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Background Malignant cutaneous adnexal tumors (MCATs) are rare and their natural history is poorly understood. Available literature indicates aggressive behavior with a significant risk of metastasis. Study Design Retrospective review of our institutional surgical oncology databases was performed for patients diagnosed with MCATs (2001-2020). We hypothesized that most patients have a low risk of lymph node involvement, recurrence, and death. Kaplan-Meier statistical analysis was used to assess risk of recurrence and 5-year survival. Results We identified 41 patients diagnosed with MCATs (median age 59 years, 68% were men). Most patients had long-standing cutaneous lesions (median 24 months) and no palpable adenopathy. Most patients had stage I or II disease (98%). Primary tumors were treated with wide local excision (n = 28 [68%]), Mohs surgery (n = 5 [12%]), or amputation (n = 8 [19%]). Of 25 patients who underwent SLNB (61%), 1 had lymphatic metastasis. These include apocrine carcinoma (1 of 3), digital papillary adenocarcinoma (0 of 8), porocarcinoma (0 of 4), and additional MCAT sub-types (0 of 10). Three patients (7%) had disease recurrence at a median interval of 3.6 years (interquartile range 1.5 to 4.4 years). Five patients (12%) died at a median interval of 7 years (interquartile range 6.7 to 9.2 years), but only 1 patient was known to have succumbed to MCAT. Overall 5-year survival rate was 96% (95% CI, 75% to 99%). Conclusions Despite the historical impression that MCATs have a high metastatic potential, most patients have low recurrence rates and excellent 5-year survival rates. Lymphatic disease identified after SLNB in early-stage tumors is rare and the value of this staging procedure in MCAT remains unclear. more...

Under current AJCC staging criteria, stage IIC patients paradoxically have worse outcomes than IIIA patients despite the lack of nodal metastatic disease. This study sought to identify additional clinicopathologic characteristics correlated with worse patient outcomes. Retrospective chart review of stage IIC and IIIA melanoma patients were evaluated between 1995 and 2011 with clinical follow-up through 2015. Records were reviewed for demographics, clinical characteristics, and tumor pathology. Fisher's exact test and Wilcoxon's rank-sum test were used to assess group differences. Clinicopathologic features were evaluated relative to overall survival (OS), time to distant metastases, and local/regional recurrence. Overall, 128 patients were included (45 stage IIC and 83 stage IIIA) with a median follow-up time of 5.7 years. Compared with stage IIIA patients, stage IIC patients were older, and their melanomas were more likely to be nodular, amelanotic, thicker, have higher mitotic rate, tumor lymphocytic infiltrate, no radial growth phase, and less likely to have associated precursor lesions. Stage IIC patients had shorter OS and time to distant metastases; multivariate regression revealed that older age (>55 years) and mitotic rate (>5 mitoses/mm) were independent predictors of OS. Melanomas in stage IIC disease may be biologically distinct from those that are seen in stage IIIA. While sentinel node biopsies remain the standard-of-care, these results suggest that clinicians may want to assess the clinicopathologic characteristics described above to aggressively counsel, screen for distant disease, and consider adjuvant therapy, in particular for older patients and higher mitotic rates in thicker primary tumors, regardless of nodal status. more...

The superiority of surgical cut-down of the cephalic vein versus percutaneous catheterization of the subclavian vein for the insertion of totally implantable venous access devices (TIVADs) is debated. To compare the safety and efficacy of surgical cut-down versus percutaneous placement of TIVADs. This is a single-institution retrospective cohort study of oncologic patients who had TIVADs implanted by 14 surgeons. Primary outcomes were inability to place TIVAD by the primary approach and postoperative complications within 30 days. Multivariate analysis was performed by logistic regression. Secondary outcomes included operative time. Two hundred and forty-seven (55.9%) percutaneous and 195 (44.1%) cephalic cut-down patients were identified. The 30-day complication rate was 5.2 per cent: 14 patients (5.7%) in the percutaneous and nine (4.6%) in the cut-down group. The technique was not a significant predictor of having a 30-day complication (odds ratio = 0.820; 95% confidence interval 0.342–1.879). Implantation failure was observed in 16 percutaneous patients (6.5%) and 28 cut-down patients (14.4%) (adjusted odds ratio for cephalic vs cut-down = 2.387; 95% confidence interval 1.275–4.606). The median operative time for percutaneous patients was 46 minutes (interquartile range = 35, 59) versus 37.5 minutes (interquartile range = 30, 49) for cut-down patients(P < 0.0001). Both the percutaneous and cut-down technique are safe and effective for TIVAD implantation. Operative times were shorter and the odds of implantation failure higher for cephalic cut-down. As implantation failure is common, surgeons should familiarize themselves with both techniques. more...

