Is the neutrophil-to-lymphocyte ratio a useful prognostic indicator in melanoma patients?

The neutrophil-to-lymphocyte ratio (NLR) is gaining traction as a biomarker with utility in a variety of malignancies including melanoma. Intact lymphocyte function is necessary for tumor surveillance and destruction, and neutrophils play a role in suppressing lymphocyte proliferation and in the induction of lymphocyte apoptosis. Early research in melanoma indicates that in high-risk localized melanoma, a high NLR is correlated with worse overall and disease-free survival. Similarly, in metastatic melanoma treated with both metastasectomy and immunotherapies, an elevated NLR is predictive of shortened overall survival and progression-free survival. Future studies incorporating NLR into more traditional melanoma prognostic markers while employing more granular outcomes, are needed to realize the full potential of NLR.

Prognosis and Management of Thick and Ultrathick Melanoma.

OBJECTIVES: Thick melanomas, defined as ≥4 mm in thickness, represent ~5% of new melanoma diagnoses and have been associated with poor overall survival (OS). Ultrathick melanomas, those lesions ≥8 mm in thickness, have been associated with worse survival. We sought to compare prognostic factors for thick and ultrathick melanoma. METHODS: Retrospective analysis of a prospective database of all patients receiving an operation for melanoma, June 2005 to December 2016 was performed. Multivariate Cox proportional hazards regression analyses were performed to identify predictors of progression-free survival (PFS) and OS. RESULTS: Of 95 patients with thick melanoma, 37 (39%) had ultrathick tumors (≥8 mm thick). Thick and ultrathick lesions were not significantly different on the basis of tumor location, ulceration, mitotic rate, lymphovascular invasion, or performance or positivity of sentinel node biopsy or therapeutic lymphadenectomy. Disease recurrence was identified in 38 patients overall (40%), more commonly in ultrathick disease (55% vs. 29%, P=0.008). Serum neutrophil to lymphocyte ratio (NLR) was available for 36 patients, of whom 23 (64%) had high NLR (>3.0). Decreased PFS was independently associated with ultrathick tumors (HR, 2.9; P=0.003), head/neck location (HR, 2.6; P=0.023), and positive lymph nodes (HR, 3.3; P=0.004). Decreased OS was independently associated with high NLR (HR, 5.0; P=0.042). CONCLUSIONS: Disease progression was higher in the ultrathick melanoma group. Thicker tumors, head/neck location, and positive lymph nodes were associated with decreased PFS. High NLR was associated with decreased OS. Ultrathick melanomas represent advanced malignancy; however, patients may derive benefit from surgical treatment to achieve locoregional control.

Suboptimal Compliance With National Comprehensive Cancer Network Melanoma Guidelines: Who Is at Risk?

BACKGROUND: National Comprehensive Cancer Network (NCCN) melanoma treatment guidelines are based on best available literature. We evaluated NCCN excision margin and sentinel lymph node biopsy (SLNB) guideline adherence to identify patient populations at risk for suboptimal care. METHODS: Retrospective review of prospectively maintained database of all patients who underwent operation for invasive melanoma from January 2005 to 2015. RESULTS: In total, 865 patients underwent operation for 522 thin (60.3%), 268 intermediate-thickness (31.0%), and 75 thick (8.7%) melanomas. Tumor location was 349 extremity (40.4%), 348 trunk (40.2%), and 168 head/neck (19.4%). SLNB was performed in 422 patients (48.8%); 75 (17.8%) were positive, and 67 (15.9%) underwent therapeutic lymphadenectomy. A total of 154 lesions (17.8%) were ulcerated; 444 had mitotic rate ≥1 (51.3%). In total, 788 patients (91.1%) fulfilled both NCCN guidelines. Recommended surgical margins were achieved in 837 patients (96.8%) and SLNB was performed as appropriate in 806 patients (93.2%); 10 patients (1.2%) were deficient for both. Deficient margins and lack of SLNB were associated with increased invasion depth and head/neck location; deficient SLNB was associated with age 80 and above (P<0.0001). Overall recurrence was 7.1%: 15 local (1.7%), 23 regional (2.7%), and 23 distant (2.7%) failures. Local recurrence was associated with head/neck location (P=0.031); all recurrence types were associated with increased tumor thickness. CONCLUSIONS: NCCN excision and SLNB guidelines were almost always met. Patients at risk for not meeting criteria included the elderly and those with head/neck tumors. Failure to meet NCCN criteria was not associated with increased disease recurrence. Surgeons must carefully balance the risks of not pursuing NCCN guidelines with treatment goals.

Advances in the surgical treatment of esophageal cancer.

Surgical resection remains the predominant modality in the management of esophageal cancer. Transthoracic and transhiatal esophagectomy are the procedures that are most frequently performed. Minimally invasive esophagectomy is feasible but will require further evaluation with well-designed trials and long-term follow-up before it can be widely adopted. Technical improvements have lowered the rate of cervical anastomotic leak and improved the management of thoracic anastomotic leak. Outcome studies demonstrated that the optimal mortality, morbidity, and survival outcomes are obtained when esophageal resections are performed by experienced surgeons in high-volume institutions.

