Topical Treatment of Cutaneous Squamous Cell Carcinoma in Situ and the Impact of Clinical Risk Factors and Positive Histologic Margins at the Time of Diagnosis.

BACKGROUND: Limited data exist for the efficacy of topical 5-fluorouracil (5-FU) and imiquimod for cutaneous squamous cell carcinoma (cSCC) in situ (cSCCis) with positive histologic margins at the time of diagnosis. OBJECTIVE: Identify the efficacy of topical 5-FU and imiquimod in the treatment of cSCCis with positive histologic margins at the time of diagnosis in relation to clinical risk factors. MATERIALS AND METHODS: Pathology records were screened at a single institution from 2014 to 2021 for cSCCis with positive histologic margins. Patients were included if they were treated with curative intent with topical 5-FU or imiquimod. Recurrences were evaluated in relation to multiple clinical risk factors. RESULTS: Of 215 patients treated with 5-FU or imiquimod after biopsy-proven cSCCis, 19 patients had recurrent cSCCis and 1 patient had upstaging to invasive cSCC. Recurrence was more likely in larger lesions at the time of initial biopsy ( p = .033) and in patients treated with topical imiquimod compared with topical 5-FU ( p < .01). CONCLUSION: Topical 5-FU is an appropriate therapy for cSCCis in the correct clinical scenario. Extra consideration should be taken for use of 5-FU in larger diameter cSCCis lesions. Although limited by sample size, our study does not support the use of imiquimod for cSCCis.

Clinical Impact and Accuracy of Shave Biopsy for Initial Diagnosis of Cutaneous Melanoma.

INTRODUCTION: Effective treatment of malignant melanomas is dependent upon accurate histopathological staging of preoperative biopsy specimens. While narrow excision is the gold standard for melanoma diagnosis, superficial shave biopsies have become the preferred method by dermatologists but may transect the lesion and result in inaccurate Breslow thickness assessment. This is a retrospective cohort study evaluating an initial method of biopsy for diagnosis of cutaneous melanoma and indication for reoperation based on inaccurate initial T-staging. METHODS: We retrospectively analyzed consecutive patients referred to the Medical College of Wisconsin, a tertiary cancer center, with a diagnosis of primary cutaneous melanoma. Adult patients seen between 2015 and 2018 were included. Fisher's exact test was used to assess the association between method of initial biopsy and need for unplanned reoperation. RESULTS: Three hundred twenty three patients with cutaneous melanoma from the head and neck (H&N, n = 101, 31%), trunk (n = 90, 15%), upper extremity (n = 84, 26%), and lower extremity (n = 48, 28%) were analyzed. Median Breslow thickness was 0.54 mm (interquartile range = 0.65). Shave biopsy was the method of initial biopsy in 244 (76%), excision in 23 (7%), and punch biopsy in 56 (17%). Thirty nine (33%) shave biopsies had a positive deep margin, as did seven (23%) punch biopsies and 0 excisional biopsies. Residual melanoma at definitive excision was found in 131 (42.5%) of all surgical specimens: 95 (40.6%) shave biopsy patients, 32 (60.4%) punch biopsy patients, and four (19.0%) excision biopsy patients. Recommendations for excision margin or sentinel lymph node biopsy changed in 15 (6%) shave biopsy patients and five (9%) punch biopsy patients. CONCLUSIONS: Shave biopsy is the most frequent method of diagnosis of cutaneous melanoma in the modern era. While shave and punch biopsies may underestimate true T-stage, there was no difference in need for reoperation due to T-upstaging based on initial biopsy type, supporting current diagnostic practices. Partial biopsies can thus be used to guide appropriate treatment and definitive wide local excision when adjusting for understaging.

Xanthomatous Dermal Changes in a Patient With Locally Advanced Basal Cell Carcinoma Treated Using Vismodegib.

