Histopathologic Characteristics, Recurrence Patterns, and Survival of 129 Patients With Desmoplastic Melanoma

Background Desmoplastic melanoma (DM) has been associated with higher local recurrence rates than other types of cutaneous melanoma. Current controversies regarding locoregional treatment strategies warrant further investigation. Methods Retrospective review of a prospectively maintained melanoma database identified 129 patients with DM out of >12,500 melanoma patients referred for treatment from 1980 to 2003. Clinical and histopathologic characteristics, recurrence, and survival were analyzed. Results The median follow-up was 4.0 years. Of the 129 patients identified, 82 (63.6%) were male, and the median age was 55.2 years. American Joint Committee on Cancer staging was I, II, and III in 25.6%, 68.0%, and 6.4% of patients, respectively, and the mean tumor thickness was 4.42 mm. Overall survival was 76% at 5 years and 64% at 10 years; median survival was 13.0 years. A total of 51 patients (39.5%) experienced disease recurrence, with a median time to recurrence of 1.3 years. The first recurrence was local in 18 patients (14.0%), nodal in 18 patients (14.0%), and distant in 15 patients (11.6%), with median survivals of 6.7, 7.8, and 1.8 years, respectively. Statistically significant predictors of recurrence were a final positive margin status and stage, and predictors of overall survival were patient age and stage. Conclusions Compared with other types of melanoma, DMs do demonstrate a tendency toward local recurrence, thus suggesting that narrower excision margins may not be appropriate in this population. Scrutiny of final surgical margins is critical to the local management of DM. In addition, the potential for regional nodal involvement must be considered at the time of diagnosis and during surveillance for disease recurrence.     

Histopathologic excision margin affects local recurrence rate: analysis of 2681 patients with melanomas < or =2 mm thick

OBJECTIVE: Prospective trials have shown that 1-cm and 2-cm margins are safe for melanomas <1 mm thick and > or =1 mm thick, respectively. It is unknown whether narrower margins increase the risk of LR or mortality. SUMMARY BACKGROUND DATA: To determine the relationship between histopathologic excision margin, local recurrence (LR) and survival for patients with melanomas < or =2 mm thick. METHODS: Data were extracted from the Sydney Melanoma Unit database for all patients with cutaneous melanoma < or =2 mm thick, diagnosed up to 1996. Patients with positive excision margins or follow-up <12 months were excluded, leaving 2681 for analysis. Outcome measures were LR (recurrence <5 cm from the excision scar), in-transit recurrence, and disease-specific survival. Factors predicting LR and overall survival were tested with Cox proportional hazards analysis. RESULTS: Median follow-up was 83.8 months. LR was identified in 55 patients (median time to recurrence, 37 months). At 120 months, the actuarial LR rate was 2.9%. Five-year survival after LR was 52.8%. In multivariate analysis, only margin of excision and tumor thickness were predictive of LR (both P = 0.003). When all patients with a margin <0.8 cm in fixed tissue (corresponding to a margin of <1 cm in vivo) were excluded from analysis, margin was no longer significant in predicting LR. Thickness, ulceration, and site were predictive of survival, but margin was not (P = 0.49). CONCLUSIONS: Histopathologic margin affects the risk of LR. However, if the in vivo margin is > or =1 cm, it no longer predicts risk of LR. Patient survival is not affected by margin.     

Histopathologic Criteria for Local Excision of Colorectal Cancer: Multivariate Analysis