Laparoscopic adrenalectomy: balancing the operative indications with the technical advances.

Laparoscopic adrenalectomy contributed significantly to reduction of morbidity and improvement of postoperative patient recovery time. The adoption of this technique had substantial impact on the management of adrenal incidentalomas. Although laparoscopic adrenalectomy should be in general avoided for known primary adrenal cancers, it is appropriate for metastasectomy of isolated adrenal metastatic disease.

An effective in vitro antitumor response against human pancreatic carcinoma with paclitaxel and daunorubicin by induction of both necrosis and apoptosis.

The highly metastatic human pancreatic cell line L3.6 was used to study mechanisms for antitumor activity with various chemotherapeutic drug combinations. The most effective drugs were daunorubicin (IC50 0.4 microM), doxorubicin (IC50 22 microM), paclitaxel (IC50 5.3 microM) and 5-fluorouracil (IC50 5.4 microM). The most effective drug combination was equitoxic concentrations of paclitaxel and daunorubicin. Kinetic analysis demonstrated that both paclitaxel and daunorubicin had to be added simultaneously for maximum cytotoxicity. Daunorubicin treatment alone demonstrated ROS (reactive oxygen species) induction and cellular morphological changes more consistent with chemical damage in a total of 93% of the cells and apoptotic changes in 20% of the cell population. The apoptosis induced by daunorubicin does not appear to be caspase-dependent, as demonstrated by the lack of conversion of the procaspases 8 and 3. Within 24 h of treatment with paclitaxel, Bcl-2 formed a doublet at 26 kilodaltons and the expression was abrogated with daunorubicin and the combination of the two drugs as determined by Western blots. These data suggest that the human pancreatic cell line L3.6 is more effectively killed following treatment with chemotherapeutic agents that cause death through at least two pathways, a caspase-dependent and caspase-independent apoptosis and necrosis.

The metastatic potential of human pancreatic cell lines in the liver of nude mice correlates well with cathepsin B activity.

BACKGROUND: Cathepsin B, a lysosomal cysteine protease, has a major role in the mechanisms of tumor metastasis. The aim of the present work was to examine the correlation between cathepsin B activity and the metastatic potential of human pancreatic cancer. METHODS: The primary cell line COLO 357 and the derivative tumor cell lines FG, L3.1, L3.2, L3.3, L3.4, and L3.5, which are characterized by progressively increasing metastatic potential, were injected intrasplenically in the athymic mice. Cathepsin B activity, metastasis, and ultrastructural characteristics were assessed. RESULTS: An increased number of liver tumor nodules was observed with each subsequent intrasplenic inoculation (p = 0.001), associated with lymph node, splenic, and pancreatic involvement. Cathepsin B activity progressively increased (p = 0.001) and was strongly positively correlated with the metastatic potential. However, no correlation was found between the metastatic potential and ultrastructural characteristics. CONCLUSIONS: These findings further support the central role of cathepsin B in metastasis in a combined in vitro/in vivo model.

The preventive effect of ketoconazole on experimental metastasis from a human pancreatic carcinoma may be related to its effect on prostaglandin synthesis.

BACKGROUND: Arachidonic acid metabolites known to affect platelet function also interfere with tumor growth and metastases. The purpose of this study was to evaluate the anti-metastatic potential of ketoconazole, a thromboxane synthetase and 5-lipoxygenase inhibitor, on hepatic metastasis from a human pancreatic adenocarcinoma in nude mice and its effect on serum prostaglandin levels. METHODS: The human pancreatic tumor cells (RWP-2) were injected intrasplenically in nude mice grouped into control, ketoconazole (270 microg), ketoconazole (360 microg), and ketoconazole (540 microg). The agent was administered intraperitoneally 30 min before and every 24 h after the tumor cell inoculation for 8 days. In a separate experiment thromboxane B2 (TxB2), prostaglandin D2 (PGD2), prostaglandin E2 (PGE2) and 6-Keto-F1a (stable prostacyclin derivative) were measured on blood from controls, tumor bearing animals and animals bearing tumors treated with 270 microg of ketoconazole. RESULTS: Statistically significant differences were observed between the control and three-treatment groups on the reduction of liver tumor nodules (p < 0.001), and in the liver surface areas occupied by tumor (p < 0.001). The TxB2 levels decreased from 150.6 ng/mL in the tumor bearing to 104.8 ng/mL in the ketoconazole treated animals (p < 0.05). PGD2, PGE2 and 6-keto-F1a levels increased to 7.1 ng/mL, 8.3 ng/mL, and 13.6 ng/mL from 3 ng/mL, 5.8 ng/mL, and 0.02 ng/mL respectively (p < 0.001). CONCLUSIONS: These results indicate that ketoconazole significantly reduced hepatic metastases from the human pancreatic carcinoma RWP-2 in the nude mouse model, and inhibited thromboxane B2 formation, potentiating a concomitant redirection of platelet endoperoxide metabolism into PGD2, PGE2, and 6-keto-F1a. It is hypothesized that the changes in the arachidonic acid metabolism mediate the ameliorating effect of ketoconazole on experimental hepatic metastasis.