Axillary web syndrome after axillary dissection.

BACKGROUND: Some patients undergoing axillary lymph node dissection (ALND) experience postoperative pain and limited range of motion associated with a palpable web of tissue extending from the axilla into the ipsilateral arm. The purpose of this study is to characterize the previously undescribed axillary web syndrome (AWS). METHODS: To identify patients with AWS, a retrospective review was performed of all invasive breast cancer patients treated by a single surgeon (REM) between 1980 and 1996. Records were also reviewed of 4 more recent patients who developed AWS after undergoing sentinel node lymph node dissection (SLND) without ALND. RESULTS: Among 750 sequentially treated patients, 44 (6%) developed AWS between 1 and 8 weeks after their axillary procedure. The palpable subcutaneous cords extended from the axillary crease down the ipsilateral arm, across the antecubital space, and in severe cases down to the base of the thumb. The web was associated with pain and limited shoulder abduction (< or = 90 degrees in 74% of patients). AWS resolved in all cases within 2 to 3 months. AWS also occurred after SLND. Tissue sampling of webs in 4 patients showed occlusion in lymphatic and venous channels. CONCLUSIONS: AWS is a self-limiting cause of morbidity in the early postoperative period. More limited axillary surgery, with less lymphovenous disruption, might reduce the severity and incidence of this syndrome, although SLND does not eliminate its occurrence.

Familial fibrocystic pancreatic atrophy with endocrine cell hyperplasia and pancreatic carcinoma.

Understanding the pathology of familial pancreatic carcinoma may provide important insights into pancreatic tumorigenesis. We now describe in detail the pancreatic pathology of an autosomal dominant pancreatic carcinoma kindred with distinct clinical, genetic, and pathologic manifestations differing from all other reported forms of sporadic or familial pancreatic neoplasia. Affected individuals develop a prodrome of diabetes mellitus, pancreatic exocrine insufficiency, and characteristic pancreatic imaging abnormalities. Eleven family members have undergone total pancreatectomy, revealing a unique and characteristic fibrocystic, lobulocentric pancreatic atrophy. This was patchy to diffuse in distribution and was invariably associated with a nesidioblastosis-like endocrine cell hyperplasia. All but one resected pancreas demonstrated glandular epithelial dysplasia: 10 had low-grade dysplasia (pancreatic intraductal neoplasia grade II of III or PanIN II) and seven also had high-grade dysplasia (pancreatic intraductal neoplasia grade III of III or PanIN III). Dysplasia was multifocal in small-to medium-sized duct-like structures within areas of acinar atrophy, microcystic change, and mucinous hyperplasia. Two pancreata had carcinomas of multiple and unusual histologic subtypes, including small cell undifferentiated carcinoma and giant cell anaplastic carcinoma. The findings in this kindred yield important information on a distinctive and previously unrecognized pancreatic cancer precursor. Recognition of this entity may help identify additional kindreds and perhaps the underlying genetic defect. As is the case for other familial cancers, the as yet unknown specific genetic defect may have wider implications for pancreatic cancer in general.

Internal mammary lymph node drainage patterns in patients with breast cancer documented by breast lymphoscintigraphy.

BACKGROUND: Metastases to internal mammary lymph nodes (IMN) may occur in patients with breast cancer and may alter treatment recommendations. The purpose of this study was to identify the frequency of IMN drainage in patients undergoing breast lymphoscintigraphy and sentinel lymph node dissection (SLND). METHODS: The combined technique of peritumoral injection of radiocolloid and Lymphazurin blue for SLND was performed on 220 patients. All patients underwent preoperative lymphoscintigraphy before SLND. Lesion location by quadrant included: 110 upper outer (UOQ), 49 lower outer (LOQ), 30 upper inner (UIQ), 24 lower inner (LIQ), and 7 central. RESULTS: Drainage to any nodal basin was observed in 184 of 220 patients (84%). IMN drainage was documented in 37 of 220 (17%) of patients. IMN drainage without evidence of axillary drainage occurred in 2 of 220 patients(1%). Drainage to the IMN based on quadrant location of the lesion was as follows: UOQ, 10%; LOQ, 27%; UIQ, 17%; LIQ, 25%; and central, 29%. CONCLUSIONS: Internal mammary lymph node drainage shown by breast lymphoscintigraphy is common. Tumors in all quadrants may drain to IMNs, although drainage is significantly more common from quadrants other than the UOQ. Further studies are needed to determine whether lymphoscintigraphy drainage patterns identify patients at the highest risk for IMN metastases who may benefit from radiotherapy.