ABSTRACT: Basal cell carcinoma (BCC) is the most commonly diagnosed cutaneous cancer in the United States with more than 2.5 million treated annually. Genetic studies have revealed that approximately 90% of BCCs have a mutation in the hedgehog-signaling pathway. Patients with BCC usually have an excellent prognosis with surgical modalities, however, patients with locally advanced BCC may potentially experience significant cosmetic or functional impairment, with only surgical intervention. Vismodegib is a hedgehog pathway inhibitor that has been successful in treating patients with locally advanced BCC. We report a patient with BCC with a good response to vismodegib and a novel xanthomatous change in the excision specimen.

Improving Effective Preventative Care Within an Urban Working Population.

OBJECTIVE: To assess whether standardized screening and service navigation improve access to primary care in low wage workers. METHODS: Four rapid plan-do-study-act cycles were conducted over an 8-week period. Each cycle consisted of four core interventions. Data were collected every 2 to 3 days, then analyzed on run charts and aggregate data tables. RESULTS: Effective care was achieved by increasing the percentage of patients with a primary care provider from 52% to 79%. Patients' perception of health increased from 3.6 to 4.4 and team communication and support score increased from 3.9 to 4.2 on a 5-point Likert scale. CONCLUSIONS: Patient engagement and a standardized referral process aids in the establishment of routine, effective care. Application of "smart phrases" in electronic health records provides sustainability for use in other occupational medicine practices.

Evaluating the Utility of Routine Imaging in Squamous Cell Carcinoma of the Nail Unit.

BACKGROUND: Squamous cell carcinoma (SCC) is the most common malignant tumor of the nail unit. No guidelines currently exist regarding the role of imaging in this specific location. OBJECTIVE: To investigate the utility of routine imaging in SCC of the nail apparatus. METHODS: A multi-institutional retrospective review of patients treated for nail unit SCC was performed. Data were collected on patient characteristics, tumor qualities, treatment, and radiographic imaging. A change in treatment was defined as more aggressive treatment (amputation) rather than local excision or Mohs micrographic surgery (MMS). RESULTS: One hundred seven patients with nail unit SCC were identified. Approximately 44/107 (41.1%) of patients were imaged and 63/107 (58.9%) were not. Mohs micrographic surgery was the most common primary treatment (66.4%). Mohs micrographic surgery was more commonly performed in nonimaged patients, and amputation was more commonly performed in imaged patients (p < .001). Bony changes were identified in 13/44 (29.5%) of imaged patients. In 8/44 (18.2%), imaging findings caused a change in treatment. In 99/107 (92.5%) of the cohort, imaging was either not performed or did not change management. CONCLUSION: In select cases, imaging may help guide patient management. Sufficient evidence does not yet exist to support routine imaging for patients with nail unit SCC.

Inflammation and Hemostatic Activation may Contribute to Postsurgical Thrombosis in Patients With Bladder Cancer.

The alterations of the inflammatory and thrombotic components in patients with cancer are not clearly understood. The purpose of this study was to profile markers of inflammation and thrombotic activation specifically in the patients with bladder cancer undergoing radical cystectomy. For this study, 134 samples were collected from patients undergoing radical cystectomy. Antiphospholipid antibodies (immunoglobulin G subtype), microparticles, and antiglycosaminoglycan antibodies were measured with a commercially available enzyme-linked immunosorbent assay kits. These biomarkers were compared in patients with bladder cancer and normal individuals (n = 20). Patients had an average value of 6.7 ± 11.9 ng/mL (median: 2.8, confidence interval: 4.69-8.75, andPvalue: .0038) of antiphospholipid antibodies versus normal individuals 1.96 ± 0.9 ng/mL (median: 1.8 and confidence interval: 1.5-2.35). Microparticles level in patients was 8.31 ± 6.14 ng/mL, (median: 6.1, confidence interval: 7.26-9.37, andPvalue: <.0001) versus normal individuals 3.57 ± 2.34 ng/mL (median: 2.85 and confidence interval: 2.476-4.664). The antiglycosaminoglycan antibodies in patients had an average value of 0.22 ± 0.1 optical density (OD; median: 0.2, confidence interval: 0.21-0.24, andPvalue: .0213) compared to normal individuals 0.25 ± 0.08 OD (median: 0.25 and confidence interval: 0.22-0.23). The correlation of antiglycosaminoglycan antibodies with antiphospholipid antibodies showed Spearmanrvalue = .2364 (95% confidence interval: 0.05-0.4 andPvalue .009). The correlation of antiglycosaminoglycan antibodies versus microparticles showed Spearmanr= -.195 (95% confidence interval: 0.37-0.01 andPvalue .0321). These data suggest that patients with bladder cancer have subclinical activation of thrombotic and inflammatory processes that may be further exacerbated by surgical procedures and lead to venous thromboembolism-related complications.