The superiority of surgical cut-down of the cephalic vein versus percutaneous catheterization of the subclavian vein for the insertion of totally implantable venous access devices (TIVADs) is debated. To compare the safety and efficacy of surgical cut-down versus percutaneous placement of TIVADs. This is a single-institution retrospective cohort study of oncologic patients who had TIVADs implanted by 14 surgeons. Primary outcomes were inability to place TIVAD by the primary approach and postoperative complications within 30 days. Multivariate analysis was performed by logistic regression. Secondary outcomes included operative time. Two hundred and forty-seven (55.9%) percutaneous and 195 (44.1%) cephalic cut-down patients were identified. The 30-day complication rate was 5.2 per cent: 14 patients (5.7%) in the percutaneous and nine (4.6%) in the cut-down group. The technique was not a significant predictor of having a 30-day complication (odds ratio = 0.820; 95% confidence interval 0.342-1.879). Implantation failure was observed in 16 percutaneous patients (6.5%) and 28 cut-down patients (14.4%) (adjusted odds ratio for cephalic vs cut-down = 2.387; 95% confidence interval 1.275-4.606). The median operative time for percutaneous patients was 46 minutes (interquartile range = 35, 59) versus 37.5 minutes (interquartile range = 30, 49) for cut-down patients(P0.0001). Both the percutaneous and cut-down technique are safe and effective for TIVAD implantation. Operative times were shorter and the odds of implantation failure higher for cephalic cut-down. As implantation failure is common, surgeons should familiarize themselves with both techniques. more...

Totally implantable venous access devices (portacaths, or "ports"), are widely used for intermittent central venous access especially for cancer patients. Although ports have a superior safety margin compared with other long-term venous access devices, there are a number of complications associated with their use.This is a narrative review. We searched PubMed and Google Scholar for articles about complications related to the use of portacaths. "Similar articles" feature of PubMed and reference list of the existing literature were also reviewed for additional relevant studies.In this review, we provide the latest evidence regarding the most common ones of these adverse events and how to diagnose and treat them. Immediate complications including pneumothorax, hemothorax, arterial puncture, and air embolism as well as late complications such as port infection, malfunction, and thrombosis are covered in detail.Physicians should be familiar with port complications and their diagnosis and management. more...

Purpose: To determine if melanoma within the tumor microenvironment will result in immunosuppression within the draining lymph node as measured by down-regulation of T-cell receptor ζ (TCR ζ) expression.Experimental Design: Patients with clinical stage I to III melanoma undergoing wide local excision and sentinel lymph node biopsy or therapeutic lymph node dissection were consented to have a portion of their lymph node sampled. Lymph nodes were classified as macroscopically involved (TI), microscopically involved (MI), noninvolved with positive wide excision (NI+), or noninvolved with negative wide excision (NI−). Lymphocytes were stained using antibodies to TCR ζ and other immune cells and analyzed via flow cytometer. Reverse transcription-PCR was used to assess for mediators of immunosuppression.Results: Fifty patient lymph node samples (15 TI, 7 MI, 9 NI+, and 19 NI−) were evaluated. Increasing involvement of tumor in the lymph node was associated with decreasing TCR ζ chain expression (TI 56%, MI 76%, and NI− 89%). Differences between TI and MI (P = 0.005), TI and NI− (P = 0.0001), and MI and NI− (P = 0.019) were statistically significant. There was also a significant difference between TCR ζ chain expression of NI+ and NI− (73% versus 89%; P = 0.0016). A trend toward increased arginase expression in tumor-involved lymph nodes was detected by reverse transcription-PCR.Conclusions: Melanoma involvement of regional nodes is associated with loss of TCR ζ expression that is inversely related to tumor burden. Residual melanoma within the wide local excision specimen is associated with TCR ζ loss in noninvolved sentinel lymph nodes, suggesting that immune modulation precedes tumor spread. more...