Sporotrichosis masquerading as pyoderma gangrenosum: case report and review of 19 cases of sporotrichosis.

We present the case of a 59-year-old woman who had large ulcerations on her right leg that were diagnosed initially as pyoderma gangrenosum and treated with three immunosuppressive agents (cyclosporin, prednisone and azathioprine) for 6 months. Results of a biopsy at 6 months showed numerous cigar-shaped bodies consistent with Sporothrix schenckii; identification was confirmed by tissue culture. A retrospective review was performed for all cases diagnosed as sporotrichosis from tissue culture or biopsy specimens at the Mayo Clinic. Nineteen cases were identified. The present case was the only one in which fungal organisms were visible on histological examination. The present case emphasizes the importance of making a definitive histological diagnosis in unusual ulcer cases or in suspected cases of pyoderma gangrenosum before the initiation of immunosuppressive therapy. The large number of cigar-shaped bodies in the tissue is a rare finding in sporothrix infection and has been reported in only two cases previously.

F plasmid conjugative DNA transfer: the TraI helicase activity is essential for DNA strand transfer.

The product of the Escherichia coli F plasmid traI gene is required for DNA transfer via bacterial conjugation. This bifunctional protein catalyzes the unwinding of duplex DNA and is a sequence-specific DNA transesterase. The latter activity provides the site- and strand-specific nick required to initiate DNA transfer. To address the role of the TraI helicase activity in conjugative DNA transfer traI mutants were constructed and their function in DNA transfer was evaluated using genetic and biochemical methods. A traI deletion/insertion mutant was transfer-defective as expected. A traI C-terminal deletion that removed the helicase-associated motifs was also transfer-defective despite the fact that the region of traI encoding the transesterase activity was intact. Biochemical studies demonstrated that the N-terminal domain was sufficient to catalyze oriT-dependent transesterase activity. Thus, a functional transesterase was not sufficient to support DNA transfer. Finally, a point mutant, TraI-K998M, that lacked detectable helicase activity was characterized. This protein catalyzed oriT-dependent transesterase activity in vitro and in vivo but failed to complement a traI deletion strain in conjugative DNA transfer assays. Thus, both the transesterase and helicase activities of TraI are essential for DNA strand transfer.

Melanocyte destruction after antigen-specific immunotherapy of melanoma: direct evidence of t cell-mediated vitiligo.

Current strategies for the immunotherapy of melanoma include augmentation of the immune response to tumor antigens represented by melanosomal proteins such as tyrosinase, gp100, and MART-1. The possibility that intentional targeting of tumor antigens representing normal proteins can result in autoimmune toxicity has been postulated but never demonstrated previously in humans. In this study, we describe a patient with metastatic melanoma who developed inflammatory lesions circumscribing pigmented areas of skin after an infusion of MART-1-specific CD8(+) T cell clones. Analysis of the infiltrating lymphocytes in skin and tumor biopsies using T cell-specific peptide-major histocompatibility complex tetramers demonstrated a localized predominance of MART-1-specific CD8(+) T cells (>28% of all CD8 T cells) that was identical to the infused clones (as confirmed by sequencing of the complementarity-determining region 3). In contrast to skin biopsies obtained from the patient before T cell infusion, postinfusion biopsies demonstrated loss of MART-1 expression, evidence of melanocyte damage, and the complete absence of melanocytes in affected regions of the skin. This study provides, for the first time, direct evidence in humans that antigen-specific immunotherapy can target not only antigen-positive tumor cells in vivo but also normal tissues expressing the shared tumor antigen.

Alar batten cartilage grafting in nasal reconstruction: functional and cosmetic results.

