Citations

Background: Vascular invasion (VI) is an important predictor of distant metastasis and possible radioactive iodine (RAI) benefit in follicular, Hürthle cell, and poorly differentiated thyroid carcinomas, but its role in well-differentiated papillary thyroid cancer (WDTC) remains unclear. Methods: Archived pathological material of all differentiated thyroid carcinoma patients undergoing primary surgical treatment at Memorial Sloan-Kettering Cancer Center between 1986 and 2003 was reviewed by two dedicated thyroid pathologists. Only WDTCs were included in the present study. Standard statistical methods were used to assess the relationship between VI and outcomes of interest, including 10-year disease-specific survival (DSS), regional recurrence-free survival (RRFS), and distant recurrence-free survival (DRFS). Results: VI was present in 47 of 698 WDTC (6.7%). VI was significantly associated with tumor size >4.0 cm, extrathyroidal extension, distant metastasis, and RAI treatment. On univariate analysis, VI was predictive of decreased 10-year DRFS, but not DSS or RRFS. On multivariate analysis, VI was not an independent predictor of DRFS. Univariate survival analysis of 422 RAI-naïve WDTC showed that both size >4 cm and VI were predictors of outcome, but only size remained independently predictive on multivariate analysis. Conclusion: The presence of VI is not an independent predictor of outcome in WDTC.

Nitric oxide (NO) is capable of blunting α-adrenergic vasoconstriction in contracting skeletal muscles of experimental animals (functional sympatholysis). We therefore tested the hypothesis that exogenous NO administration can blunt α-adrenergic vasoconstriction in resting human limbs by measuring forearm blood flow (FBF; Doppler ultrasound) and blood pressure in eight healthy males during brachial artery infusions of three α-adrenergic constrictors (tyramine, which evokes endogenous norepinephrine release; phenylephrine, an α1-agonist; and clonidine, an α2-agonist). To simulate exercise hyperemia, the vasoconstriction caused by the α-agonists was compared during adenosine-mediated (>50% NO independent) and sodium nitroprusside-mediated (SNP; NO donor) vasodilation of the forearm. Both adenosine and SNP increased FBF from ∼35–40 to ∼200–250 ml/min. All three α-adrenergic constrictor drugs caused marked reductions in FBF and calculated forearm vascular conductance ( P < 0.05). The relative reductions in forearm vascular conductance caused by the α-adrenergic constrictors during SNP infusion were similar (tyramine, –74 ± 3 vs. –65 ± 2%; clonidine, –44 ± 6 vs. –44 ± 6%; P > 0.05) or slightly greater (phenylephrine, –47 ± 6 vs. –33 ± 6%; P < 0.05) compared with the responses during adenosine. In conclusion, these results indicate that exogenous NO sufficient to raise blood flow to levels simulating those seen during exercise does not blunt α-adrenergic vasoconstriction in the resting human forearm.

To compare the effects of the κ-opioid agonist asimadoline and placebo on visceral sensation and gastrointestinal (GI) motor functions in humans, 91 healthy participants were randomized in a double-blind fashion to 0.15, 0.5, or 1.5 mg of asimadoline or placebo orally twice a day for 9 days. We assessed satiation (nutrient drink test), colonic compliance, tone, perception of colonic distension (barostat), and whole gut transit (scintigraphy). Treatment effect was assessed by analysis of covariance. Asimadoline increased nutrient drink intake ( P = 0.03). Asimadoline decreased colonic tone during fasting ( P = 0.03) without affecting postprandial colonic contraction, compliance, or transit. Gas scores in response to colonic distension were decreased with 0.5 mg of asimadoline at low levels (8 mmHg above operating pressure) of distension ( P = 0.04) but not at higher levels of distension. Asimadoline at 1.5 mg increased gas scores at 16 mmHg of distension ( P = 0.03) and pain scores at distensions of 8 and 16 mmHg ( P = 0.003 and 0.03, respectively) but not at higher levels of distension. Further studies of this compound in diseases with altered satiation or visceral sensation are warranted.

