Research Spotlight

Habib, J. G. and J. A. O’Shaughnessy (2016). “The hedgehog pathway in triple-negative breast cancer.” Cancer Med: 2016 Aug [Epub ahead of print].

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Treatment of triple-negative breast cancer (TNBC) remains challenging due to the underlying heterogeneity of this disease coupled with the lack of predictive biomarkers and effective targeted therapies. Intratumoral heterogeneity, particularly enrichment for breast cancer stem cell-like subpopulations, has emerged as a leading hypothesis for systemic therapy resistance and clinically aggressive course of poor prognosis TNBC. A growing body of literature supports the role of the stem cell renewal Hedgehog (Hh) pathway in breast cancer. Emerging preclinical data also implicate Hh signaling in TNBC pathogenesis. Herein, we review the evidence for a pathophysiologic role of Hh signaling in TNBC and explore mechanisms of crosstalk between the Hh pathway and other key signaling networks as well as their potential implications for Hh-targeted interventions in TNBC.

Wexler, O., M. S. Gough, M. A. Morgan, C. M. Mack, M. J. Apostolakos, K. P. Doolin, R. A. Mooney, E. Arning, T. Bottiglieri and A. P. Pietropaoli (2016). “Methionine metabolites in patients with sepsis.” J Intensive Care Med: 2016 Sep [Epub ahead of print].

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OBJECTIVE: Sepsis is characterized by microvascular dysfunction and thrombophilia. Several methionine metabolites may be relevant to this sepsis pathophysiology. S-adenosylmethionine (SAM) serves as the methyl donor for trans-methylation reactions. S-adenosylhomocysteine (SAH) is the by-product of these reactions and serves as the precursor to homocysteine. Relationships between plasma total homocysteine concentrations (tHcy) and vascular disease and thrombosis are firmly established. We hypothesized that SAM, SAH, and tHcy levels are elevated in patients with sepsis and associated with mortality. METHODS: This was a combined case-control and prospective cohort study consisting of 109 patients with sepsis and 50 control participants without acute illness. The study was conducted in the medical and surgical intensive care units of the University of Rochester Medical Center. Methionine, SAM, SAH, and tHcy concentrations were compared in patients with sepsis versus control participants and in sepsis survivors versus nonsurvivors. RESULTS: Patients with sepsis had significantly higher plasma SAM and SAH concentrations than control participants (SAM: 164 [107-227] vs73 [59-87 nM], P < .001; SAH: 99 [60-165] vs 35 [28-45] nM, P < .001). In contrast, plasma tHcy concentrations were lower in sepsis patients compared to healthy control participants (4 [2-6]) vs 7 [5-9] muM; P = .04). In multivariable analysis, quartiles of SAM, SAH, and tHcy were independently associated with sepsis (P = .006, P = .05, and P < .001, respectively). Sepsis nonsurvivors had significantly higher plasma SAM and SAH concentrations than survivors (SAM: 223 [125-260] vs 136 [96-187] nM; P = .01; SAH: 139 [81-197] vs 86 [55-130] nM, P = .006). Plasma tHcy levels were similar in survivors vs nonsurvivors. The associations between SAM or SAH and hospital mortality were no longer significant after adjusting for renal dysfunction. CONCLUSIONS: Methionine metabolite concentrations are abnormal in sepsis and linked with clinical outcomes. Further study is required to determine whether these abnormalities have pathophysiologic significance.

Warren, A. M., A. L. Jones, M. Bennett, J. K. Solis, M. Reynolds, E. E. Rainey, G. Viere and M. L. Foreman (2016). “Prospective evaluation of posttraumatic stress disorder in injured patients with and without orthopaedic injury.” J Orthop Trauma 30(9): e305-311.

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OBJECTIVES: The study purposes were to prospectively evaluate occurrence of posttraumatic stress (PTS) symptoms at hospital admission and 6 months later in patients with orthopaedic injury; to explore differences in PTS symptoms in those with and without orthopaedic injury; and to determine whether PTS symptoms are influenced by orthopaedic injury type. DESIGN: Prospective, longitudinal observational study. SETTING: Level 1 Trauma Center. PATIENTS/PARTICIPANTS: Two hundred fifty-nine participants admitted for at least 24 hours. MAIN OUTCOME MEASUREMENTS: The Primary Care Posttraumatic Stress Disorder (PTSD) Screen (PC-PTSD) measured PTSD symptoms during hospitalization. The PTSD Checklist-Civilian Version (PCL-C) measured PTS symptoms at 6 months. RESULTS: In orthopaedic patients, 28% had PTS at 6 months, compared with 34% of nonorthopaedic patients. Odds ratios (ORs) were calculated to determine the influence of pain, physical and mental function, depression, and work status. At 6 months, if the pain score was 5 or higher, the odds of PTS symptoms increased to 8.38 (3.55, 19.8) (P < 0.0001). Those scoring below average in physical function were significantly more likely to have PTS symptoms [OR = 7.60 (2.99, 19.32), P < 0.0001]. The same held true for mental functioning and PTS [OR = 11.4 (4.16, 30.9), P < 0.0001]. Participants who screened positive for depression had a 38.9 (14.5, 104) greater odds (P < 0.0001). Participants who did not return to work after injury at 6 months were significantly more likely to have PTS [OR = 16.5 (1.87, 146), P = 0.012]. CONCLUSIONS: PTSD is common in patients after injury, including those with orthopaedic trauma. At 6 months, pain of 5 or greater, poor physical and mental function, depression, and/or not returning to work seem to be predictive of PTSD. Orthopaedic surgeons should identify and refer for PTSD treatment given the high incidence postinjury.