BACKGROUND: Alar batten cartilage grafts can restore form and function to a compromised ala, prevent stenosis of the nasal valve, and maintain unrestricted air movement. Soft tissue reconstructive options can be combined with alar batten grafts. OBJECTIVE: Our purpose was to analyze functional and cosmetic outcomes in a series of patients undergoing alar batten cartilage grafting. METHODS: We analyzed the functional and cosmetic outcomes of 25 patients in whom reconstruction involved alar batten cartilage grafts. Assessment included defect characteristics, function and cosmesis (rated by physician and patient), and complications. RESULTS: Eighty-three percent of patients had good to excellent functional and cosmetic results by patient and physician assessment. Three patients were rated as having poor cosmetic results by the physician; all 3 patients graded these results as good. One episode of graft failure occurred, and recipient and donor site complications were minor. CONCLUSION: Alar batten cartilage grafts appear to be an excellent option for reconstruction of substantial alar defects.

Increased false negative sentinel node biopsy rates after preoperative chemotherapy for invasive breast carcinoma.

BACKGROUND: Sentinel lymph node dissection (SLND) has been a promising new technique in breast carcinoma staging, but could be unreliable in certain patient subsets. The current study assessed whether age, preoperative chemotherapy, tumor size, and/or previous excisional biopsy influenced the identification of sentinel nodes (SLNs) or the reliability of a node-negative SLND in predicting a node negative axilla. METHODS: Eighty-two patients who had clinically negative axillae underwent SLND followed by Level I/II axillary lymph node dissection (ALND). SLNDs were performed using both technetium-99m (Tc-99m) labeled colloid and isosulfan blue dye. SLNs were analyzed by hematoxlyin and eosin and immunocytochemical techniques. RESULTS: SLNs were successfully identified in 80% of patients. Mapping success was decreased among postmenopausal women but was not influenced by preoperative chemotherapy, large tumor size, or previous excisional biopsy. Of the 31 successfully mapped, node positive patients, 5 had false negative (FN) SLNDs (overall FN rate = 16%). Of the 9 successfully mapped patients who had received preoperative chemotherapy and had positive axillary nodes, 3 had FN SLND (FN rate = 33%). The presence of clinically positive lymph nodes before chemotherapy did not predict which patients would have a subsequent FN SLND. T3 tumor size, but not previous excision, was associated significantly with increased FN rate, although the FN rate for previous excision was 11%. No FN SLND occurred with T1/T2 tumors that were not excised previously and had not received preoperative chemotherapy. CONCLUSIONS: Preoperative chemotherapy was associated with an unacceptably high FN rate for SLND. While larger tumor size also was associated with FN SLND, this effect might have been due to preoperative chemotherapy use in these patients. Small sample size precluded determining whether excisional biopsy before mapping increased FN SLND rates independently.

Sentinel lymph node mapping for breast cancer: analysis in a diverse patient group.

PURPOSE: To evaluate sentinel lymph node mapping in patients with breast cancer. MATERIALS AND METHODS: Sixty-two patients with breast cancer scheduled to undergo axillary nodal dissection underwent scintigraphic localization of sentinel lymph nodes with filtered technetium 99m sulfur colloid. At surgery, isosulfan blue was injected. Sentinel nodes were identifiable by blue color and by radioactivity with hand-held gamma probe. Results were analyzed statistically. RESULTS: A sentinel lymph node was identified in 49 patients (79%). Lymph nodes were positive for metastatic disease in 26 patients (42%). The mapping success rate was 78% (n = 21) in the 27 patients with no prior surgery, 78% (n = 18) in the 23 patients with prior surgery, and 86% (n = 12) in the 14 patients with prior chemotherapy. Axillary nodes were positive in 11 (41%) of the 27 patients with no prior intervention, six (26%) of the 23 patients with prior surgery, and 10 (71%) of the 14 patients with prior chemotherapy. There were no false-negative findings in patients without prior intervention. Four patients with positive nodes had false-negative sentinel nodes. CONCLUSION: Sentinel lymph node mapping and biopsy without axillary dissection is appropriate in patients with breast cancer who have not undergone prior intervention. Further study is necessary to ascertain the accuracy of the procedure for patients who have undergone presurgical chemotherapy or previous excisional biopsy.

Early diagnosis and treatment of pancreatic dysplasia in patients with a family history of pancreatic cancer.

