Paracicatricial melanocytes as a sign of melanoma.

Intradermal melanocytes in the setting of melanoma represent a diagnostic challenge to dermatopathologists as their presence may represent superficially invasive melanoma vs benign nevus cells or reactive dermal melanocytes. Previous dermatologic literature suggests that the absence of cytologic atypia in intradermal melanocytes and their presence in nonmelanocytic neoplasms lends to their characterization as reactive, benign, melanocytic proliferation. A 67-year-old female presented for evaluation of a 10-mm irregularly pigmented dark brown macule on the left cheek. Initial shave biopsy showed transected malignant melanoma measuring at least 0.6 mm in thickness. Multiple reexcision specimens demonstrated residual melanoma with banal appearing intradermal epithelioid melanocytes within and surrounding the scar. The melanocytes tracked into the skin graft, which had previously been free from involvement. Positron emission tomography-computed tomography (PET CT) and lymph node biopsies did not show evidence of metastatic melanoma. Ten months after her diagnosis and following five surgical excisions, the patient was diagnosed with metastatic melanoma to the brain and succumbed to intracranial hemorrhage. We present a case in which paracicatricial melanoma may simulate benign paracicatricial melanocytic hyperplasia. These findings have significant therapeutic and prognostic implications for the practicing dermatologist and dermatopathologist.

The role of preoperative positron emission tomography/computed tomography (PET/CT) in patients with high-risk melanoma.

BACKGROUND: Positron emission tomography/computed tomography (PET/CT) scanning is commonly used for the preoperative staging of patients with at least intermediate thickness (>1 mm) melanomas. Its role in staging at initial diagnosis for clinically asymptomatic patients is not yet established. METHODS: We examined records of all patients receiving an operation for at least an intermediate thickness melanoma from June 2005 to June 2011. Results of preoperative PET/CT scans were evaluated in asymptomatic patients with a negative physical exam. Outcome measures included changes in clinical management, as well as incidence of true- and false-positives. RESULTS: PET/CT scans were performed for 149 patients with at least an intermediate thickness melanoma. Positive scans were identified in 28% (41/149) of patients. An invasive procedure to further aid in diagnosis was performed in 44% (18), yet only 6 (15%) patients were diagnosed with metastatic cancer (85% false positive rate). Each of these patients had regional disease subsequently diagnosed by a sentinel lymph node biopsy. No distant metastatic disease was identified. CONCLUSIONS: Preoperative PET/CT in asymptomatic patients is of limited benefit in staging asymptomatic melanoma patients with at least an intermediate thickness melanoma and may lead to unnecessary invasive procedures.

Association between hospital intraoperative blood transfusion practices for surgical blood loss and hospital surgical mortality rates.

OBJECTIVE: Blood loss during surgery is an important operative complication in patients undergoing major noncardiac surgery and may increase postoperative morbidity and mortality. Variations in the delivery of operative blood transfusions to treat blood loss depend not only on the patient and surgery characteristics but also on the hospital transfusion practices, and may explain differences in the hospitals' postoperative outcomes. We determine the relationship between hospital-level rates of intraoperative blood transfusion and 30-day mortality among older patients with significant intraoperative blood loss. METHODS: Among 46,608 operative patients aged 65 years or older whose estimated blood loss was 500 mL or greater in 122 Veterans Affairs (VA) hospitals during years 1997 to 2004, we examined the relationship between hospital-level transfusion rates and adjusted 30-day postoperative mortality rates using linear regression modeling. RESULTS: Hospital-level rates of intraoperative blood transfusion for older surgical patients with significant blood loss varied from 10% to 92%. Hospitals in the highest tertile for the rate of intraoperative transfusion had the highest number of patients with 500 mL or more surgical blood loss and lowest risk-adjusted 30-day surgical mortality. For every 10% increase in the rate of intraoperative blood transfusion, there was a 0.7% (95% CI: 0.3%-1.1%) decrease in the hospital's adjusted 30-day postoperative mortality for these high-risk patients. CONCLUSIONS: Large variation exists in hospitals' intraoperative blood transfusion practices for older patients with significant surgical blood loss. Hospitals with higher transfusion rates for patients with significant surgical blood loss have lower adjusted 30-day mortality for these patients. Hospital intraoperative blood transfusion practices may be a promising surgical quality indicator.