Vogelzang, N. J., K. Fizazi, J. M. Burke, R. De Wit, J. Bellmunt, T. E. Hutson, E. Crane, W. R. Berry, K. Doner, J. D. Hainsworth, P. J. Wiechno, K. Liu, M. F. Waldman, A. Gandhi, D. Barton, U. Jungnelius, A. Fandi, C. N. Sternberg and D. P. Petrylak (2016). “Circulating tumor cells in a phase 3 study of docetaxel and prednisone with or without lenalidomide in metastatic castration-resistant prostate cancer.” Eur Urol: 2016 Aug [Epub ahead of print].

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Elevated circulating tumor cell (CTC) blood levels (>/=5 cells/7.5ml) convey a negative prognosis in metastatic castration-resistant prostate cancer but their prognostic significance in patients receiving chemotherapy is uncertain. The association between CTC counts (at baseline or after treatment), overall survival (OS), and response to docetaxel with lenalidomide was evaluated in a 208-patient subset from the MAINSAIL trial, which compared docetaxel-prednisone-lenalidomide and docetaxel-prednisone-placebo in metastatic castration-resistant prostate cancer patients. Baseline CTCs were <5 cells/7.5ml blood in 87 (42%) patients and >/=5 cells/7.5ml in 121 (58%) patients. Neither tumor response nor prostate-specific antigen response correlated with baseline CTCs. However, CTC count >/=5 cells/7.5ml was significantly associated with lower OS (hazard ratio: 3.23, p = 0.0028). Increases in CTCs from <5 cells/7.5ml to >/=5 cells/7.5ml after three cycles were associated with significantly shorter OS (hazard ratio: 5.24, p=0.025), whereas CTC reductions from >/=5 cells/7.5ml to <5 cells/7.5ml were associated with the best prognosis (p=0.003). PATIENT SUMMARY: Our study in metastatic castration-resistant prostate cancer patients treated with docetaxel chemotherapy, with or without lenalidomide, showed that patient survival was best predicted by circulating tumor cell count at the start of treatment. A rising circulating tumor cell count after three cycles of therapy predicted poor survival, while a decline predicted good survival.

Tominaga, G. T., K. L. Staudenmayer, S. Shafi, K. M. Schuster, S. A. Savage, S. Ross, P. Muskat, N. T. Mowery, P. Miller, K. Inaba, M. J. Cohen, D. Ciesla, C. V. Brown, S. Agarwal, M. B. Aboutanos, G. H. Utter and M. Crandall (2016). “The american association for the surgery of trauma grading scale for 16 emergency general surgery conditions: Disease-specific criteria characterizing anatomic severity grading.” J Trauma Acute Care Surg 81(3): 593-602.

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The concepts for the EGS grading scales were modeled loosely from cancer staging criteria and trauma organ injury scales. For each of EGS diseases, the descriptions and grade were specifically defined using findings derived from four distinct categories: (1) clinical, (2) imaging, (3) operative, and (4) pathologic. These categories were selected to create the most holistic picture of the disease process. Furthermore, it was recognized that not all EGS conditions would require operative intervention, so the grading system could not rely solely on operative or pathologic findings. In cases where the grade differed between the four categories, the highest grade of EGS disease would apply. For example, if the computed tomography (CT) scan shows evidence of acute gangrenous appendicitis without perforation (Grade 2) but the pathologic findings are transmural necrosis with perforation (Grade 3), then the patient would be classified as Grade 3. Definitions were derived after examination of existing grading systems, review of the literature, and expert opinion. Previously reported scoring systems for these 16 EGS diseases were reviewed. No anatomic disease grading scales were found for breast abscess, intestinal obstruction, infectious colitis, pelvic inflammatory disease, and pleural space infections. Diagnostic imaging (CT, magnetic resonance imaging [MRI], ultrasound, endoscopic, nuclear medicine scan) descriptions based on disease severity have been published for acute cholecystitis,18–20 acute diverticulitis,9,10,21,22 esophageal perforation,23 acute pancreatitis,24–26 pelvic inflammatory disease,27 perforated peptic ulcer,28 and perirectal abscess.29 These were reviewed and incorporated into our data dictionary for these disease processes where applicable. Proposed EGS disease data dictionaries for each grade of disease were then carefully reviewed and revised until a consensus was achieved.