BACKGROUND: Pancreatic cancer, the fourth most common cause of cancer death in the United States, is hereditary in an estimated 10% of cases. Surveillance of patients with a familial predisposition for pancreatic cancer has not been systematically evaluated. OBJECTIVE: To develop a surveillance program that can identify and treat patients who have precancerous conditions of the pancreas and a family history of pancreatic cancer. DESIGN: Prospective cohort study. SETTING: University medical center. PATIENTS: 14 patients from three kindreds with a history of pancreatic cancer. INTERVENTIONS: Endoscopic ultrasonography, endoscopic retrograde cholangiopancreatography (ERCP), spiral computed tomography, and serum carcinoembryonic antigen and CA19-9 analysis were performed in all patients. Four affected patients were tested for the K-ras mutation. MAIN OUTCOME MEASUREMENT: Pancreatic dysplasia was determined by histologic evaluation. RESULTS: Seven of the 14 patients were believed to have dysplasia on the basis of clinical history and abnormalities on endoscopic ultrasonography and ERCP and were referred for pancreatectomy. All 7 patients had histologic evidence of dysplasia in pancreatectomy specimens. Findings on endoscopic ultrasonography were subtle, nonspecific, and similar to those seen in patients with chronic pancreatitis. Findings on ERCP ranged from mild and focal side-branch duct irregularities and small sacculations to main-duct strictures and grapelike clusters of saccules. Some of these changes are typical of chronic pancreatitis, but others are more distinctive. Spiral computed tomography and serum tumor markers had low sensitivity in the detection of pancreatic dysplasia. Analysis for the K-ras mutation yielded positive results in 3 of 4 patients with dysplasia. CONCLUSIONS: Thorough screening of patients with a family history of pancreatic cancer is feasible. Clinical data combined with imaging studies (endoscopic ultrasonography and ERCP) can be used to identify high-risk patients who have dysplasia. The role of molecular genetic testing is uncertain at this time.

Technical aspects of sentinel node lymphoscintigraphy for breast cancer.

OBJECTIVE: A significant morbidity risk is associated with axillary nodal dissections for breast cancer. Many treatment decisions are based on axillary nodal status. Lymphatic mapping and sentinel node biopsy have been investigated to determine if the histology of the sentinel node reflects the remaining lymph node basin. We describe the technical aspects of sentinel node lymphoscintigraphy for breast cancer. METHODS: Ninety-three patients had lymphoscintigraphy for breast cancer. Patients with palpable lesions had 4 concentric injections around the site and lesions requiring localization had injections made through tubing connected to the localizing wire introducer needle. Immediate static images were acquired and the sentinel node was marked for surgery. Marks were reverified using a handheld gamma probe. RESULTS: Lymph nodes were visualized by lymphoscintigraphy in 87% of cases. Time to visualization of lymph nodes ranged from 1-120 min with a mean of 28 min. An average of 1.5 nodes were visualized. The overall success rate for identifying the sentinel node at time of surgery was 85%. CONCLUSION: We conclude that lymphoscintigraphy for breast cancer is a detailed procedure that requires coordination with radiology and surgery teams to ensure proper identification of sentinel lymph nodes.

Photosensitive lichenoid reaction to torsemide--a loop diuretic.

Torsemide, a potent loop diuretic of the sulfonylurea class, has been available for clinical use in the United States since 1993. Adverse generalized and cutaneous reactions to this medication are uncommon and are usually mild and transient. In this article, we describe an 82-year-old man who had a photosensitive lichenoid reaction due to torsemide therapy, a previously undescribed phenomenon. The overwhelming presence of T lymphocytes within the lesional skin biopsy specimen and the photodistributed nature of the eruption supported a localized photoallergic cell-mediated hypersensitivity reaction to torsemide. The presumed epitope targeted in this reaction is unclear. Because of the potential risk for cross-reactivity of torsemide with the sulfonamide group of medications, torsemide should be used cautiously in sulfonamide-hypersensitive patients.

Nicking by transesterification: the reaction catalysed by a relaxase.