Background Carcinoid tumors in the breast are rare. Most represent metastases from other primary sites, but commonly are mistaken for primary breast lesions. Methods A literature search of the English language found 59 cases of carcinoid tumors in the breast, 21 (36%) of which were metastases. Results We present an additional 3 cases of carcinoid tumors metastatic to the breast and discuss the clinical, radiologic, and pathologic manifestations. Conclusions It is important to differentiate between primary breast carcinoid tumor and metastatic disease to the breast because of differences in treatment. All palpable breast masses and mammographically detected lesions should undergo a biopsy examination. In those patients with a known history of carcinoid tumor, pertinent clinical history, and previous surgical specimens should be reviewed to avoid an unnecessary mastectomy. If there is no history of a prior carcinoid tumor, a thorough work-up to look for an occult primary tumor elsewhere should be performed. more...

Patients receiving home total parenteral nutrition (HTPN) are at risk for the development of essential fatty acid deficiency (EFAD). This study examined the essential fatty acid status of patients on long-term HTPN for gut failure. Serum phospholipid and triglyceride fatty acids were measured in 11 patients and 10 healthy volunteers. Patients had similar levels of linoleic acid (18:2w6) in serum triglyceride fatty acids but significantly lower levels of 18:2w6 in serum phospholipids compared to controls. Although there was accumulation of Mead acid (20:3w9) in both fatty acid fractions, the ratio of 20:3w9 to arachidonic acid (20:4w6) remained less than 0.2, reflecting an adequate essential fatty acid status in these patients. There were, however, substantial increases in 20:4w6 content in both triglyceride and phospholipid fractions in serum despite the lower levels of 18:2w6 in serum phospholipids, suggesting that an accelerated hepatic conversion of 18:2w6 to 20:4w6 occurs in HTPN patients, as well as the 20-carbon members of w3 (20:3w3) and w9 (20:3w9) families. The determination of optimal parenteral fat intakes should be investigated further as important priority in patients receiving long term HTPN. more...

This study was designed to examine circulating and urine cytokine levels in patients receiving long-term home total parenteral nutrition (TPN) support. Twelve patients who had been receiving home TPN for more than 1 year (range, 1.3-19.5 years) were enrolled for study. To avoid the potential confounding effects of intercurrent infection, patients were studied during periods of clinical stability without clinical evidence of infection. Ten normal healthy volunteers served as controls. Serum levels of albumin and C-reactive protein, temperature, body weight, and blood white cell counts were determined. The levels of soluble tumor necrosis factor receptor II (sTNF-RII) and interleukin 6 (IL-6) were measured in serum and 24-hr urine. The results showed that the concentrations of sTNF-RII and IL-6 in 24-hr urine and serum were significantly higher in patients, indicating that long-term home TPN may be associated with a persistent low-grade inflammatory state. more...

The aim of this pilot study was to assess tolerance of a beverage containing ω-3 fatty acids (fish oil) in patients with malabsorption receiving chronic parenteral nutrition (PN). The authors wanted to determine whether fish oil could be absorbed and incorporated into plasma fatty acids and reduce markers of inflammation.This was a small intervention study in home-dwelling PN-dependent patients with chronic malabsorption. Ten patients were provided a drink containing 1.5 g of fish oil per day for 12 weeks. Baseline and post-supplement serum fatty acid profiles were compared.Five of 10 patients withdrew from the study because of GI side effects, principally worsened diarrhea, associated with the supplement. Modest increases were found in 20:5ω-3, 22:5ω-3, and 22:6ω-3 levels in both phospholipids and triglycerides in plasma (all P.05). In phospholipids, a reduced arachidonic acid level was seen (P = .02). These changes were not sufficient to effect improvements in serum tumor necrosis factor-alpha (TNFα), soluble TNF receptor, C-reactive protein, or interleukin-6.Some patients with severe malabsorption can absorb oral ω-3 fatty acid supplements and incorporate these fatty acids into serum phospholipids and triglycerides. However, side effects are very common, and no anti-inflammatory effect was found, presumably related to the modest level of fatty acid change. more...