Background: Local treatment of colorectal cancer, including endoscopic removal of colonic polyps and transanal resection of rectal tumors, has become widely accepted. However, risk factors predicting the presence of lymph node metastasis have not been fully investigated. To determine the criteria for local excision of colorectal cancer, histopathologic factors independently predicting the lymph node metastasis were investigated.Methods: We performed a retrospective histopathologic study on 335 patients who underwent resection of colorectal cancer and dissection of regional lymph nodes between 1982 and 1996. Features of node-positive tumors (n = 150) were compared with those of node-negative tumors (n = 185), with special reference to the histopathologic findings of the resected tumor. Multivariate analysis was done using the stepwise logistic regression test.Results: Node-positive tumors, when compared with node-negative tumors, were characterized by tumor larger than 6 cm (42% vs. 22%), serosal invasion (88% vs. 56%), lymphatic invasion (32% vs. 5%), venous invasion (9% vs. 2%), and histology other than well-differentiated (66% vs. 29%). Multivariate analysis showed that factors independently associated with lymph node metastasis were serosal invasion, lymphatic invasion, and histologic type. When these three risk factors were negative, lymph node metastasis was rare (5%). When one, two, or three factors were positive, the frequency of lymph node metastasis was 38%, 66%, and 85%, respectively.Conclusions: In colorectal cancer, factors independently associated with lymph node metastasis are serosal invasion, lymphatic invasion, and histologic type. When these three parameters are favorable, local treatment of colorectal cancer does not require additional lymph node dissection.     

Reevaluation of the Locoregional Recurrence Rate in Melanoma Patients With a Positive Sentinel Node Compared to Patients With Palpable Nodal Involvement

Background  

The main aims of this study were to evaluate the occurrence of the various forms of locoregional recurrence in sentinel node–positive melanoma patients, to determine whether the different definitions that are being used to describe in-transit metastases influence this rate, and to identify factors associated with locoregional recurrence. A comparison was made with the rate of locoregional recurrence in patients who underwent lymph node dissection for palpable metastases.     

Immediate Local and Regional Recurrence After the Excision of a Polypoid Melanoma: Tumor Dormancy or Tumor Activation?

Recurrent melanoma occurs in approximately one third of the patients who are treated for cutaneous melanoma. Although the majority of recurrences occur within the first few years of primary therapy, a significant number remain at risk beyond 10 years. Tumor dormancy provides the conceptual framework to explain a prolonged quiescent state in which tumor cells are present, but tumor progression is not clinically apparent. Surgery, or other perturbing factors, might modulate the transition of dormant cancer cells to rapidly growing ones. These may be due to a perturbation of the mechanisms of tumor regulation such as local immunity or angiogenesis. Here, the case of a woman is discussed in whom the surgical removal of a polypoid melanoma was followed, in less than a month, by local recurrence and locoregional lymph nodal metastases, which were previously clinically absent.     

Role of Sentinel Lymph Node Biopsy in Patients With Thin (<1 mm) Primary Melanoma

Background: Thin melanomas have become increasingly prevalent, and lesions 1 mm in thickness are frequently diagnosed. They are considered highly curable when treated solely with wide local excision, with reported 5-year disease-free survivals of 95% to 98%. However, thin Clark level III and IV melanomas may have increased potentials for metastasizing and late recurrences because of dermal lymphatics located at the interface of the papillary and reticular dermis. We have addressed this controversial area by reviewing the outcomes of patients with invasive thin melanomas.Methods: We performed 266 sentinel lymph node biopsy procedures, using both radioisotope and blue dye, over a 5-year period. Sixty-five of the 266 invasive melanomas were thin and were treated by wide local excision and sentinel lymph node biopsy.Results: Two (3%) of the 65 thin melanomas were found to have a positive sentinel lymph node. In melanomas thinner than .75 mm, no positive sentinel lymph node was found. Therefore, only 3% of patients may benefit from tumor upstaging by sentinel lymph node biopsy.Conclusions: The occurrence of regional lymph node metastases in thin melanomas is rather low. Our data suggest that sentinel lymph node biopsy may not justified in patients with melanoma <.75 mm thick.     

Pathology Review Significantly Affects Diagnosis and Treatment of Melanoma Patients: An Analysis of 5011 Patients Treated at a Melanoma Treatment Center

Background

Pathologists sometimes disagree on the diagnosis of melanoma or its histopathologic staging, which may have implications for treatment and follow-up. For this reason, melanoma patients referred to Melanoma Institute Australia (MIA) for further treatment routinely have their pathology slides reviewed by MIA pathologists. This study sought to determine whether diagnosis, staging, and treatment of melanoma patients changed significantly after central pathology review.

Methods

A total of 5,011 pairs of non-MIA and MIA pathology reports on the same primary melanoma specimen were reviewed. Differences in diagnosis, American Joint Committee on Cancer (AJCC) T classification, and treatment recommendations based on the non-MIA and MIA pathology reports were determined.