Circulating Tumor Cells as Potential Biomarkers in Bladder Cancer.

PURPOSE: We explored the diagnostic use of circulating tumor cells in patients with neoadjuvant bladder cancer using enumeration and next generation sequencing. MATERIALS AND METHODS: A total of 20 patients with bladder cancer who were eligible for cisplatin based neoadjuvant chemotherapy were enrolled in an institutional review board approved study. Subjects underwent blood draws at baseline and after 1 cycle of chemotherapy. A total of 11 patients with metastatic bladder cancer and 13 healthy donors were analyzed for comparison. Samples were enriched for circulating tumor cells using the novel IsoFlux™ System microfluidic collection device. Circulating tumor cell counts were analyzed for repeatability and compared with Food and Drug Administration cleared circulating tumor cells. Circulating tumor cells were also analyzed for mutational status using next generation sequencing. RESULTS: Median circulating tumor cell counts were 13 at baseline and 5 at followup in the neoadjuvant group, 29 in the metastatic group and 2 in the healthy group. The concordance of circulating tumor cell levels, defined as low-fewer than 10, medium-11 to 30 and high-greater than 30, across replicate tubes was 100% in 15 preparations. In matched samples the IsoFlux test showed 10 or more circulating tumor cells in 4 of 9 samples (44%) while CellSearch® showed 0 of 9 (0%). At cystectomy 4 months after baseline all 3 patients (100%) with medium/high circulating tumor cell levels at baseline and followup had unfavorable pathological stage disease (T1-T4 or N+). Next generation sequencing analysis showed somatic variant detection in 4 of 8 patients using a targeted cancer panel. All 8 cases (100%) had a medium/high circulating tumor cell level with a circulating tumor cell fraction of greater than 5% purity. CONCLUSIONS: This study demonstrates a potential role for circulating tumor cell assays in the management of bladder cancer. The IsoFlux method of circulating tumor cell detection shows increased sensitivity compared with CellSearch. A next generation sequencing assay is presented with sufficient sensitivity to detect genomic alterations in circulating tumor cells.

Impact of warm versus cold ischemia on renal function following partial nephrectomy.

