Cutaneous squamous cell carcinoma metastasis to parotid, analysis of outcomes with positive margins at initial resection

"Several studies have been conducted evaluating prognostic factors in primary salivary gland cancer as well as in cutaneous squamous cell carcinoma (SCCa) with metastasis to the salivary glands. However, there is currently a gap in the literature regarding the outcomes specifically related to positive margins at initial marginal analysis for cutaneous SCCa in patients with metastasis to the parotid. Patients with metastasis of cutaneous squamous cell carcinoma (SCCa) to intraparotid lymph nodes are often treated with parotidectomy (Figures 2 and 3) and neck dissection (Figure 1). Pathology reports may comment on the presence of carcinoma at the inked edge of a specimen, but the clinical significance of this 'positive margin' is understudied. With this study, we aim to expand on the current literature to specifically evaluate overall survival and disease-free survival rates in patients who underwent surgery with parotidectomy and neck dissection for metastatic SCCa to the parotid gland."--Introduction

Taking Free Flap Surgery Abroad: A Collaborative Approach to a Complex Surgical Problem.

Accessibility to health care, especially complex surgical care, represents one of the major health care disparities in developing countries. While surgical teams may be willing to travel to these areas to help address these needs, there are many logistical and ethical dilemmas inherent in this pursuit. We reviewed our approach to the establishment of the team-based surgical outreach program, wherein we perform head and neck free tissue transfer surgery in Haiti. We describe the challenges encountered in the delivery of surgical care as well as ethical dilemmas relevant to surgical outreach trips, highlighting an approach reliant on strong local cooperation. Despite the obstacles in place, our experience shows that free flap surgery can be successfully and ethically performed in these areas of great need

Transarterial chemoembolization is ineffective for neuroendocrine tumors metastatic to the caudate lobe: a single institution review.

BACKGROUND: Caudate lobe liver metastases occur commonly in patients with neuroendocrine tumors. It is unknown, however, how these lesions respond to regional therapy and how their presence impacts outcomes. We reviewed our experience treating these lesions using transarterial chemoembolization (TACE). METHODS: We reviewed radiographic response to TACE in 86 patients with metastatic neuroendocrine tumors to the liver. We determined the impact of caudate lesions on outcomes in comparison to the cohort of patients without caudate lesions, as well as response of caudate lesions to TACE versus lesions elsewhere in the liver. RESULTS: Caudate lesions were identified in 45 (52%) patients. All patients had disease in other liver segments. Only seven caudate lesions (12.3%) had a radiographic response to TACE, whereas 82% of lesions elsewhere in the liver demonstrated a response. The presence or absence of a caudate lesion did not impact the overall radiographic (82.2% vs. 82.9%), symptomatic (64.4% vs. 56.1%), or biochemical (97.6% vs. 88.9%) response to TACE (P \u3e 0.1 for all). However, median overall survival was reduced in those presenting with caudate lesions (87.1 vs. 45.6 months, P = 0.031). CONCLUSIONS: Metastatic neuroendocrine tumors to the caudate lobe respond poorly to TACE. Symptomatic or threatening caudate lobe lesions should be considered for palliative resection in spite of additional inoperable liver metastases

TP53-inducible Glycolysis and Apoptosis Regulator (TIGAR) Metabolically Reprograms Carcinoma and Stromal Cells in Breast Cancer.