When rats are fed a protein deficient (PD) diet for 7 days, rates of proteolysis in skeletal muscle decrease by 40-50% (N. E. Tawa, Jr., and A. L. Goldberg. Am. J. Physiol. 263 (Endocrinol. Metab. 26): E317-325, 1992). To identify the underlying biochemical adaptations, we measured different proteolytic processes in incubated muscles. The capacity for intralysosomal proteolysis, as shown by sensitivity to methylamine or lysosomal protease inhibitors, fell 55-75% in muscles from PD rats. Furthermore, extracts of muscles of PD rats showed 30-70% lower activity of many lysosomal proteases, including cathepsins B, H, and C, and carboxypeptidases A and C, as well as other lysosomal hydrolases. The fall in cathepsin B and proteolysis was evident by 3 days on the PD diet, and both returned to control levels 3 days after refeeding of the normal diet. In muscles maintained under optimal conditions, 80-90% of protein breakdown occurs by nonlysosomal pathways. In muscles of PD rats, this ATP-dependent process was also 40-60% slower. Even though overall proteolysis decreased in muscles of PD rats, their capacity for Ca(2+)-dependent proteolysis increased (by 66%), as did the activity of the calpains (+150-250%). Thus the lysosomal and the ATP-dependent processes decrease coordinately and contribute to the fall in muscle proteolysis in PD animals. more...

9078 Background: Sentinel lymph node (SLN) status is used in melanoma AJCC staging to distinguish between stage I or II and stage III disease. However patients (pts) with stage IIC (Breslow > 4 mm,... more...

Muscle wasting accompanies aging and pathological conditions ranging from cancer, cachexia, and diabetes to denervation and immobilization. We show that activation of NF-kappaB, through muscle-specific transgenic expression of activated IkappaB kinase beta (MIKK), causes profound muscle wasting that resembles clinical cachexia. In contrast, no overt phenotype was seen upon muscle-specific inhibition of NF-kappaB through expression of IkappaBalpha superrepressor (MISR). Muscle loss was due to accelerated protein breakdown through ubiquitin-dependent proteolysis. Expression of the E3 ligase MuRF1, a mediator of muscle atrophy, was increased in MIKK mice. Pharmacological or genetic inhibition of the IKKbeta/NF-kappaB/MuRF1 pathway reversed muscle atrophy. Denervation- and tumor-induced muscle loss were substantially reduced and survival rates improved by NF-kappaB inhibition in MISR mice, consistent with a critical role for NF-kappaB in the pathology of muscle wasting and establishing it as an important clinical target for the treatment of muscle atrophy. more...

Certain patients receiving home total parenteral nutrition (HPN) are likely to develop iron-deficiency anemia because of inadequate absorption or chronic iron loss from gastrointestinal lesions. The objective of this study was to examine the incidence and prevalence of iron deficiency anemia in patients on long-term HPN (6 months) and to investigate both the efficacy of and rate of adverse reactions to parenteral iron dextran therapy.The records of 55 patients treated with HPN for6 months between January 1, 1994 and December 31, 1999 were examined.Thirty patients (55%) had evidence of iron-deficiency anemia. Ten patients were diagnosed at the initiation of HPN, and in 20 patients, iron deficiency developed after receiving HPN. The time between initiation of HPN and development of anemia ranged from 2 to 97 months (mean 28.8+/-26.2 months). Mild iron loss from the gastrointestinal tract seemed to be the predominant reason for iron deficiency. Regular treatment with small amounts of iron in HPN appeared to be safe and efficacious, with no reported side effects. Total dose infusion of iron was associated with adverse reactions in as many as 25% of these patients, although all reactions were mild and self-limited.Iron-deficiency anemia is common in patients receiving chronic HPN. Regular small doses of iron in HPN formula, rather than total dose infusion, is the preferred treatment. more...

e20039 Background: Mitotic rate was incorporated into the AJCC 7th edition staging system for cutaneous melanoma because of its prognostic impact on melanoma-specific survival in patients with thin... more...

e15188 Background: Totally implantable venous access devices (ports) can be used in pancreatic cancer treatment. Long-term device placement facilitates agent infusion and reduces discomfort from re... more...