Factors predictive of the status of sentinel lymph nodes in melanoma patients from a large multicenter database.

BACKGROUND: Numerous predictive factors for cutaneous melanoma metastases to sentinel lymph nodes have been identified; however, few have been found to be reproducibly significant. This study investigated the significance of factors for predicting regional nodal disease in cutaneous melanoma using a large multicenter database. METHODS: Seventeen institutions submitted retrospective and prospective data on 3463 patients undergoing sentinel lymph node (SLN) biopsy for primary melanoma. Multiple demographic and tumor factors were analyzed for correlation with a positive SLN. Univariate and multivariate statistical analyses were performed. RESULTS: Of 3445 analyzable patients, 561 (16.3%) had a positive SLN biopsy. In multivariate analysis of 1526 patients with complete records for 10 variables, increasing Breslow thickness, lymphovascular invasion, ulceration, younger age, the absence of regression, and tumor location on the trunk were statistically significant predictors of a positive SLN. CONCLUSIONS: These results confirm the predictive significance of the well-established variables of Breslow thickness, ulceration, age, and location, as well as consistently reported but less well-established variables such as lymphovascular invasion. In addition, the presence of regression was associated with a lower likelihood of a positive SLN. Consideration of multiple tumor parameters should influence the decision for SLN biopsy and the estimation of nodal metastatic disease risk.

Operative blood loss, blood transfusion, and 30-day mortality in older patients after major noncardiac surgery.

OBJECTIVE: Anemia and operative blood loss are common in the elderly, but evidence is lacking on whether intraoperative blood transfusions can reduce the risk of postoperative death. METHODS: We analyzed retrospective data from 239,286 patients 65 years of older who underwent major noncardiac surgery in 1997 to 2004 at veteran hospitals nationwide. Propensity-score matching was used to adjust for differences between patients who received intraoperative blood transfusions (9.4%) and those who did not, and data were used to determine the association between intraoperative blood transfusion and 30-day postoperative mortality. RESULTS: After propensity-score matching, intraoperative blood transfusion was associated with mortality risk reductions in patients with preoperative hematocrit levels of <24% (odds ratio: 0.60, 95% CI: 0.41-0.87), and in patients with hematocrit of 30% or greater when there is substantial (500-999 mL) blood loss (odds ratio: 0.35, 95% CI: 0.22-0.56 for hematocrit levels between 30%-35.9% and 0.78, 95% CI: 0.62-0.97 for hematocrit levels of 36% or greater). When operative blood loss was <500 mL, transfusion was not associated with mortality reductions for patients with hematocrit levels of 24% or greater, and conferred increased mortality risks in patients with preoperative hematocrit levels between 30% to 35.9% (odds ratio 1.29, 95% CI: 1.04-1.60). CONCLUSIONS: Intraoperative blood transfusion is associated with a lower 30-day postoperative mortality among elderly patients undergoing major noncardiac surgery if there is substantial operative blood loss or low preoperative hematocrit levels (<24%). Transfusion is associated with increased mortality risks for those with preoperative hematocrit levels between 30% and 35.9% and <500 mL of blood loss.

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.

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.

Preoperative hematocrit levels and postoperative outcomes in older patients undergoing noncardiac surgery.