INTRODUCTION: We evaluated renal function following partial nephrectomy with cold ischemia (CI) versus warm ischemia (WI). METHODS: Data were collected from 1,396 patients at six institutions who underwent partial nephrectomy for a renal mass with normal contralateral kidney to evaluate percent change in glomerular filtration rate (GFR) at 3-18 months. A multivariate linear regression model tested the association of percent change GFR with clinical, operative, and pathologic factors. RESULTS: A total of 874 patients (63 %) underwent PN with CI and 522 (37 %) with WI. All patients undergoing laparoscopic and robotic-assisted partial nephrectomy (n = 443) had WI, whereas 92 % of open partial nephrectomy patients (n = 953) had CI. The CI group had a lower mean baseline GFR (72 vs. 80 ml/min/1.73 m(2)), longer median ischemia time (33 vs. 29 min), and larger mean tumor size (3.2 vs. 2.9 cm) with more advanced pathologic stage (T1b-T3: 25 vs. 16 %) (all p values <0.001). Patients with CI and WI demonstrated 12.3 and 10.1 % reductions in renal function from baseline, respectively (p = 0.067). Increasing age, female gender, and increasing tumor size were associated with reduction in renal function (all p values <0.001). Neither renal hypothermia nor operative technique independently predicted reduced renal function. Sensitivity analyses limited to ischemia time >30 min, baseline estimated glomerular filtration rate <60 ml/min/1.73 m(2), or tumors >4 cm did not significantly alter the findings. CONCLUSIONS: Increasing age, female gender, and larger tumor size independently predict a decrease in renal function following partial nephrectomy with a normal contralateral kidney. Within the limitations of a non-randomized comparison, including lack of parenchymal preservation percentage, neither surgical approach (open or laparoscopic) nor presence of hypothermia appears to be associated with long-term renal function.

Chronic kidney disease before and after partial nephrectomy.

PURPOSE: We performed a multi-institutional retrospective cohort study to evaluate baseline renal function of patients who underwent partial nephrectomy for renal tumors, and determined rates of progression to higher stages of chronic kidney disease. MATERIALS AND METHODS: The Modification of Diet in Renal Disease study equation was used to estimate glomerular filtration rate. Preoperative and postoperative serum creatinine values were obtained from patients who underwent partial nephrectomy at 6 institutions with a normal contralateral kidney, and had baseline chronic kidney disease stage I (estimated glomerular filtration rate greater than 90 ml/minute/1.73 m(2)), II (estimated glomerular filtration rate 60 to 89 ml/minute/1.73 m(2)) or III (estimated glomerular filtration rate 30 to 59 ml/minute/1.73 m(2)). The end point was change in chronic kidney disease stage at long-term followup (3 to 18 months). Multivariate logistic and Cox regression models tested the association of newly acquired chronic kidney disease stage III or greater with pertinent demographic, tumor and surgical factors. RESULTS: For 1,228 patients with followup creatinine data at least 3 months after partial nephrectomy median baseline glomerular filtration rate was 74 ml/minute/1.73 m(2). At baseline 19%, 59% and 22% of patients had chronic kidney disease stage I, II and III, respectively. At long-term followup for patients with baseline chronic kidney disease stage I or II median postoperative glomerular filtration rate was 67 ml/minute/1.73 m(2) with 29% having progression to chronic kidney disease stage III or greater. Increasing age, female gender, increasing tumor size, clamping of the renal artery and vein, and lower preoperative estimated glomerular filtration rate were independently associated with newly acquired chronic kidney disease stage III or greater. The presence of comorbid conditions such as coronary artery disease, diabetes mellitus or hypertension did not independently predict an increased risk of higher chronic kidney disease stage. CONCLUSIONS: Chronic kidney disease stage III or greater will develop postoperatively in approximately a third of patients with an estimated glomerular filtration rate greater than 60 ml/minute/1.73 m(2), and this progression is associated with definable demographic, tumor and surgical factors.

Chronic Kidney Disease Epidemiology Collaboration versus Modification of Diet in Renal Disease equations for renal function evaluation in patients undergoing partial nephrectomy.