DNA relaxases play an essential role in the initiation and termination of conjugative DNA transfer. Purification and characterization of relaxases from several plasmids has revealed the reaction mechanism: relaxases nick duplex DNA in a site- and strand-specific manner by catalysing a transesterification. The product of the reaction is a nicked double-stranded DNA molecule with a sequestered 3'-OH and the relaxase covalently bound to the 5' end of the cleaved strand via a phosphotyrosyl linkage. The relaxase-catalysed transesterification is isoenergetic and reversible; a second transesterification ligates the nicked DNA. However, the covalent nucleoprotein complex is relatively long-lived, a property that is likely to be essential for its role as an intermediate in the process of conjugative DNA transfer. Subsequent unwinding of the nicked DNA intermediate is required to produce the single strand of DNA transferred to the recipient cell. This reaction is catalysed by a DNA helicase, an activity intrinsic to the relaxase protein in some, but not all, plasmid systems. The first relaxase-catalysed transesterification is essential for initiation of conjugative strand transfer, whereas the second is presumably required for termination of the process. The relaxase, in conjunction with several auxiliary proteins, forms the relaxation complex or relaxosome first described nearly 30 years ago as being associated with conjugative and mobilizable plasmids.

Updated analysis of an outpatient chemoimmunotherapy regimen for treating metastatic melanoma.

PURPOSE: Aggressive inpatient chemoimmunotherapy protocols for metastatic melanoma have yielded encouraging response rates but have required lengthy hospitalizations. To reduce or eliminate the need for hospitalization, we have developed an outpatient chemoimmunotherapy regimen and assessed its efficacy and toxicity in 53 patients treated at the University of Washington Medical Center. PATIENTS AND METHODS: Eligible patients with measurable metastatic melanoma received carmustine (150 mg/m2 every 6-8 weeks) and dacarbazine (660 mg/m2) and cisplatin (75 mg/m2) every 3 to 4 weeks in an infusion center plus tamoxifen (20 mg/day). Patients self-administered subcutaneous recombinant interleukin-2 (rIL-2) at 3 MIU/m2/day on days 3 to 9, and recombinant interferon alfa-2a (rIFN-alpha 2a) at 3 MIU on day 3 and at 5 MIU/m2/day on days 5, 7, and 9. Maintenance rIFN-alpha 2a was self-administered subcutaneously at 5 MIU/m2 tiw for 12 months after complete or stable partial response. Response and survival were assessed. RESULTS: Fifty-three patients (median age = 49 years) have received 181 cycles. To date, there have been 10 complete responses (19%) lasting 2 to 28+ months and 12 partial responses (23%) lasting 2 to 11 months, for an overall response rate of 42% (95% confidence interval, 28%-55%). The median overall survival was 12 months. Grade 3/4 vomiting occurred in 32% of cycles, but hospitalization for supplemental intravenous fluids was required in only 11% of cycles for a median of 3 days. Grade 4 thrombocytopenia and neutropenia occurred in 9% and 8% of cycles, respectively. Grade 3 renal dysfunction occurred in only one cycle and was reversible. CONCLUSION: A chemoimmunotherapy regimen for patients with metastatic melanoma has been defined that is well tolerated on an outpatient basis and is associated with a median survival comparable to that with aggressive inpatient chemoimmunotherapy regimens.

Yeast alpha mating factor structure-activity relationship derived from genetically selected peptide agonists and antagonists of Ste2p.

alpha-Factor, a 13-amino-acid pheromone secreted by haploid alpha cells of Saccharomyces cerevisiae, binds to Ste2p, a seven-transmembrane, G-protein-coupled receptor present on haploid alpha cells, to activate a signal transduction pathway required for conjugation and mating. To determine the structural requirements for alpha-factor activity, we developed a genetic screen to identify from random and semirandom libraries novel peptides that function as agonists or antagonists of Ste2p. The selection scheme was based on autocrine strains constructed to secrete random peptides and respond by growth to those that were either agonists or antagonists of Ste2p. Analysis of a number of peptides obtained by this selection procedure indicates that Trp1, Trp3, Pro8, and Gly9 are important for agonist activity specifically. His2, Leu4, Leu6, Pro10, a hydrophobic residue 12, and an aromatic residue 13 are important for both agonist and antagonist activity. Our results also show that activation of Ste2p can be achieved with novel, unanticipated combinations of amino acids. Finally, the results suggest the utility of this selection scheme for identifying novel ligands for mammalian G-protein-coupled receptors heterologously expressed in S. cerevisiae.