Results

A melanoma diagnosis changed in 5.1 % of cases after review. Where both pathologists agreed on a diagnosis of melanoma, AJCC T classification changed in 22.1 % after review. After MIA review, planned surgical excision margins changed in 11.2 % of cases, and a recommendation for sentinel lymph node biopsy (SLNB) changed in 8.6 %. Non-MIA reports less frequently contained criteria to define AJCC T classification (86.6 vs. 97.6 %), select appropriate surgical excision margins (95.2 vs. 99.6 %) and make a recommendation for SLNB (94.5 vs. 99.4 %), (each p < 0.001). On multivariate analysis, partial biopsies were independently associated with more frequent changes in AJCC T classification (p < 0.001), planned surgical excision margins (p < 0.001), and SLNB recommendations (p < 0.001) on the basis of MIA pathology review.

Conclusions

Diagnosis, AJCC T classification, and treatment recommendations often change after pathology review by specialist melanoma pathologists. We recommend pathology review be considered for all patients attending specialist melanoma treatment centers.     

Local Recurrence following Total Mesorectal Excision with Double-stapling Anastomosis for Rectal Cancers: Analysis of Risk Factors

This study reviewed the local recurrence rate in patients who had undergone total mesorectal excision and double-stapling low anterior resection for mid and distal rectal cancers. It also aimed to identify risk factors for local recurrence through univariate and multivariate analyses. Consecutive patients with rectal cancers within 12 cm of the anal verge treated with total mesorectal excision and double-stapling low anterior resection from August 1993 to December 2000 were studied. The demographic data, operative details, tumor characteristics, and follow-up data were collected prospectively. Factors that might affect the local recurrence rate were analyzed with univariate and multivariate analyses. A total of 270 patients were included in the study (156 men, 114 women). The mean +/- SD age was 64.83 +/- 11.27 years. The mean +/- SD level of the tumor was 7.17 +/- 1.90 cm. All anastomoses were performed within 5 cm of the anal verge. During the mean follow-up of 35.5 months, 12 patients developed local recurrence. The 5-year actuarial local recurrence rate was 7.3%. The presence of lymphovascular invasion and the resection margin of < or = 1 cm were found to be risk factors for local recurrence in the univariate analysis. In the multivariate analysis, the presence of lymphovascular invasion was the only independent factor for local recurrence. In the group of patients with lymphovascular invasion, proximal tumors (6-12 cm from the anal verge) were shown to have a significantly lower local recurrence than those within 6.1 cm from the anal verge (4.2% vs. 37.8%; p <0.001). Low anterior resection performed with double stapling and total mesorectal excision achieved a local recurrence rate of 7.3%. The presence of lymphovascular invasion was the only independent risk factor for local recurrence. A high local recurrence rate was associated with distal cancers (? 6 cm from the anal verge) with lymphovascular invasion. Adjuvant therapy for local control should be considered for this subgroup of patients.     

The Impact of the Introduction of Total Mesorectal Excision on Local Recurrence Rate and Survival in Rectal Cancer: Long-Term Results

Purpose  

To investigate the influence of the introduction of total mesorectal excision (TME) on local recurrence rate and survival in patients with rectal cancer.     

Improved Staging of Node-Negative Patients With Intermediate to Thick Melanomas (>1 mm) With the Use of Lymphatic Mapping and Sentinel Lymph Node Biopsy