To determine whether endothelial function is altered by chronic surgical sympathectomy, we infused ACh, isoproterenol, nitroprusside (NTP), and the nitric oxide synthase inhibitor N G-mono-methyl-l-arginine (l-NMMA) into the brachial arteries of nine patients 5–64 mo after thoracic sympathectomy for hyperhidrosis. Age- and gender-matched controls were also studied. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. Lower body negative pressure was used to assess reflex vasoconstrictor responses. Tyramine, which acts locally and causes norepinephrine release from sympathetic nerves, was also administered via the brachial artery. FBF at rest was 2.5 ± 0.4 ml · dl−1 · min−1 in the patients and 2.5 ± 0.3 ml · dl−1 · min−1 in the controls ( P = 0.95). The normal vasoconstrictor responses to lower body negative pressure were abolished in the patients. By contrast, tyramine produced dose-dependent vasoconstriction in the patients that was identical to that of controls. The dose-response curves to ACh were similar in patients and controls, with maximum values of 19.3 ± 4.4 vs. 25.5 ± 2.8 ml · dl−1 · min−1, respectively. l-NMMA reduced baseline FBF similarly and reduced the maximal FBF response to ACh in both groups (patients 8.9 ± 3.5 vs. controls 9.7 ± 2.5 ml · dl−1 · min−1). The vasodilation to isoproterenol was similar and blunted to the same extent in both groups by l-NMMA. The responses to NTP in patients and controls were similar and not affected byl-NMMA. We conclude that, in humans, chronic surgical sympathectomy does not cause major disruptions in vascular function in the forearm. The normal vasoconstrictor responses to tyramine indicate that there were viable sympathetic nerves in the forearm that were not engaged by LBNP.

Objectives To evaluate oncological outcomes after combination intravesical therapy with gemcitabine ( GC ) and mitomycin C ( MMC ) in the setting of recurrent non‐muscle‐invasive bladder cancer ( NMIBC ) after failure of previous intravesical therapy. Patients and Methods We retrospectively identified patients with recurrent NMIBC after previous intravesical therapy, who refused or were not candidates for cystectomy, between 2005 and 2011. GC and MMC were sequentially instilled weekly for 6–8 weeks. Data were collected regarding patient demographics, bladder cancer history, and number and type of intravesical therapies before GC / MMC . Outcomes evaluated included time to recurrence and/or progression after GC / MMC . Recurrence‐free outcomes were estimated using the Kaplan–Meier method, and Cox proportional hazards regression models were used to test the association of clinicopathological features with outcomes. Results In all, 27 patients were identified, 23 with high‐risk disease (high‐grade or carcinoma in situ ) and four with intermediate‐risk disease (multifocal or recurrent low‐grade). All patients received prior intravesical therapy, and 17 patients (63%) received multiple courses. Twenty‐four patients were treated with BCG . The median (range) disease‐free survival of all patients was 15.2 (1.7–39.3) months. Seventeen patients (63%) developed recurrent bladder cancer, a median of 15.2 months after therapy. One patient progressed to muscle‐invasive disease 5 months after treatment, and one developed metastatic disease 22 months after treatment. Three patients went on to cystectomy. Ten patients (37%) had no evidence of disease at last follow‐up, with a median follow‐up of 22.1 months. Conclusion The combination of intravesical GC and MMC could offer durable recurrence‐free survival to some patients with recurrent NMIBC who are not candidates for, or refuse, cystectomy.