We tested the safety of a nonviral somatic-cell gene-therapy system in patients with severe hemophilia A.An open-label, phase 1 trial was conducted in six patients with severe hemophilia A. Dermal fibroblasts obtained from each patient by skin biopsy were grown in culture and transfected with a plasmid containing sequences of the gene that encodes factor VIII. Cells that produced factor VIII were selected, cloned, and propagated in vitro. The cloned cells were then harvested and administered to the patients by laparoscopic injection into the omentum. The patients were followed for 12 months after the implantation of the genetically altered cells. An interim analysis was performed.There were no serious adverse events related to the use of factor VIII-producing fibroblasts or the implantation procedure. No long-term complications developed, and no inhibitors of factor VIII were detected. In four of the six patients, plasma levels of factor VIII activity rose above the levels observed before the procedure. The increase in factor VIII activity coincided with a decrease in bleeding, a reduction in the use of exogenous factor VIII, or both. In the patient with the highest level of factor VIII activity, the clinical changes lasted approximately 10 months.Implantation of genetically altered fibroblasts that produce factor VIII is safe and well tolerated. This form of gene therapy is feasible in patients with severe hemophilia A. more...

Several observations have suggested that the enhanced proteolysis and atrophy of skeletal muscle in various pathological states is due primarily to activation of the ubiquitin-proteasome pathway. To test this idea, we investigated whether peptide aldehyde inhibitors of the proteasome, N-acetyl-leucyl-leucyl-norleucinal (LLN), or the more potent CBZ-leucyl-leucyl-leucinal (MG132) suppressed proteolysis in incubated rat skeletal muscles. These agents (e.g., MG132 at 10 microM) inhibited nonlysosomal protein breakdown by up to 50% (P < 0.01), and this effect was rapidly reversed upon removal of the inhibitor. The peptide aldehydes did not alter protein synthesis or amino acid pools, but improved overall protein balance in the muscle. Upon treatment with MG132, ubiquitin-conjugated proteins accumulated in the muscle. The inhibition of muscle proteolysis correlated with efficacy against the proteasome, although these agents could also inhibit calpain-dependent proteolysis induced with Ca2+. These inhibitors had much larger effects on proteolysis in atrophying muscles than in controls. In the denervated soleus undergoing atrophy, the increase in ATP-dependent proteolysis was reduced 70% by MG132 (P < 0.001). Similarly, the rise in muscle proteolysis induced by administering thyroid hormones was reduced 40-70% by the inhibitors. Finally, in rats made septic by cecal puncture, the increase in muscle proteolysis was completely blocked by MG132. Thus, the enhanced proteolysis in many catabolic states (including denervation, hyperthyroidism, and sepsis) is due to a proteasome-dependent pathway, and inhibition of proteasome function may be a useful approach to reduce muscle wasting. more...

To define the adaptations that conserve amino acids and muscle protein when dietary protein intake is inadequate, rats (60-70 g final wt) were fed a normal or protein-deficient (PD) diet (18 or 1% lactalbumin), and their muscles were studied in vitro. After 7 days on the PD diet, both protein degradation and synthesis fell 30-40% in skeletal muscles and atria. This fall in proteolysis did not result from reduced amino acid supply to the muscle and preceded any clear decrease in plasma amino acids. Oxidation of branched-chain amino acids, glutamine and alanine synthesis, and uptake of alpha-aminoisobutyrate also fell by 30-50% in muscles and adipose tissue of PD rats. After 1 day on the PD diet, muscle protein synthesis and amino acid uptake decreased by 25-40%, and after 3 days proteolysis and leucine oxidation fell 30-45%. Upon refeeding with the normal diet, protein synthesis also rose more rapidly (+30% by 1 day) than proteolysis, which increased significantly after 3 days (+60%). These different time courses suggest distinct endocrine signals for these responses. The high rate of protein synthesis and low rate of proteolysis during the first 3 days of refeeding a normal diet to PD rats contributes to the rapid weight gain ("catch-up growth") of such animals. more...

