Global trends in esophageal cancer.

BACKGROUND AND OBJECTIVES: Esophageal Cancer (EC) is a lethal malignancy with poor prognosis and significant variations in the incidence, mortality, and histopathology based on geographic regions. The aim of this study was to quantitatively analyze these variations to identify patterns and areas for further research. METHODS: We utilized the GLOBOCAN 2012, and Cancer Incidence in five Continents, Volume X (CI5X) database to analyze variations in EC incidence and mortality. RESULTS: We found the EC incidence and mortality is geographically varied with a particularly high burden in East Asia and Eastern/Southern Africa where esophageal squamous cell carcinoma (SCC) predominates over adenocarcinoma (AC). Interestingly, there is a dichotomy between the high incidence of esophageal SCC in East Africa and low incidence in West Africa. The global incidence and mortality from EC is expected to rise in the coming decades. Asia, and China in particular, will continue to be the areas most burdened by EC, while Africa is expected to surpass the incidence and mortality rates of Europe. CONCLUSIONS: The global burden of EC is expected to rise in the coming years. Understanding the geographic, environmental, and genetic contributors to the development of EC will be essential in combating its prevalence.

Neoadjuvant treatment of pancreatic adenocarcinoma: a systematic review and meta-analysis of 5520 patients.

BACKGROUND: Recent years have seen standardization of the anatomic definitions of pancreatic adenocarcinoma, and increasing utilization of neoadjuvant therapy (NAT). The aim of the current review was to summarize the evidence for NAT in pancreatic adenocarcinoma since 2009, when consensus criteria for resectable (R), borderline resectable (BR), and locally advanced (LA) disease were endorsed. METHODS: PubMed search was undertaken along with extensive backward search of the references of published articles to identify studies utilizing NAT for pancreatic adenocarcinoma. Abstracts from ASCO-GI 2014 and 2015 were also searched. RESULTS: A total of 96 studies including 5520 patients were included in the final quantitative synthesis. Pooled estimates revealed 36% grade ≥ 3 toxicities, 5% biliary complications, 21% hospitalization rate and low mortality (0%, range 0-16%) during NAT. The majority of patients (59%) had stable disease. On an intention-to-treat basis, R0-resection rates varied from 63% among R patients to 23% among LA patients. R0 rates were > 80% among all patients who were resected after NAT. Among R and BR patients who underwent resection after NAT, median OS was 30 and 27.4 months, respectively. CONCLUSIONS: The current study summarizes the recent literature for NAT in pancreatic adenocarcinoma and demonstrates improving outcomes after NAT compared to those historically associated with a surgery-first approach for pancreatic adenocarcinoma.

The role of Sox9 in mouse mammary gland development and maintenance of mammary stem and luminal progenitor cells.

BACKGROUND: Identification and characterization of molecular controls that regulate mammary stem and progenitor cell homeostasis are critical to our understanding of normal mammary gland development and its pathology. RESULTS: We demonstrate that conditional knockout of Sox9 in the mouse mammary gland results in impaired postnatal development. In short-term lineage tracing in the postnatal mouse mammary gland using Sox9-CreER driven reporters, Sox9 marked primarily the luminal progenitors and bipotent stem/progenitor cells within the basal mammary epithelial compartment. In contrast, long-term lineage tracing studies demonstrate that Sox9+ precursors gave rise to both luminal and myoepithelial cell lineages. Finally, fate mapping of Sox9 deleted cells demonstrates that Sox9 is essential for luminal, but not myoepithelial, lineage commitment and proliferation. CONCLUSIONS: These studies identify Sox9 as a key regulator of mammary gland development and stem/progenitor maintenance.

Telomerase-immortalized human mammary stem/progenitor cells with ability to self-renew and differentiate.