OBJECT Adrenocorticotropic hormone (ACTH) adenomas have been recognized as a more aggressive and invasive subtype of pituitary adenomas. An additional and clinically relevant peculiarity of these tumors is their ability to modify their clinical expression from a silent form to Cushing disease or vice versa. The aim of this study was to review a series of patients with pituitary adenomas and analyze the clinical implications of the transformation of clinical expression in 5 cases that showed this phenomenon. METHODS The authors retrospectively reviewed a series of patients with pituitary adenoma and collected clinical, biohumoral, and neuroradiological data of those who presented with a transformation from silent ACTH adenomas to functioning tumors or vice versa. In all the cases, preoperative assessment consisted of brain MRI, ophthalmological examination, and complete baseline endocrinological investigation. In patients with clinical and/or biochemical findings suspicious for Cushing syndrome, a low-dose dexamethasone suppression test was performed to rule in or out this diagnosis. Endocrinological evaluations were repeated 1 month after surgery, 3 months after surgery, and every 6 months or annually thereafter. Ophthalmological evaluations and brain MRIs were repeated after 3 months and then every 6 or 12 months thereafter. RESULTS Five patients (2 men and 3 women) included in this series had corticotropic tumors that showed transformation from an endocrinologically silent form to manifest Cushing disease and vice versa. The mean age at presentation was 40 years (range 18–51 years). In 3 of these patients, a transformation from silent to functioning ACTH adenoma with manifest Cushing disease occurred. In 1 patient, the authors observed the transition from a functioning to a silent adenoma with spontaneous resolution of hypercortisolism. Another patient's silent adenoma “shifted” to a functioning adenoma and then regressed back to a silent form with spontaneous resolution of Cushing disease. This patient again developed hypercortisolism, which finally resolved spontaneously. In this series, the transformation occurred after a mean of 3.5 years (range 6 months to 7 years). The shift from an ACTH-silent to a functioning adenoma was observed in 9% of the ACTH-silent adenomas in this series (4 of 44 cases), and the spontaneous remission of Cushing disease to a silent corticotroph cell adenoma occurred in 1.5% of cases of this series (2 of 132 functioning ACTH adenomas). At follow-up (mean 107 months; range 60–177 months), cortisol levels were within normal limits in all 5 cases. However, 1 patient required Gamma Knife radiosurgery and eventually adrenalectomy for disease control to be achieved. CONCLUSIONS The ability of silent ACTH adenomas to transform their secretion pattern poses a challenge for neurosurgeons and endocrinologists. Because the transformation is often unexpected, the clinical and biochemical data can be underestimated. Furthermore, this bizarre and unpredictable postoperative tumor behavior can lead to misinterpretation of clinical and endocrinological outcomes. Even if these cases are very rare, they are not anecdotal in large series. Thus, ACTH adenomas require careful biohumoral and neuroradiological follow-up to detect possible transformations.

Purpose Optimal early detection and prevention for breast cancer depend on accurate identification of women at increased risk. We present a risk prediction model that incorporates histologic features of biopsy tissues from women with benign breast disease (BBD) and compare its performance to the Breast Cancer Risk Assessment Tool (BCRAT). Methods We estimated the age-specific incidence of breast cancer and death from the Mayo BBD cohort and then combined these estimates with a relative risk model derived from 377 patient cases with breast cancer and 734 matched controls sampled from the Mayo BBD cohort to develop the BBD–to–breast cancer (BBD-BC) risk assessment tool. We validated the model using an independent set of 378 patient cases with breast cancer and 728 matched controls from the Mayo BBD cohort and compared the risk predictions from our model with those from the BCRAT. Results The BBD-BC model predicts the probability of breast cancer in women with BBD using tissue-based and other risk factors. The concordance statistic from the BBD-BC model was 0.665 in the model development series and 0.629 in the validation series; these values were higher than those from the BCRAT (0.567 and 0.472, respectively). The BCRAT significantly underpredicted breast cancer risk after benign biopsy (P = .004), whereas the BBD-BC predictions were appropriately calibrated to observed cancers (P = .247). Conclusion We developed a model using both demographic and histologic features to predict breast cancer risk in women with BBD. Our model more accurately classifies a woman's breast cancer risk after a benign biopsy than the BCRAT.

Background Probe‐based confocal laser endomicroscopy (pCLE) provides microscopic imaging during an endoscopic procedure. Its introduction as a standard modality in gastroenterology has brought significant progress in management strategies, affecting many aspects of clinical care and requiring standardisation of practice and training. Objective This study aimed to provide guidance on the standardisation of its practice and training in Barrett's oesophagus, biliary strictures, colorectal lesions and inflammatory bowel diseases. Methods Initial statements were developed by five group leaders, based on the available clinical evidence. These statements were then voted and edited by the 26 participants, using a modified Delphi approach. After two rounds of votes, statements were validated if the threshold of agreement was higher than 75%. Results Twenty‐six experts participated and, among a total of 77 statements, 61 were adopted (79%) and 16 were rejected (21%). The adoption of each statement was justified by the grade of evidence. Conclusion pCLE should be used to enhance the diagnostic arsenal in the evaluation of these indications, by providing microscopic information which improves the diagnostic performance of the physician. In order actually to implement this technology in the clinical routine, and to ensure good practice, standardised initial and continuing institutional training programmes should be established.