Marcus M. Monroe

The role of colorectal cancer stem cells in metastatic disease and therapeutic response

Colorectal cancer is the third-leading cause of cancer related mortality in the United States. The intricate molecular mechanisms involved in the regenerative process of the normal intestine and the identity of putative somatic intestinal stem cells have become clear. In parallel with this, experiment evidence has emerged supporting the century old hypothesis that solid tumor initiation, progression, chemoresistance and recurrence is the result of a small population of cancer cells with self-renewal and pluripotency capabilities. These “cancer stem cells” (CSCs) present a unique opportunity to better understand the biology of solid tumors in general, as well as targets for future therapeutics. In this review, we will summarize the current understanding of intestinal stem cell biology and translate it to colorectal CSCs to provide a basis for understanding chemoresistance, cancer recurrence and metastasis. A more complete understanding of the biology of colorectal CSCs will translate into the development of better chemotherapeutic and biological agents for the treatment of colorectal cancer.

Wee-1 Kinase Inhibition Overcomes Cisplatin Resistance Associated with High Risk TP53 Mutations in Head and Neck Cancer through Mitotic Arrest Followed by Senescence

Although cisplatin has played a role in “standard-of-care” multimodality therapy for patients with advanced squamous cell carcinoma of the head and neck (HNSCC), the rate of treatment failure remains particularly high for patients receiving cisplatin whose tumors have mutations in the TP53 gene. We found that cisplatin treatment of HNSCC cells with mutant TP53 leads to arrest of cells in the G2 phase of the cell cycle, leading us to hypothesize that the wee-1 kinase inhibitor MK-1775 would abrogate the cisplatin-induced G2 block and thereby sensitize isogenic HNSCC cells with mutant TP53 or lacking p53 expression to cisplatin. We tested this hypothesis using clonogenic survival assays, flow cytometry, and in vivo tumor growth delay experiments with an orthotopic nude mouse model of oral tongue cancer. We also used a novel TP53 mutation classification scheme to identify which TP53 mutations are associated with limited tumor responses to cisplatin treatment. Clonogenic survival analyses indicate that nanomolar concentration of MK-1775 sensitizes HNSCC cells with high-risk mutant p53 to cisplatin. Consistent with its ability to chemosensitize, MK-1775 abrogated the cisplatin-induced G2 block in p53-defective cells leading to mitotic arrest associated with a senescence-like phenotype. Furthermore, MK-1775 enhanced the efficacy of cisplatin in vivo in tumors harboring TP53 mutations. These results indicate that HNSCC cells expressing high-risk p53 mutations are significantly sensitized to cisplatin therapy by the selective wee-1 kinase inhibitor, supporting the clinical evaluation of MK-1775 in combination with cisplatin for the treatment of patients with TP53 mutant HNSCC. Mol Cancer Ther; 14(2); 608–19. ©2014 AACR.

Cancer Stem Cells in Head and Neck Squamous Cell Carcinoma

Accumulating evidence suggests that self-renewal and differentiation capabilities reside only in a subpopulation of tumor cells, termed cancer stem cells (CSCs), whereas the remaining tumor cell population lacks the ability to initiate tumor development or support continued tumor growth. In head and neck squamous cell carcinoma (HNSCC), as with other malignancies, cancer stem cells have been increasingly shown to have an integral role in tumor initiation, disease progression, metastasis and treatment resistance. In this paper we summarize the current knowledge of the role of CSCs in HNSCC and discuss the therapeutic implications and future directions of this field.

Invasive Fungal Rhinosinusitis

Document a 15‐year experience with 29 cases of acute invasive fungal rhinosinusitis (AIFR) and evaluate factors predictive of disease clearance and overall survival.

Vasopressor use in free tissue transfer surgery

Objective: To document the frequency of vasopressor use in free tissue transfer surgery and to compare the incidence of flap complications and flap survival in patients receiving or not receiving intraoperative vasopressors. Study Design and Setting: Case series with chart review of free tissue transfers performed between 2004 and 2006 at a large-volume tertiary academic hospital. Results: Of 241 free flaps, 169 had data available for analysis. Flap survival was 96.5 percent. The rate of other flap complications was 29 percent. A total of 139 (82%) patients received vasopressors intraoperatively. Of these, four (2.9%) flap failures and 40 (29%) complications occurred. In the 30 (18%) patients who did not receive vasopressors, two (6.7%) flap failures and nine (30%) complications occurred. The most common reasons for flap failure were arterial thrombus (n = 3) and thrombosis of the venous pedicle (n = 3). Conclusion: Intraoperative vasopressors are used more frequently than previously realized but do not appear to increase overall flap failure and the incidence of complications. Intraoperative vasopressor use in free flap surgery may not be as harmful as previously feared.