CONTEXT: Elderly patients are at high risk of both abnormal hematocrit values and cardiovascular complications of noncardiac surgery. Despite nearly universal screening of patients for abnormal preoperative hematocrit levels, limited evidence demonstrates the adverse effects of preoperative anemia or polycythemia. OBJECTIVE: To evaluate the prevalence of preoperative anemia and polycythemia and their effects on 30-day postoperative outcomes in elderly veterans undergoing major noncardiac surgery. DESIGN: Retrospective cohort study using the VA National Surgical Quality Improvement Program database. Based on preoperative hematocrit levels, we stratified patients into standard categories of anemia (hematocrit <39.0%), normal hematocrit (39.0%-53.9%), and polycythemia (hematocrit > or =54%). We then estimated increases in 30-day postoperative cardiac event and mortality risks in relation to each hematocrit point deviation from the normal category. SETTING AND PATIENTS: A total of 310,311 veterans aged 65 years or older who underwent major noncardiac surgery between 1997 and 2004 in 132 Veterans' Affairs medical centers across the United States. MAIN OUTCOME MEASURES: The primary outcome measure was 30-day postoperative mortality; a secondary outcome measure was composite 30-day postoperative mortality or cardiac events (cardiac arrest or Q-wave myocardial infarction). RESULTS: Thirty-day mortality and cardiac event rates increased monotonically, with either positive or negative deviations from normal hematocrit levels. We found a 1.6% (95% confidence interval, 1.1%-2.2%) increase in 30-day postoperative mortality associated with every percentage-point increase or decrease in the hematocrit value from the normal range. Additional analyses suggest that the adjusted risk of 30-day postoperative mortality and cardiac morbidity begins to rise when hematocrit levels decrease to less than 39% or exceed 51%. CONCLUSIONS: Even mild degrees of preoperative anemia or polycythemia were associated with an increased risk of 30-day postoperative mortality and cardiac events in older, mostly male veterans undergoing major noncardiac surgery. Future studies should determine whether these findings are reproducible in other populations and if preoperative management of anemia or polycythemia decreases the risk of postoperative mortality.

Hospital Blood Transfusion Patterns During Major Noncardiac Surgery and Surgical Mortality.

We retrospectively examined intraoperative blood transfusion patterns at US veteran's hospitals through description of national patterns of intraoperative blood transfusion by indication for transfusion in the elderly; assessment of temporal trends in the use of intraoperative blood transfusion; and relationship of institutional use of intraoperative blood transfusion to hospital 30-day risk-adjusted postoperative mortality rates.Limited data exist on the pattern of intraoperative blood transfusion by indication for transfusion at the hospital level, and the relationship between intraoperative transfusion rates and institutional surgical outcomes.Using the Department of Veterans Affairs Surgical Quality Improvement Program database, we assigned 424,015 major noncardiac operations among elderly patients (≥65 years) in 117 veteran's hospitals, from 1997 to 2009, into groups based on indication for intraoperative blood transfusion according to literature and clinical guidelines. We then examined institutional variations and temporal trends in surgical blood use based on these indications, and the relationship between these institutional patterns of transfusion and 30-day postoperative mortality.Intraoperative transfusion occurred in 38,056/424,015 operations (9.0%). Among the 64,390 operations with an indication for transfusion, there was wide variation (median: 49.9%, range: 8.7%-76.2%) in hospital transfusion rates, a yearly decline in transfusion rates (average 1.0%/y), and an inverse relationship between hospital intraoperative transfusion rates and hospital 30-day risk-adjusted mortality (adjusted mortality of 9.8 ±â€Š2.8% vs 8.3 ±â€Š2.1% for lowest and highest tertiles of hospital transfusion rates, respectively, P = 0.02). In contrast, for the 225,782 operations with no indication for transfusion, there was little variation in hospital transfusion rates (median 0.7%, range: 0%-3.4%), no meaningful temporal change in transfusion (average 0.0%/y), and similar risk-adjusted 30-day mortality across all tertiles of hospital transfusion rates.Among patients ≥65 years with an indication for intraoperative transfusion, intraoperative transfusion patterns varied widely across hospitals and declined through the 1997 to 2009 study period. Hospitals with higher transfusion rates in these patients have lower risk-adjusted 30-day postoperative mortality rates.

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 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.

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.