8000 Background: Metastatic melanoma is associated with various measures of systemic and local immune suppression. We hypothesized that immune suppression in the regional LN basin exists and may facilitate melanoma progression. Methods: We collected portions of regional LNs from tumor uninvolved sentinel LNs (USLN) (remote from primary melanoma removal) and from macroscopically involved nodes (TILN) from therapeutic node dissections in successive melanoma patients. Lymphocytes were extracted, stained using surface and internal antibodies to T cell receptor zeta chain (TCRζ), T regulatory cells (CD4+CD25+ Fox 3p+) (Tregs) and tumor associated myeloid cells (CD11b+ CD14- CD15+) (TAMC), and analyzed via flow cytometer. Results from USLN specimens were compared with TILN. Results: 30 LNs (14 USLN/16 TILN) from 30 patients were evaluated. Median age of patients was 48 years (range 30–83); 20 were male. USLN patients were stage IB (12) or IIA (2); TILN patients were stage IIIB (5), IIIC (5), and IV (6). 7 patients with TILN and none with USLN have progressed. TILN had significantly less TCRζ chain expression than SLN (62% vs. 85%; p = 0.0001). This amounts to a localized decrease of 23% of TCRζ expression (95% CI 13%; 34%). No significant relationship between lymph node involvement and Treg or TAMC was documented. Conclusion: Regional LN involvement with melanoma is associated with a significant reduction in lymphocyte TCRζ expression indicating immune suppression. The mechanism for this is uncertain, but does not appear to be related to changes in Tregs or TAMC (arginase producing cells). We plan to further investigate TCRζ expression in microscopically involved SLNs and SLNs removed at time of primary excision to see if immune changes precede macroscopic tumor involvement. Supported by Harvard Skin SPORE Project 5 and Immune Monitoring Core P50CA93683–01 No significant financial relationships to disclose. more...

In an earlier article I examined the depictions and deeper meanings of lyrics attached to a large group of serious American songs popular in the decades before the Civil War.' There I attempted to establish the symbolic nature of many lyrics as they traced humankind's passage through life-from an arcadian childhood and innocence to an adult world full of strife, sorrow, and aloneness and finally to a permanent home in Heaven (guided by the spirits of loved ones). In what follows I attempt to do the same for the music, particularly the melodies. To that end, the focus of part 2 of "Serious Songs of the Early Nineteenth Century" centers on what the music in these songs is intended to express and those practices and attitudes that invest this expression. To consider the melodies associated with these song lyrics as mere successions of single tones that are organized rhythmically and designed for strophic repetition at a moderately slow tempo tells us little about their purpose. To maintain that tone is apparently connected to tone, that a simplistic sense of flow and anticipation of the melody does ensue, and that a perception of the start and finish of the phrase and strain is planted firmly in the auditor's mind tells us nothing about any inner significance the music might have had for nineteenth-century Americans. We can agree that a melody will alter the "music" residing more...

This is a study of serious American songs written primarily in the four decades before the Civil War and meant to reach a wide audience, an audience that made no particular distinctions between what we now classify as the art song versus the popular song. These are works that exhibit a grave and pensive frame of mind and examine a grave if not somber subject. They are not satirical, nor do they feature gaiety or hints at light-heartedness. Their themes revolve about home, loved ones, the beloved, the adversities of adult life, death, and the hope for an afterlife. Part I of the investigation, published in this issue, focuses entirely upon the lyrics, not the music, of these songs. Part II, which will follow in a later issue of American Music, will concern itself with the melodies, their meaning, and relation to the lyrics. One should avoid the temptation of painting the views of antebellum men and women in stark black or white. Despite the forbidding questions that divided Americans during the three decades before the Civil War--slavery, states' rights, agrarian versus industrial intereststhere were significant values that the public held in common. Aside from divisive issues, such as those just cited, antebellum American society shared the belief, for example, that a person's full personal development required an assent to commonly accepted standards of right and wrong. more...