Background: Elective lymph node dissection ELND may contribute to a survival benefit in certain stratified subsets of melanoma patients. We hypothesized that lymphatic mapping and sentinel lymph node SLN biopsy with complete node dissection if metastases are present may improve both staging and survival of patients with clinically negative nodes, without subjecting all patients to the morbidity associated with complete ELND.Methods: We reviewed the data for all 14,914 N0 patients of the AJCC Melanoma Staging Database to determine the effect of SLN biopsy and ELND on staging and survival.Results: Retrospective analysis revealed that there was an apparent statistically significant survival advantage to SLN biopsy in patients with melanomas >1 mm n = 9024; 68.5% and 26.2% reduction in mortality compared with patients staged to be N0 by clinical exam and ELND, respectively; P < .0001. Five-year survivals were 90.5%, 77.7%, and 69.8%, respectfully, for patients staged by SLN biopsy n = 2552, ELND n = 2014, and clinical examination alone n = 5192. The survival advantage of SLN biopsy was statistically significant for each T-stage category T2, T3, and T4 and ulceration status. There was no advantage to SLN biopsy in patients with melanomas <1 mm n = 5890.Conclusions: SLN biopsy provides more accurate staging and may contribute to a survival benefit in populations of patients with melanoma.*Members of the AJCC Melanoma Staging Committee: Charles M. Balch, MD, Antonio C. Buzaid, MD, Seng-Jaw Soong, PhD, Michael B. Atkins, MD, Natale Cascinelli, MD, Daniel G. Coit, MD, Irvin D. Fleming, MD, Jeffrey E. Gershenwald, MD, Alan Houghton Jr., MD, John M. Kirkwood, MD, Kelly M. McMasters, MD, Martin F. Mihm, MD, Donald L. Morton, MD, Douglas S. Reintgen, MD, Merrick I. Ross, MD, Arthur Sober, MD, John A. Thompson, MD, and John F. Thompson, MD.Presented in part at the 54th Annual Meeting of the Society of Surgical Oncology, Washington, DC, March 15-18, 2001.     

Metabolomics Profiling of Patients With A−β+ Ketosis-Prone Diabetes During Diabetic Ketoacidosis

When stable and near-normoglycemic, patients with “A−β+” ketosis-prone diabetes (KPD) manifest accelerated leucine catabolism and blunted ketone oxidation, which may underlie their proclivity to develop diabetic ketoacidosis (DKA). To understand metabolic derangements in A−β+ KPD patients during DKA, we compared serum metabolomics profiles of adults during acute hyperglycemic crises, without (n = 21) or with (n = 74) DKA, and healthy control subjects (n = 17). Based on 65 kDa GAD islet autoantibody status, C-peptide, and clinical features, 53 DKA patients were categorized as having KPD and 21 type 1 diabetes (T1D); 21 nonketotic patients were categorized as having type 2 diabetes (T2D). Patients with KPD and patients with T1D had higher counterregulatory hormones and lower insulin-to-glucagon ratio than patients with T2D and control subjects. Compared with patients withT2D and control subjects, patients with KPD and patients with T1D had lower free carnitine and higher long-chain acylcarnitines and acetylcarnitine (C2) but lower palmitoylcarnitine (C16)-to-C2 ratio; a positive relationship between C16 and C2 but negative relationship between carnitine and β-hydroxybutyrate (BOHB); higher branched-chain amino acids (BCAAs) and their ketoacids but lower ketoisocaproate (KIC)-to-Leu, ketomethylvalerate (KMV)-to-Ile, ketoisovalerate (KIV)-to-Val, isovalerylcarnitine-to-KIC+KMV, propionylcarnitine-to-KIV+KMV, KIC+KMV-to-C2, and KIC-to-BOHB ratios; and lower glutamate and 3-methylhistidine. These data suggest that during DKA, patients with KPD resemble patients with T1D in having impaired BCAA catabolism and accelerated fatty acid flux to ketones—a reversal of their distinctive BCAA metabolic defect when stable. The natural history of A−β+ KPD is marked by chronic but varying dysregulation of BCAA metabolism.     

Impact of Her‐2‐Targeted Therapy on Overall Survival in Patients With Her‐2 Positive Metastatic Breast Cancer