Safety of Vasopressor Use in Head and Neck Microvascular Reconstruction A Prospective Observational Study

Objectives. To evaluate the safety of intraoperative vasopressor administration in a prospective series of patients undergoing free tissue transfer surgery for a variety of indications. Study Design. Prospective observational noninferiority study. Setting. Tertiary academic hospital. Subjects. A total of 169 consecutive patients undergoing free tissue transfer for a variety of indications between late 2007 and 2009. Methods. Intraoperative vasopressor use and surgical outcomes data were prospectively collected. This study was designed to test the noninferiority of intraoperative vasopressor exposure versus no intraoperative vasopressor use on early flap failure. Results. A total of 169 free flaps were performed during the study period. Six early free flap failures occurred overall. The proportion of patients experiencing early flap failure was 4.4% (4/90) in those exposed to intraoperative vasopressors versus 2.5% (2/79) in those not exposed, with an absolute difference of 1.9 percentage points (90% confidence interval, −1.4 to 5.2). Thirty-eight percent of patients in the vasopressor group experienced medical and/or surgical complications other than total flap loss versus 43% in the nonvasopressor group (odds ratio, 0.80; 95% confidence interval, 0.43-1.49). Conclusions. Intraoperative vasopressor use may be more common than previously realized in free tissue transfer surgery. Intraoperative vasopressor use does not result in a significant absolute increase in the rate of flap deaths.

False-negative sentinel lymph node biopsy in head and neck melanoma.

Objective. The results of sentinel lymph node biopsy (SLNB) can be useful for staging and deciding on adjuvant treatment for patients with head and neck melanoma. False-negative SLNB can result in treatment delay. This study aimed to evaluate the characteristics and outcome of patients with false-negative SLNB in cutaneous melanoma of the head and neck. Study Design. Longitudinal cohort study using a prospective institutional tumor registry. Setting. Academic health center. Subjects and Methods. Data from 153 patients who underwent SLNB for melanoma of the head and neck were analyzed. False-negative biopsy was defined as recurrence of tumor in a previously identified negative nodal basin. Statistical analysis was performed on registry data. Results. Positive sentinel lymph nodes were identified in 19 (12.4%) patients. False-negative SLNB was noted in 9 (5.9%) patients, with a false-negative SLNB rate of 32.1%. Using multivariate regression analysis, only examination of a single sentinel lymph node was a significant predictor of false-negative SLNB (P = .01). The mean treatment delay for the false-negative SLNB group was 470 days compared with 23 days in the positive SLNB group (P < .001). The 2-year overall survival of patients with false-negative SLNB was 75% compared with 84% and 98% in positive and negative SLNB groups, respectively (P = .02). Conclusions. False-negative SLNB is more likely to occur when a single sentinel lymph node is harvested. There is significant treatment delay in patients with false-negative SLNB. False-negative SLNB is associated with poor outcome in patients with melanoma of the head and neck.

Evidence-Based Practice: Management of the Clinical Node-Negative Neck in Early-Stage Oral Cavity Squamous Cell Carcinoma

This article provides a critical review of the evidence surrounding the management of the clinical node-negative patient with early-stage oral cavity squamous cell carcinoma.

An audit and feedback system for effective quality improvement in head and neck surgery: Can we become better surgeons?

An evaluation system was established for measuring physician performance. This study was designed to determine whether an initial evaluation with surgeon feedback improved subsequent performance.

Treatment-related determinants of survival in early-stage (T1-2N0M0) oral cavity cancer: A population-based study

National guidelines support both surgical and radiotherapy (RT) as initial treatment options for early‐stage oral cavity squamous cell carcinoma (SCC). There remains limited data evaluating the survival outcomes of RT and the current practice patterns for these lesions.