A subgroup of breast cancers has several metabolic compartments. The mechanisms by which metabolic compartmentalization develop in tumors are poorly characterized. TP53 inducible glycolysis and apoptosis regulator (TIGAR) is a bisphosphatase that reduces glycolysis and is highly expressed in carcinoma cells in the majority of human breast cancers. Hence we set out to determine the effects of TIGAR expression on breast carcinoma and fibroblast glycolytic phenotype and tumor growth. The overexpression of this bisphosphatase in carcinoma cells induces expression of enzymes and transporters involved in the catabolism of lactate and glutamine. Carcinoma cells overexpressing TIGAR have higher oxygen consumption rates and ATP levels when exposed to glutamine, lactate, or the combination of glutamine and lactate. Coculture of TIGAR overexpressing carcinoma cells and fibroblasts compared with control cocultures induce more pronounced glycolytic differences between carcinoma and fibroblast cells. Carcinoma cells overexpressing TIGAR have reduced glucose uptake and lactate production. Conversely, fibroblasts in coculture with TIGAR overexpressing carcinoma cells induce HIF (hypoxia-inducible factor) activation with increased glucose uptake, increased 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3), and lactate dehydrogenase-A expression. We also studied the effect of this enzyme on tumor growth. TIGAR overexpression in carcinoma cells increases tumor growth in vivo with increased proliferation rates. However, a catalytically inactive variant of TIGAR did not induce tumor growth. Therefore, TIGAR expression in breast carcinoma cells promotes metabolic compartmentalization and tumor growth with a mitochondrial metabolic phenotype with lactate and glutamine catabolism. Targeting TIGAR warrants consideration as a potential therapy for breast cancer

A Randomized Controlled Trial of Sertraline in Young Children With Autism Spectrum Disorder.

Objective: Selective serotonin reuptake inhibitors like sertraline have been shown in observational studies and anecdotal reports to improve language development in young children with fragile X syndrome (FXS). A previous controlled trial of sertraline in young children with FXS found significant improvement in expressive language development as measured by the Mullen Scales of Early Learning (MSEL) among those with comorbid autism spectrum disorder (ASD) in post hoc analysis, prompting the authors to probe whether sertraline is also indicated in nonsyndromic ASD. Methods: The authors evaluated the efficacy of 6 months of treatment with low-dose sertraline in a randomized, double-blind, placebo-controlled trial in 58 children with ASD aged 24 to 72 months. Results: 179 subjects were screened for eligibility, and 58 were randomized to sertraline (32) or placebo (26). Eight subjects from the sertraline arm and five from the placebo arm discontinued. Intent-to-treat analysis showed no significant difference from placebo on the primary outcomes (MSEL expressive language raw score and age equivalent combined score) or secondary outcomes. Sertraline was well tolerated, with no difference in side effects between sertraline and placebo groups. No serious adverse events possibly related to study treatment occurred. Conclusion: This randomized controlled trial of sertraline treatment showed no benefit with respect to primary or secondary outcome measures. For the 6-month period, treatment in young children with ASD appears safe, although the long-term side effects of low-dose sertraline in early childhood are unknown. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02385799

Stromal Monocarboxylate Transporter MCT4 is a Poor Prognostic Factor in Squamous Cell Carcinoma

ABSTRACT Introduction: Monocarboxylate transporter 4 (MCT4) is the main exporter of lactate out of cells. It is also a critical component in the glycolytic metabolism of cancer cells. In this study, stromal MCT4 in oral SCC was correlated with risk of recurrence (ROR), extent of primary tumor (pT) and nodal metastasis (pN), perineural invasion (PNI), lymphovascular invasion (LVI), HPV status, extracapsular extension (ECE) and positive margin. Methods: Clinical data were collected for 86 consecutive patients with oral HNSCC. Tissue microarrays (TMA) were constructed from paraffin blocks of resection specimens and stained for MCT4. Immunohistochemistry (IHC) staining was assessed and quantified by digital image analysis with Aperio software. Using a co-localization algorithm we assessed the intensity of staining and the percentage of positive cells in the tumoral stromal cells. Correlations of MCT4 expression with clinicopathological features and survival were studied. Results: Increased IHC staining for MCT4 was strongly associated with an increased risk of recurrence, OR 1.96 (95%CI: 1.17-3.40), presence of PNI, OR 2.25 (95%CI: 1.33-3.95), higher pT, OR 1.68 (95%CI: 0.99-2.89), higher pN, OR 2.07 (95%CI: 1.25-3.57) and presence of LVI, OR 2.21 (95%CI: 1.11-4.67). We didn’t find any significant association between stromal MCT4 expression and HPV status, presence of ECE or positive margin. Conclusions: This study demonstrates that MCT4, a marker of glycolysis in cancer-associated stroma, is highly expressed in oral SCC. The IHC staining pattern of stromal MCT4 suggests that high MCT4 expression appears to be a useful marker for tumor progression and prognosis. We propose MCT4 serves as a new prognostic factor in oral SCC and can act as a potential therapeutic target marker considering pharmacological development of MCT4 inhibitors