There is increasing evidence that breast and other cancers originate from and are maintained by a small fraction of stem/progenitor cells with self-renewal properties. Whether such cancer stem/progenitor cells originate from normal stem cells based on initiation of a de novo stem cell program, by reprogramming of a more differentiated cell type by oncogenic insults, or both remains unresolved. A major hurdle in addressing these issues is lack of immortal human stem/progenitor cells that can be deliberately manipulated in vitro. We present evidence that normal and human telomerase reverse transcriptase (hTERT)-immortalized human mammary epithelial cells (hMECs) isolated and maintained in Dana-Farber Cancer Institute 1 (DFCI-1) medium retain a fraction with progenitor cell properties. These cells coexpress basal (K5, K14, and vimentin), luminal (E-cadherin, K8, K18, or K19), and stem/progenitor (CD49f, CD29, CD44, and p63) cell markers. Clonal derivatives of progenitors coexpressing these markers fall into two distinct types--a K5(+)/K19(-) type and a K5(+)/K19(+) type. We show that both types of progenitor cells have self-renewal and differentiation ability. Microarray analyses confirmed the differential expression of components of stem/progenitor-associated pathways, such as Notch, Wnt, Hedgehog, and LIF, in progenitor cells compared with differentiated cells. Given the emerging evidence that stem/progenitor cells serve as precursors for cancers, these cellular reagents represent a timely and invaluable resource to explore unresolved questions related to stem/progenitor origin of breast cancer.

Defining MRI Superiority over CT for Colorectal and Neuroendocrine Liver Metastases.

BACKGROUND: We compared CT and MRI for staging metastatic colorectal or neuroendocrine liver metastases (CRLMs and NELMs, respectively) to assess their impact on tumor burden. METHODS: A prospectively maintained database was queried for patients who underwent both imaging modalities within 3 months, with two blinded radiologists (R1 and R2) independently assessing the images for liver lesions. To minimize recall bias, studies were grouped by modality, and were randomized and evaluated separately. RESULTS: Our query yielded 76 patients (42 CRLMs; 34 NELMs) with low interrater variability (intraclass correlation coefficients: CT = 0.941, MRI = 0.975). For CRLMs, there were no significant differences in lesion number or size between CT and MRI. However, in NELMs, Eovist®-enhanced MRI detected more lesions (R1: 14.3 vs. 12.1, p = 0.02; R2: 14.4 vs. 12.4, p = 0.01) and smaller lesions (R1: 5.7 vs. 4.4, p = 0.03; R2: 4.8 vs. 2.9, p = 0.02) than CT. CONCLUSIONS: CT and MRI are equivalent for CRLMs, but for NELMs, MRI outperforms CT in detecting more and smaller lesions, potentially influencing treatment planning and surgery.

Sternal fixation for isolated traumatic sternal fractures improves pain and upper extremity range of motion.

INTRODUCTION: Sternal fractures are debilitating due to intractable pain, constant fracture movement and limited range of motion (ROM) of the upper extremities (UE). Traditional treatment comprises mainly of pain control, delaying return to daily activities. Recently, sternal fixation has gained popularity. There is, however, a lack of literature demonstrating efficacy. We report our experience of traumatically fractured sternal fixation. METHODS: Following IRB approval, a retrospective chart review was completed for all patients undergoing sternal fixation by a single trauma surgeon at our Level I trauma center. Basic demographics were obtained. Primary outcomes included average cumulative pain scores, total cumulative narcotic amounts and total number of pain medication agents utilized prior to and after sternal fixation. Secondary outcome included physical therapy UE ROM before and after surgery. Paired t tests were used for comparison; significance set at p < 0.05. RESULTS: Thirteen patients underwent sternal fixation from 8/2016 to 2/2018. Average age was 54.4 ± 20.8 years; 54% were female. All patients experienced blunt trauma; average injury severity score was 15.8 ± 10.9 and abbreviated chest injury score was 2.5 ± 0.51. Average intensive care unit/hospital length of stay was 2.3/10.2 days. Average pain scores significantly improved by a score of 3.5 postoperatively (preoperative = 7.08 ± 2.3, postoperative = 3.54 ± 2.5; p = 0.001). Total pain medications required by sternal fixation patients significantly decreased by 1 medication postoperatively (preoperative = 4.2 medications, postoperative = 3.2 medications; p = 0.002). Average narcotic requirements significantly decreased by 7.59 morphine milligram milliequivalents (MME) after sternal fixation (preoperative amount = 71.78 MME, postoperative amount = 64.19 MME; p = 0.041). Every patient had limited UE ROM preoperatively; however, all but one patient resumed full UE ROM postoperatively (p < 0.001). There were no postoperative complications. CONCLUSIONS: Sternal fixation is a safe and effective procedure resulting in improved pain, decreased narcotic requirements, and faster recovery.