Upon disease progression on trastuzumab‐based therapy, patients with HER‐2 positive metastatic breast cancer (MBC) may switch to lapatinib or continue on trastuzumab. We aimed to assess the impact of both strategies on overall survival (OS) in all patients treated for HER‐2 positive MBC at the Medical University Vienna from 1999 until 2009. A total of 201 patients were identified from a breast cancer data base. Of these 115 (57.2%) received multiple lines of trastuzumab‐based therapy, whereas 58 (28.9%) were treated with a single line. A control group of 28 patients (13.9%) had never received trastuzumab as they were treated before 1999, when trastuzumab was registered. OS from diagnosis of metastatic disease was defined as primary study endpoint. Trastuzumab significantly prolonged OS in HER‐2 positive MBC (41 versus 13 months; p < 0.001). Administration of multiple lines further improved OS; this, however, did not reach statistical significance (47 versus 28 months; p = 0.069). Positive estrogen receptor (ER) status (HR 1.6; 95% CI 1.13–2.27) was associated with better outcome compared to negative estrogen receptor status (p = 0.02). Addition of lapatinib did not improve OS significantly in patients with prior trastuzumab‐based therapy (62 versus 47 months; p = n.s.). Patients receiving lapatinib after diagnosis of BM, however, experienced an improvement of OS (22 versus 5 months; p = 0.022). Trastuzumab improves OS in patients with HER‐2 positive MBC with further nonsignificant improvement when administered in multiple lines. Lapatinib did not further improve OS in the entire population; however, lapatinib might improve OS in patients with BM.     

Symposium VI: Calcium Homeostasis in Cardiac Myocytes: β‐Adrenergic Stimulation Modulation of Heart Rate via Synchronization of Ryanodine Receptor Ca2+ Release

Abstract A robust “fight or flight response”, largely mediated via acute β‐adrenergic receptor (β‐AR) stimulation to the heart to increase its beating rate and contractile performance, is an essential component of the vertebrate survival instinct. While it has long been recognized that activation of β‐AR increases the spontaneous beating rate of sinoatrial nodal cells (SANC), specific links between stimulation of β‐ARs and the resultant increase in firing rate have not been evaluated. Our recent studies^1–2 employed imaging of subcellular Ca²⁺ release coupled with recording of membrane potential or current in single, isolated cardiac SANC, to seek novel links between β‐AR stimulation and ryanodine receptor Ca²⁺ release and heart rate. An overview of these recent results, which provides novel insights into mechanisms of cardiac reserve that underlie the “fight or flight instinct, is presented here.     

Survival Rate and Application Number of Total Hip Arthroplasty in Patients With Femoral Neck Fracture: An Analysis of Clinical Studies and National Arthroplasty Registers

BackgroundTotal hip arthroplasty (THA) is an increasingly popular treatment option for fractured neck of femur (NOF). The primary aim of this study is to systematically review all literature on primary THA and hemiarthroplasty (HA) after fractured NOF to calculate an overall revision rate. Furthermore, we wanted to compare primary THA implantations after fractured NOF between different countries in terms of THA number per inhabitant.MethodsAll clinical studies on THA and HA for femoral neck fractures between 1999 and 2019 were reviewed and evaluated with a special interest on revision rate. Revision rate was calculated as “revision per 100 component years.” THA registers were compared between different countries with respect to the number of primary implantations per inhabitant.ResultsTHA studies showed a mean revision rate of 11.8% after 10 years, which was lower than a 24.6% 10-year revision rate for HA. We identified 8 arthroplasty registers that revealed an annual average incidence of THA for fractured NOF of 9.7 per 100,000 inhabitants.ConclusionThis study showed that patients with THA were less likely to be revised at 10 years compared to HA. We found similar annual numbers of THAs for fractured NOF per inhabitant across countries. The results of this analysis can be used to rank present and future national THA numbers within an international context.     

Bone Health in Patients With Hematopoietic Disorders of Bone Marrow Origin: Systematic Review and Meta‐ Analysis