Tumor Metabolism in the Microenvironment of Nodal Metastasis in Head and Neck Squamous Cell Carcinoma

ABSTRACT Introduction: Monocarboxylate transporter 4 (MCT4) is a cell membrane transporter of lactate. MCT4 is a tumor-specific marker of oxidative stress, glycolysis and hypoxia in tumor stromal cells. We investigated HPV positive and negative tumors with regional metastases to cervical lymph nodes (LN) to study how the metastatic tumor cells interact with their microenvironment. By selecting cancers with extracapsular extension (ECE), we intended to evaluate the interaction between metastases and the surrounding extranodal tissue. Methods: Clinical data were collected from 24 advanced stage oropharyngeal squamous cell carcinoma (OPSCC) patients with neck LN metastasis. All patients presented with at least N1 disease and had ECE. Sixteen cases were negative for HPV and eight were positive. Ten patients (42%) had ECE \u3c 1 mm, and 14 (58%) had ECE \u3e than 1 mm. The extent of ECE was quantified on H&E stains by distance from the edge of capsule. The paraffin-embedded metastatic LN sections were stained with MCT4 and quantification was accomplished using the Aperio Co-localization algorithm. Results: High stromal MCT4 expression was strongly associated with the extent of ECE regardless of HPV status (p=0.031). The stromal MCT4 expression in ECE area was significantly higher as opposed to the surrounding extranodal tissue adjacent to intact capsule (p\u3c0.001). We also found a borderline difference in expression of MCT4 in HPV- LN with ECE \u3e1mm vs. \u3c1mm(p=0.06). Conclusions: MCT4 is a marker of oxidative stress and higher expression of stromal MCT4 in ECE area is significantly correlated with the extent of ECE. The stromal cells separating nests of cancer cells in ECE area have apparent expression of the MCT4. Together these findings provide new insight into the critical role of stromal MCT4 in nodal metastasis and ECE in OPSCC and it may be useful to develop a novel prognostic marker and new anti-cancer agents

TP53-inducible Glycolysis and Apoptosis Regulator (TIGAR) Metabolically Reprograms Carcinoma and Stromal Cells in Breast Cancer

A subgroup of breast cancers has several metabolic compartments. The mechanisms by which metabolic compartmentalization develop in tumors are poorly characterized. TP53 inducible glycolysis and apoptosis regulator (TIGAR) is a bisphosphatase that reduces glycolysis and is highly expressed in carcinoma cells in the majority of human breast cancers. Hence we set out to determine the effects of TIGAR expression on breast carcinoma and fibroblast glycolytic phenotype and tumor growth. The overexpression of this bisphosphatase in carcinoma cells induces expression of enzymes and transporters involved in the catabolism of lactate and glutamine. Carcinoma cells overexpressing TIGAR have higher oxygen consumption rates and ATP levels when exposed to glutamine, lactate, or the combination of glutamine and lactate. Coculture of TIGAR overexpressing carcinoma cells and fibroblasts compared with control cocultures induce more pronounced glycolytic differences between carcinoma and fibroblast cells. Carcinoma cells overexpressing TIGAR have reduced glucose uptake and lactate production. Conversely, fibroblasts in coculture with TIGAR overexpressing carcinoma cells induce HIF (hypoxia-inducible factor) activation with increased glucose uptake, increased 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3), and lactate dehydrogenase-A expression. We also studied the effect of this enzyme on tumor growth. TIGAR overexpression in carcinoma cells increases tumor growth in vivo with increased proliferation rates. However, a catalytically inactive variant of TIGAR did not induce tumor growth. Therefore, TIGAR expression in breast carcinoma cells promotes metabolic compartmentalization and tumor growth with a mitochondrial metabolic phenotype with lactate and glutamine catabolism. Targeting TIGAR warrants consideration as a potential therapy for breast cancer