Pregnancy influences breast cancer stage at diagnosis in women 30 years of age and younger.

BACKGROUND: To evaluate the purported decreased survival of pregnancy-associated (PA) breast cancer, a previously described homogeneous cohort of women of childbearing age with primary operable cancer was studied. The current analysis was designed to (a) identify those patients among the cohort known to have PA cancer and (b) compare clinical factors, pathologic characteristics, stage at diagnosis, and survival statistics for PA and non-PA cancer subgroups. METHODS: All patients < or =30 years of age who underwent definitive operation between 1950 and 1989 at the Memorial Sloan-Kettering Cancer Center (MSKCC) for primary operable (stages 0-IIIA) breast adenocarcinoma were analyzed. RESULTS: Twenty-two of the 227 young women with primary operable breast cancer had PA cancer. Disease-related survival was decreased (p = 0.004) in these 22 women compared with the remaining 205 patients with non-PA cancer. PA cancer patients were found to have larger tumors (p < 0.005), and a greater proportion had advanced staged (IIB or IIIA) cancers (p < 0.02). Among patients diagnosed with early invasive cancers (stages I or IIA), no difference (p = NS) in survival was observed comparing PA and non-PA subgroups (73% vs. 74% 10-year survival). Patients with stage IIIA cancer had shorter disease-free and overall survival when associated with pregnancy (0% vs. 35% 10-year survival). CONCLUSIONS: Women 30 years of age or younger with PA breast cancer have decreased survival compared with patients with non-PA cancer from the same cohort. Women with PA cancer have larger, more advanced cancers at the time of definitive surgery. Women with early staged PA cancers appear to have survival similar to that for women with early staged non-PA cancer.

Hippocampal place fields: relationship between degree of field overlap and cross-correlations within ensembles of hippocampal neurons.

The capacity to record from multiple neurons in awake freely moving animals provides a means for characterizing organizational principles of place field encoding within ensembles of hippocampal neurons. In this study, cross-correlations between pairs of hippocampal place cells and degree of overlap between their respective place fields were analyzed during behavioral performance of delayed matching (DMS) or non-matching sample (DNMS) tasks, or while the same rats chased pellets in a different environment. The relationship between field overlap and cross-correlations of neural spike activity within ensembles was shown to be a positive, exponentially increasing, function. Place fields from the same neurons were markedly "remapped" between the Delay and Pellet-chasing tasks, with respect to physical location and size of fields. However individual pairs of place cells within each ensemble retained nearly the same degree of overlap and cross-correlation even though the spatial environment and the tasks differed markedly. This suggested that place cells were organized in functional "clusters" which exhibited the same inter-relations with respect to place field overlap and cross-correlations, irrespective of actual field of location. When cross-correlations between place cells were compared to placement of the array recording electrodes within the hippocampus, the strongest correlations were found along previously defined posterior-projecting fiber gradients between CA3 and CA1 subfields (Ishizuka et al. [1990], J Comp Neurol 295:580-623; Li et al. [1994] (J Comp Neurol 339:181-208). These findings suggest that the functional organization of place fields conforms to anatomical principles suspected to operate within hippocampal ensembles.

Microsatellite instability and K-ras mutations associated with pancreatic adenocarcinoma and pancreatitis.

ras oncogene mutations and microsatellite instability (MIN) have been described in pancreatic cancer studies from paraffin blocks and fresh frozen tissue. We sought to determine whether they could be detected in endoscopic retrograde cholangiopancreatography-derived pancreatic juice. ras mutations were detected in the pancreatic juice of 40% (2 of 5) of patients with pancreatic cancer and 2 of 5 patients with pancreatitis. MIN was detected at a single locus in the pancreatic juice of 40% of pancreatic cancer patients and at > or = 2 loci of 100% of pancreatitis patients. The finding of MIN in pancreatitis specimens was verified in studies performed on paraffin blocks. MIN was not detected in normal pancreas controls. All of the cancer patients who had ras mutations in their pancreatic juice also had evidence of MIN at one or more loci (P < or = 0.05), suggesting that MIN is associated with the development of a ras mutation. More importantly, the finding of MIN in pancreatitis specimens suggests that MIN can occur in nonneoplastic conditions of the pancreas and may represent the saturation of an intact mismatch repair system.