PURPOSE: A novel equation, the Chronic Kidney Disease Epidemiology Collaboration, has been proposed to replace the Modification of Diet in Renal Disease for estimated glomerular filtration rate due to higher accuracy, particularly in the setting of normal renal function. We compared these equations in patients with 2 functioning kidneys undergoing partial nephrectomy. MATERIALS AND METHODS: We assembled a cohort of 1,158 patients from 5 institutions who underwent partial nephrectomy between 1991 and 2009. Only subjects with 2 functioning kidneys were included in the study. The end points were baseline estimated glomerular filtration rate, last followup estimated glomerular filtration rate (3 to 18 months), absolute and percent change estimated glomerular filtration rate ([absolute change/baseline] × 100%), and proportion of newly developed chronic kidney disease stage III. The agreement between the equations was evaluated using Bland-Altman plots and the McNemar test for paired observations. RESULTS: Mean baseline estimated glomerular filtration rate derived from the Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration equations were 73 and 77 ml/minute/1.73 m(2), respectively, and following surgery were 63 and 67 ml/minute/1.73 m(2), respectively. Mean percent change estimated glomerular filtration rate was -12% for both equations (p = 0.2). The proportion of patients with newly developed chronic kidney disease stage III following surgery was 32% and 25%, according to the Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration equations, respectively (p = 0.001). CONCLUSIONS: For patients with 2 functioning kidneys undergoing partial nephrectomy the Chronic Kidney Disease Epidemiology Collaboration equation provides slightly higher glomerular filtration rate estimates compared to the Modification of Diet in Renal Disease equation, with 7% fewer patients categorized as having chronic kidney disease stage III or worse.

Morphologies and projections of defined classes of neurons in the submucosa of the guinea-pig small intestine.

Four types of neurons have previously been identified by neurochemical markers in the submucosal ganglia of the guinea-pig small intestine, and functional roles have been ascribed to each type. However, morphological differences among the classes have not been determined, and there is only partial information about their projections within the submucosa. In the present work, we used intracellular microelectrodes to fill neurons of each type with biocytin, which was then converted to a permanent dye, so that the shapes of the neurons could be determined and their projections within the submucosa could be followed. Cell bodies of noncholinergic secretomotor/ vasodilator neurons had Dogiel type I morphology. These neurons, which are vasoactive intestinal peptide immunoreactive, had single axons that ran through many ganglia without providing terminals around other neurons. Cholinergic secretomotor neurons with neuropeptide Y immunoreactivity had Stach type IV morphology, and cholinergic secretomotor/vasodilator neurons had stellate cell bodies. The axons of these two types ran short distances in the plexus and did not innervate other submucosal neurons. Neurons of the fourth type, intrinsic primary afferent neurons, had cell bodies with Dogiel type II morphology and their processes supplied networks of varicose processes around other nerve cells. It is concluded that each functionally defined type of submucosal neuron has a characteristic morphology and that intrinsic primary afferent neurons synapse with secretomotor neurons to form monosynaptic secretomotor reflex circuits.

Neuronal and glial localization of GABA transporter immunoreactivity in the myenteric plexus.

The neurotransmitter gamma-aminobutyric acid (GABA) is removed from the extracellular space by sodium and chloride dependent high affinity plasma membrane transporters. In the rat central nervous system, three GABA transporters, GAT1, GAT2 and GAT3, have been cloned and localized by immunohistochemistry. The purpose of this study was to examine the distribution of these transporters within the myenteric plexus of the rat gastrointestinal tract. We investigated their cellular locations using GAT1-3 specific antisera in lightly fixed segments of rat duodenum, ileum and colon. Immunohistochemistry revealed a large number of GAT2-immunoreactive structures that surrounded neurons within each ganglion of the myenteric plexus. GAT2 was colocalized in these structures with the glial cell marker p75(NTR), suggesting that the predominant high affinity GABA transporter within enteric glia is GAT2. GAT3 immunoreactivity was localized within many nerve cell bodies, and no labeling for GAT1 was detected, although it was present in retina, which was used as a control. Double labeling for calretinin and nitric oxide synthase (NOS) revealed colocalization of GAT3 with approximately 75% of calretinin-immunoreactive neurons and 15% of NOS-immunoreactive neurons. This suggests that a small proportion of inhibitory motor neurons and at least some putative intrinsic primary afferent neurons within the rat gastrointestinal tract express GAT3. Thus NOS neurons, which appear to utilize GABA as a transmitter, and calretinin-immunoreactive neurons, which do not appear to be GABAergic, both express immunoreactivity for GABA transporters.