A Quantitative Assessment of Tremor and Ataxia in Female FMR1

The fragile X-associated tremor/ataxia syndrome (FXTAS) is a relatively common cause of balance problems leading to gait disturbances in older males (40%) with the premutation. FXTAS is less common in females. We utilized the CATSYS system, a quantitative measure of movement, in 23 women with FXTAS (mean age 62.7; SD 12.3), 90 women with the premutation without FXTAS (mean age 52.9; SD 9.4), and 37 controls (mean age 56.53; SD 7.8). CATSYS distinguished differences between carriers with and without FXTAS in postural tremor, postural sway, hand coordination, and reaction time tasks. Differences were also seen between carriers without FXTAS and controls in finger tapping, reaction time, and one postural sway task. However, these differences did not persist after statistical correction for multiple comparisons. Notably, there were no differences across groups in intention tremor. This is likely due to the milder symptoms in females compared to males with FXTAS

Metformin Clinical Trial in HPV+ and HPV– Head and Neck Squamous Cell Carcinoma: Impact on Cancer Cell Apoptosis and Immune Infiltrate

Background: Metformin, an oral anti-hyperglycemic drug which inhibits mitochondrial complex I and oxidative phosphorylation has been reported to correlate with improved outcomes in head and neck squamous cell carcinoma (HNSCC) and other cancers. This effect is postulated to occur through disruption of tumor-driven metabolic and immune dysregulation in the tumor microenvironment (TME). We report new findings on the impact of metformin on the tumor and immune elements of the TME from a clinical trial of metformin in HNSCC.Methods: Human papilloma virus—(HPV–) tobacco+ mucosal HNSCC samples (n = 12) were compared to HPV+ oropharyngeal squamous cell carcinoma (OPSCC) samples (n = 17) from patients enrolled in a clinical trial. Apoptosis in tumor samples pre- and post-treatment with metformin was compared by deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Metastatic lymph nodes with extra-capsular extension (ECE) in metformin-treated patients (n = 7) were compared to archival lymph node samples with ECE (n = 11) for differences in immune markers quantified by digital image analysis using co-localization and nuclear algorithms (PD-L1, FoxP3, CD163, CD8).Results: HPV–, tobacco + HNSCC (mean Δ 13.7/high power field) specimens had a significantly higher increase in apoptosis compared to HPV+ OPSCC specimens (mean Δ 5.7/high power field) (p < 0.001). Analysis of the stroma at the invasive front in ECE nodal specimens from both HPV—HNSCC and HPV+ OPSCC metformin treated specimens showed increased CD8+ effector T cell infiltrate (mean 22.8%) compared to archival specimens (mean 10.7%) (p = 0.006). Similarly, metformin treated specimens showed an increased FoxP3+ regulatory T cell infiltrate (mean 9%) compared to non-treated archival specimens (mean 5%) (p = 0.019).Conclusions: This study presents novel data demonstrating that metformin differentially impacts HNSCC subtypes with greater apoptosis in HPV—HNSCC compared to HPV+ OPSCC. Moreover, we present the first in vivo human evidence that metformin may also trigger increased CD8+ Teff and FoxP3+ Tregs in the TME, suggesting an immunomodulatory effect in HNSCC. Further research is necessary to assess the effect of metformin on the TME of HNSCC