symptoms, as AIG can be associated with poor outcomes and risk of malignancy. Initial lab findings associated with an eventual diagnosis of AIG typically include anemia, iron deficiency, or Vitamin B12 deficiency. However, as demonstrated in this case, symptoms of AIG can rarely present before anemia or Vitamin B12 deficiency develops. To prevent permanent neurological damage, parenteral Vitamin B12 therapy must be considered even in the absence of Vitamin B12 deficiency, especially in those patients already experiencing neurological symptoms.

Expression and Potential Prognostic Value of SOX9, MCL-1 and SPOCK1 in Gastric Adenocarcinoma.

Gastric cancer is a common malignancy and remains one of the leading causes of cancer-related deaths, though its incidence is in decline in most developed countries. One of the major challenges of treating gastric cancer is tumor heterogeneity, which portends a high degree of prognostic variance and the necessity for different treatment modalities. Tumor heterogeneity is at least in part due to divergent differentiation of tumor cells to clones harboring different molecular alterations. Here we studied the expression of emerging prognostic markers SOX9, MCL-1, and SPOCK1 (Testican-1) in a cohort of gastric cancer by immunohistochemistry and investigated how individual biomarkers and their combinations predict disease prognosis. We found frequent expression of SPOCK1 (in both nuclei and cytoplasm), MCL-1 and SOX9 in gastric cancer. In univariate analysis, nuclear SPOCK1 expression and pathologic TNM stage were negative prognostic markers in this cohort. In multivariate analysis, SOX9 expression stood out as a predictor of poor prognosis. Further subgroup analysis suggested prognostic value of SOX9 expression in poorly differentiated gastric adenocarcinoma. MCL-1 showed no prognostic role in this cohort.

Disruption of Growth Hormone Receptor Signaling Abrogates Hepatocellular Carcinoma Development.

Introduction: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancers. It is an aggressive neoplasm with dismal outcome because most of the patients present with an advanced-stage disease, which precludes curative surgical options. Therefore, these patients require systemic therapies that typically induce small improvements in overall survival. Hence, it is crucial to identify new and promising therapeutic targets for HCC to improve the current outcome. The liver is a key organ in the signaling cascade triggered by the growth hormone receptor (GHR). Previous studies have shown that GHR signaling stimulates the proliferation and regeneration of liver cells and tissues; however, a definitive role of GHR signaling in HCC pathogenesis has not been identified. Methods: In this study, we used a direct and specific approach to analyze the role of GHR in HCC development. This approach encompasses mice with global (Ghr-/- ) or liver-specific (LiGhr-/- ) disruption of GHR expression, and the injection of diethylnitrosamine (DEN) to develop HCC in these mice. Results: Our data show that DEN induced HCC in a substantial majority of the Ghr+/+ (93.5%) and Ghr +/- (87.1%) mice but not in the Ghr-/- (5.6%) mice (P < 0.0001). Although 57.7% of LiGhr-/- mice developed HCC after injection of DEN, these mice had significantly fewer tumors than LiGhr+/+ (P < 0.001), which implies that the expression of GHR in the liver cells might increase tumor burden. Notably, the pathologic, histologic, and biochemical characteristics of DEN-induced HCC in mice resembled to a great extent human HCC, despite the fact that etiologically this model does not mimic this cancer in humans. Our data also show that the effects of DEN on mice livers were primarily related to its carcinogenic effects and ability to induce HCC, with minimal effects related to toxic effects. Conclusion: Collectively, our data support an important role of GHR in HCC development, and suggest that exploiting GHR signaling may represent a promising approach to treat HCC.

Blockade of growth hormone receptor signaling by using pegvisomant: A functional therapeutic strategy in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is an aggressive neoplasm with poor clinical outcome because most patients present at an advanced stage, at which point curative surgical options, such as tumor excision or liver transplantation, are not feasible. Therefore, the majority of HCC patients require systemic therapy. Nonetheless, the currently approved systemic therapies have limited effects, particularly in patients with advanced and resistant disease. Hence, there is a critical need to identify new molecular targets and effective systemic therapies to improve HCC outcome. The liver is a major target of the growth hormone receptor (GHR) signaling, and accumulating evidence suggests that GHR signaling plays an important role in HCC pathogenesis. We tested the hypothesis that GHR could represent a potential therapeutic target in this aggressive neoplasm. We measured GH levels in 767 HCC patients and 200 healthy controls, and then carried out clinicopathological correlation analyses. Moreover, specific inhibition of GHR was performed in vitro using siRNA and pegvisomant (a small peptide that blocks GHR signaling and is currently approved by the FDA to treat acromegaly) and in vivo, also using pegvisomant. GH was significantly elevated in 49.5% of HCC patients, and these patients had a more aggressive disease and poorer clinical outcome (P<0.0001). Blockade of GHR signaling with siRNA or pegvisomant induced substantial inhibitory cellular effects in vitro. In addition, pegvisomant potentiated the effects of sorafenib (P<0.01) and overcame sorafenib resistance (P<0.0001) in vivo. Mechanistically, pegvisomant decreased the phosphorylation of GHR downstream survival proteins including JAK2, STAT3, STAT5, IRS-1, AKT, ERK, and IGF-IR. In two patients with advanced-stage HCC and high GH who developed sorafenib resistance, pegvisomant caused tumor stability. Our data show that GHR signaling represents a novel "druggable" target, and pegvisomant may function as an effective systemic therapy in HCC. Our findings could also lead to testing GHR inhibition in other aggressive cancers.

Hepatic mast cell concentration directly correlates to stage of fibrosis in NASH.

Mast cells are present throughout the body in low numbers. We know their role in immediate hypersensitivity and the subsequent tissue damage due to release of cytokines, vasoactive amines, and lipid mediators when mast cells are activated. Recent research has found that there is an association between an increased concentration of mast cells in the liver and the severity of hepatic fibrosis in animal models. We currently don't understand the role of mast cells in the liver with regard to fibrosis. This retrospective review study investigated whether there is a correlation between stages of fibrosis and mast cell concentrations. One hundred six tissue slides were collected from a large military hospital of known cases of unremarkable liver, non-alcoholic fatty liver disease (Non-NASH NAFLD), and each stage of NASH (Non-alcoholic steatohepatitis). These were analyzed by staining the slides with tryptase to highlight and quantify the mast cell concentration in each diagnostic category. Three pathologists counted mast cells in five 400× fields (1 square mm) in both the periportal and parenchymal regions of each slide. These numbers were recorded and analyzed with a t test, demonstrating an increase in mast cells in NASH stage 3-4 fibrosis compared to unremarkable liver (35.48 versus 18.23, respectively, P < .001) and a direct correlation (r = 0.287) between the number of mast cells and the stage of fibrosis. Better characterizing the role of mast cells in the development of hepatic fibrosis gives us a greater understanding of the pathophysiology of non-NASH NAFLD and NASH and possibly a pharmaceutical target.