In Silico Investigations of Multi-Drug Adaptive Therapy Protocols.

The standard of care for cancer patients aims to eradicate the tumor by killing the maximum number of cancer cells using the maximum tolerated dose (MTD) of a drug. MTD causes significant toxicity and selects for resistant cells, eventually making the tumor refractory to treatment. Adaptive therapy aims to maximize time to progression (TTP), by maintaining sensitive cells to compete with resistant cells. We explored both dose modulation (DM) protocols and fixed dose (FD) interspersed with drug holiday protocols. In contrast to previous single drug protocols, we explored the determinants of success of two-drug adaptive therapy protocols, using an agent-based model. In almost all cases, DM protocols (but not FD protocols) increased TTP relative to MTD. DM protocols worked well when there was more competition, with a higher cost of resistance, greater cell turnover, and when crowded proliferating cells could replace their neighbors. The amount that the drug dose was changed, mattered less. The more sensitive the protocol was to tumor burden changes, the better. In general, protocols that used as little drug as possible, worked best. Preclinical experiments should test these predictions, especially dose modulation protocols, with the goal of generating successful clinical trials for greater cancer control.

In vitro modulation of human keratinocyte pro- and anti-inflammatory cytokine production by the capsule of Malassezia species.

Malassezia spp. are commensal, cutaneous fungi that are implicated in seborrhoeic dermatitis. We hypothesize that the lipid-rich capsule of Malassezia spp. masks the organism from host detection, and depletion of this layer elicits an inflammatory response. To test this, preparations of capsulated or acapsular [10% (v/v) Triton X-100 treated], viable and nonviable, exponential or stationary phase Malassezia furfur, Malassezia globosa, Malassezia obtusa, Malassezia restricta, Malassezia slooffiae and Malassezia sympodialis, were incubated with normal human keratinocytes. Proinflammatory (IL-6, IL-8, IL-1alpha and tumour necrosis factor-alpha) and anti-inflammatory cytokine (IL-10) release and intracellular IL-10 concentrations were quantified using enzyme-linked immunosorbent assays. Capsulated Malassezia yeasts stimulated limited or no production of inflammatory cytokines, and increased intracellular IL-10 (P < 0.05). Removal of the capsule of many Malassezia preparations caused a significantly increased production of IL-6, IL-8 and IL-1alpha, and a decrease in intracellular IL-10. Notably, acapsular viable, stationary phase M. globosa caused a 66-fold increase in IL-8 production (P < 0.001) and acapsular nonviable, stationary phase M. furfur caused a 38-fold increase in IL-6 production (P < 0.001) and a 12-fold decrease in intracellular IL-10 (P < 0.001). These results support the hypothesis that the lipid layer of Malassezia spp. modulates cytokine production by keratinocytes. This has implications in the pathogenesis of seborrhoeic dermatitis.

Use of the harmonic scalpel in superficial and total parotidectomy for benign and malignant disease.

OBJECTIVES: Use of the harmonic scalpel in superficial parotidectomy for benign parotid disease has been shown to reduce surgical time as well as intraoperative blood loss. We sought to determine whether similar results could be achieved with the expanded use of the harmonic scalpel in parotidectomy for both benign and malignant disease. STUDY DESIGN: Retrospective review. METHODS: The medical records of all patients undergoing superficial or total parotidectomy from 1999 to 2004 were reviewed. Patients were excluded for a history of bleeding disorder, prior facial nerve weakness, or concurrent neck dissection at the time of parotidectomy. RESULTS: Forty-four patients underwent harmonic scalpel parotidectomy and 41 patients underwent conventional cold knife parotidectomy (control group). Use of the harmonic scalpel was associated with a significant reduction in intraoperative blood loss (38.0 +/- 3.6 mL vs. 66.0 +/- 10.8 mL for controls, P < 0.05) and duration of drainage (31.80 +/- 2.4 h vs. 39.29 +/- 2.21 h for controls, P < 0.05). Use of the harmonic scalpel in superficial parotidectomy (n = 35) compared to controls (n = 37) was associated with a significant reduction in intraoperative blood loss (38.0 +/- 4.23 mL vs. 68.0 +/- 12.0 mL, P < 0.05) and reduced incidence of facial nerve injury (P < 0.05). In patients undergoing total parotidectomy, no significant differences were observed between the harmonic scalpel (n = 9) and control groups (n = 4) in length of surgery, intraoperative blood loss, postoperative drainage, duration of drainage, and facial nerve injury. CONCLUSIONS: Use of the harmonic scalpel in the surgical treatment of parotid disease is safe and confers some advantages over conventional methods of parotid dissection.