Pandemic Operating Room Supply Shortage and Surgical Site Infection: Considerations as We Emerge from the Coronavirus Disease 2019 Pandemic.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic created shortages of operating room (OR) supplies, forcing healthcare systems to make concessions regarding "standard" OR attire. At our institution, we were required to reduce shoe covers, reuse face masks, and allow washable head coverings. We determined if these changes affected surgical site infection (SSI) rates. STUDY DESIGN: A single institutional study was performed to compare the SSI rates reported to the National Healthcare Safety Network in the 2 years preceding COVID-19 (PRE, January 1, 2018, to December 31, 2020) with the first 12 months after the pandemic (POST, April 1, 2020, to March 31, 2021). We confirmed our findings using propensity score matching and multivariate analysis. RESULTS: Elimination of traditional shoe covers, disposable head covers, and single-use face masks was associated with a decreased SSI rate from 5.1% PRE to 2.6% POST (p < 0.001). Furthermore, this was despite a 14% increase in surgical volume and an increase in the number of contaminated/dirty cases (2.2% PRE vs 7.4% POST, p < 0.001). Use of disposable face masks decreased by 4.3-fold during this period from 3.5 million/y PRE to 0.8 million/y POST. Of note, inpatient hand hygiene throughout the hospital increased from 71% PRE to 85% POST (p < 0.001). CONCLUSIONS: This analysis has practical applications as we emerge from the pandemic and make decisions regarding OR attire. These data suggest that disposable head covers and shoe covers and frequent changes of face masks are unnecessary, and discontinuation of these practices will have significant cost and environmental implications. These data also reinforce the importance of good hand hygiene for infection prevention.

Salvage regional therapy using hepatic artery infusion pump in unresectable chemotherapy resistant colorectal liver metastases.

BACKGROUND: Little is known about the influence of hepatic artery infusion pump (HAIP) therapy in the setting of chemotherapy resistant hepatic disease in the era of modern systemic therapies. METHODS: Patients who underwent HAIP therapy for chemotherapy resistant and unresectable colorectal liver metastases (CRLM) were reviewed retrospectively. RESULTS: A total of 25 patients met inclusion criteria. 52% had isolated CRLM and 92% had five or more metastatic lesions. Partial response was noted in 40% of patients. Median hepatic progression-free survival (PFS) was 7 months in those with extrahepatic disease versus 6 months in those with isolated CRLM at the time of HAIP placement (p = 0.75). Median overall survival was 8 months in patients with extrahepatic disease and 14 months in patients with isolated CRLM (p = 0.06). CONCLUSIONS: Our findings are comparable to published data and augment the literature which supports HAIP use in chemotherapy-resistant, liver-predominant metastatic colorectal cancer patients.

Shared signaling pathways in normal and breast cancer stem cells.

Recent advances in our understanding of breast cancer biology have led to the identification of a subpopulation of cells within tumors that appear to be responsible for initiating and propagating the cancer. These tumor initiating cells are not only unique in their ability to generate tumors, but also share many similarities with elements of normal adult tissue stem cells, and have therefore been termed cancer stem cells (CSCs). These CSCs often inappropriately use many of the same signaling pathways utilized by their normal stem cell counterparts which may present a challenge to the development of CSC specific therapies. Here, we discuss three major stem cell signaling pathways (Notch, Wnt, and Hedgehog); with a focus on their function in normal mammary gland development and their misuse in breast cancer stem cell fate determination.

A block in lineage differentiation of immortal human mammary stem / progenitor cells by ectopically-expressed oncogenes.

INTRODUCTION: Emerging evidence suggests a direct role of cancer stem cells (CSCs) in the development of breast cancer. In vitro cellular models that recapitulate properties of CSCs are therefore highly desirable. We have previously shown that normal human mammary epithelial cells (hMECs) immortalized with human telomerase reverse transcriptase (hTERT) possess properties of mammary stem / progenitor cells. MATERIALS AND METHODS: In the present study, we used this cell system to test the idea that other known hMEC-immortalizing oncogenes (RhoA, HPVE6, HPVE7, p53 mutant, and treatment with γ-radiation), share with hTERT, the ability to maintain mammary stem / progenitor cells. RESULTS: The results presented here demonstrate that similar to hMECs immortalized with hTERT, all hMEC cell lines immortalized using various oncogenic strategies express stem / progenitor cell markers. Furthermore, analyses using 2D and 3D culture assays demonstrate that all the immortal cell lines retain their ability to self-renew and to differentiate along the luminal lineage. Remarkably, the stem / progenitor cell lines generated using various oncogenic strategies exhibit a block in differentiation along the myoepithelial lineage, a trait that is retained on hTERT-immortalized stem / progenitors. The inability to differentiate along the myoepithelial lineage could be induced by ectopic mutant p53 expression in hTERT-immortalized hMEC. CONCLUSIONS: Our studies demonstrate that stem / progenitor cell characteristics of hMECs are maintained upon immortalization by using various cancer-relevant oncogenic strategies. Oncogene-immortalized hMECs show a block in their ability to differentiate along the myoepithelial lineage. Abrogation of the myoepithelial differentiation potential by a number of distinct oncogenic insults suggests a potential explanation for the predominance of luminal and rarity of myoepithelial breast cancers.