Blood cell production and bone homeostasis are physically interlinked systems that exhibit active cross‐talk. We examined how bone health is affected in patients with hematopoietic disorders due to abnormal proliferation of bone marrow cells. The electronic databases Medline, Embase, PubMed, BIOSIS Previews, Web of Science, and Cochrane were searched for studies presenting numerical values for trabecular bone volume or bone mineral density in control and patients with hematopoietic disorders. We identified 5 studies for beta‐thalassemia, 6 for sickle cell anemia, 2 for polycythemia vera and essential thrombocythemia, 3 for chronic myelogenous leukemia, 6 for myelofibrosis, 5 for multiple myeloma, and 4 studies each for systemic mastocytosis, lymphocytic leukemia, and hemochromatosis. The effect of the disease state on bone density was significant and negative for beta‐thalassemia (r = –2.00; 95% confidence interval [CI] –3.41, –0.58; p < 0.005), sickle cell anemia (–0.91; –1.36, –0.47; p < 0.00005), chronic myelogenous leukemia (–0.55; –0.88, –0.22; p < 0005), mastocytosis (–0.99; –1.16, –0.82; p < 0.00001), lymphoblastic leukemia (–0.69; –0.98, –0.40; p < 0.00001), multiple myeloma (–0.67; –0.99, –0.35; p < 0.00005), and hemochromatosis (–1.15; –1.64, –0.66; p < 0.00001). The changes were negative but not significant for polycythemia vera (–0.16; –0.38, 0.05; p = 0.069) and essential thrombocythemia (–0.33; –0.92, 0.26; p = 0.14). In myelofibrosis, disease state was associated with increased bone density (0.74; 0.12, 1.36; p < 0.05). Bone density change significantly and negatively correlated with the level of ferritin and bone marrow cellularity but not with hemoglobin or erythropoietin. Thus, independent of hematopoietic lineage, abnormal proliferation of bone marrow cells appears to be associated with bone loss. Iron metabolism may independently contribute to bone homeostasis. © 2016 American Society for Bone and Mineral Research.     

An economical method of comparing inhaled bronchodilators in reversible diffuse airways obstruction: With special reference to a β-2 stimulant—salmefamol

Lal, S., Dash, C. H., and Gribben M. D. (1974).Thorax, 29, 317-322. An economical method of comparing inhaled bronchodilators in reversible diffuse airways obstruction: with special reference to a β-2 stimulant—salmefamol. A method is described for comparing the bronchodilator effect of a large number of drugs. It involves self-recording of peak expiratory flow rate by patients at home. From the experience gained, the method was used to compare isoprenaline, orciprenaline, terbutaline, salbutamol, and salmefamol with an inert pressurized aerosol. The results of the comparison show that the method is simple and practical and that salmefamol would seem to have a more prolonged bronchodilator effect than the other drugs tested.     

Additional Analysis of the Secondary End Point of Biochemical Recurrence Rate in a Phase 3 Trial (CS21) Comparing Degarelix 80 mg Versus Leuprolide in Prostate Cancer Patients Segmented by Baseline Characteristics

Background

Recent data suggest prostate-specific antigen (PSA) progression may predict overall survival in prostate cancer patients.

Objective

To compare the activity of degarelix and leuprolide regarding PSA recurrence-free survival.

Design, setting, and participants

Phase 3, 1-yr, multicentre, randomised, open-label trial comparing the efficacy and safety of degarelix at 240 mg for 1 mo, and then 80 mg monthly (240/80 mg); degarelix at 240 mg for 1 mo, and then 160 mg monthly; and leuprolide at 7.5 mg/mo. Overall, 610 patients with histologically confirmed prostate cancer (all stages), for whom androgen deprivation therapy was indicated, were included. The primary end point of this trial has been reported previously; the protocolled and exploratory subgroup analyses reported in this paper focus on degarelix at 240/80 mg (dose approved by the US Food and Drug Administration and the European Medicine Evaluation Association for the treatment of patients with hormone-naive advanced prostate cancer).

Measurements

PSA progression-free survival (two consecutive increases in PSA of 50% compared with nadir and ≥5 ng/ml on two consecutive measurements at least 2 wk apart or death) and change in PSA were reviewed. Effects of baseline disease stage (localised, locally advanced, and metastatic) and PSA level (<10, 10–20, >20–50, and >50 ng/ml) were analysed.

Results and limitations

Patients receiving degarelix showed a significantly lower risk of PSA progression or death compared with leuprolide (p = 0.05). PSA recurrences occurred mainly in patients with advanced disease and exclusively in those with baseline PSA >20 ng/ml. Patients with PSA >20 ng/ml had a significantly longer time to PSA recurrence with degarelix (p = 0.04). The relatively low number of patients in each subgroup is a limitation of this study.

Conclusions

These results generate the hypothesis that degarelix at 240/80 mg offers improved PSA control compared with leuprolide. PSA recurrences occurred almost exclusively in patients with metastatic prostate cancer or high baseline PSA during this 1-yr study. Further studies are warranted to confirm these findings.