Managing Squamous Cell Esophageal Cancer.

This article reviews the pathophysiology, risk factors, clinical presentation/diagnosis, and management of SCC.

p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes.

Cellular senescence irreversibly arrests proliferation in response to potentially oncogenic stress. Senescent cells also secrete inflammatory cytokines such as IL-6, which promote age-associated inflammation and pathology. HMGB1 (high mobility group box 1) modulates gene expression in the nucleus, but certain immune cells secrete HMGB1 as an extracellular Alarmin to signal tissue damage. We show that nuclear HMGB1 relocalized to the extracellular milieu in senescent human and mouse cells in culture and in vivo. In contrast to cytokine secretion, HMGB1 redistribution required the p53 tumor suppressor, but not its activator ATM. Moreover, altered HMGB1 expression induced a p53-dependent senescent growth arrest. Senescent fibroblasts secreted oxidized HMGB1, which stimulated cytokine secretion through TLR-4 signaling. HMGB1 depletion, HMGB1 blocking antibody, or TLR-4 inhibition attenuated senescence-associated IL-6 secretion, and exogenous HMGB1 stimulated NF-κB activity and restored IL-6 secretion to HMGB1-depleted cells. Our findings identify senescence as a novel biological setting in which HMGB1 functions and link HMGB1 redistribution to p53 activity and senescence-associated inflammation.

Derivation of myoepithelial progenitor cells from bipotent mammary stem/progenitor cells.

There is increasing evidence that breast and other cancers originate from and are maintained by a small fraction of stem/progenitor cells with self-renewal properties. Recent molecular profiling has identified six major subtypes of breast cancer: basal-like, ErbB2-overexpressing, normal breast epithelial-like, luminal A and B, and claudin-low subtypes. To help understand the relationship among mammary stem/progenitor cells and breast cancer subtypes, we have recently derived distinct hTERT-immortalized human mammary stem/progenitor cell lines: a K5(+)/K19(-) type, and a K5(+)/K19(+) type. Under specific culture conditions, bipotent K5(+)/K19(-) stem/progenitor cells differentiated into stable clonal populations that were K5(-)/K19(-) and exhibit self-renewal and unipotent myoepithelial differentiation potential in contrast to the parental K5(+)/K19(-) cells which are bipotent. These K5(-)/K19(-) cells function as myoepithelial progenitor cells and constitutively express markers of an epithelial to mesenchymal transition (EMT) and show high invasive and migratory abilities. In addition, these cells express a microarray signature of claudin-low breast cancers. The EMT characteristics of an un-transformed unipotent mammary myoepithelial progenitor cells together with claudin-low signature suggests that the claudin-low breast cancer subtype may arise from myoepithelial lineage committed progenitors. Availability of immortal MPCs should allow a more definitive analysis of their potential to give rise to claudin-low breast cancer subtype and facilitate biological and molecular/biochemical studies of this disease.

Histological, molecular and functional subtypes of breast cancers.

Increased understanding of the molecular heterogeneity that is intrinsic to the various subtypes of breast cancer will likely shape the future of breast cancer diagnosis, prognosis, and treatment. Advances in the field over the last several decades have been remarkable and have clearly translated into better patient care as evidenced by the earlier detection, better prognosis, and new targeted therapies. There have been two recent advances in the breast cancer research field that have lead to paradigm shifts: first, the identification of intrinsic breast tumor subtypes, which has changed the way we think about breast cancer and second, the recent characterization of cancer stem cells (CSCs), which are suspected to be responsible for tumor initiation, recurrence and resistance to therapy, have opened new exciting avenues to think about breast cancer therapeutic strategies. While these advances constitute major paradigm shifts within the research realm, the clinical arena has yet to adopt and apply our understanding of the molecular basis of the disease to early diagnosis, prognosis and therapy of breast cancers. Here, we will review the current clinical approach to classification of breast cancers, newer molecular-based classification schemes, and potential future of biomarkers representing a functional classification of breast cancer.