Pneumococcal carriage and disease in adults in England 2011-2019: the importance of adults as a reservoir for pneumococcus in communities.

BACKGROUND: Pneumococcal carriage in children has been extensively studied, but carriage in healthy adults and its relationship to invasive pneumococcal disease (IPD) is less understood. METHODS: Nasal wash samples from adults without close contact with young children (Liverpool, UK), 2011-2019, were cultured, and culture-negative samples tested by PCR. Pneumococcal carriage in adults 18-44 years was compared with carriage among PCV-vaccinated children 13-48 months (nasopharyngeal swabs, Thames Valley, UK) and IPD data for England for the same ages for 2014-2019. Age-group specific serotype invasiveness was calculated and used with national IPD data to estimate carriage serotype distributions for adults aged 65+ years. RESULTS: In total 98 isolates (97 carriers) were identified from 1,631 adults aged 18+ years (age and sex standardized carriage prevalence 6.4%), with only three identified solely by PCR. Despite different carriage and IPD serotype distributions between adults and children, serotype invasiveness was highly correlated (R=0.9). Serotypes 3, 37 and 8 represented a higher proportion of adult carriage than expected from direct low-level transmission from children to adults. The predicted carriage serotype distributions for 65+ years aligned more closely with the carriage serotype distribution for young adults than young children. CONCLUSIONS: The nasal wash technique is highly sensitive; additional benefit of PCR is limited. Comparison of carriage serotype distributions suggests some serotypes may be circulating preferentially within these specific young adults. Our data suggest that for some serotypes carried by adults 65+ years, other adults may be an important reservoir for transmission. Age groups such as older children should also be considered.

Clinical Predictors of Pseudohypoxia-Type Pheochromocytomas.

INTRODUCTION: Pheochromocytomas (PCCs) are rare tumors of neural crest origin with divergent transcriptional and metabolic profiles associated with mutational cluster types. Pseudohypoxia-type (PHT) PCCs have a poor prognosis; however diagnostic genetic testing is not always available. We aimed to investigate clinical parameters predictive of PHT PCCs. METHODS: Patients who underwent resection and genetic testing for PCC at two academic centers from 2006-2020 were retrospectively studied. Patients with PHT mutations (SDH-AF2/B/C/D, VHL) were compared to non-pseudohypoxia-type (nonPHT) PCCs to identify widely available clinical parameters predictive of PHT PCCs. Demographic, clinical, and pathologic characteristics were compared using student's T and ANOVA tests. Operative hemodynamic instability was defined as systolic blood pressure (SBP) > 200 mmHg, SBP increase of > 30% relative to baseline, and/or heart rate (HR) > 110 bpm. Mann-Whitney U test was used to assess area under the curve (AUC), sensitivity, and specificity. Recursive partitioning was used to model predictive thresholds for PHT PCC and develop a predictive score. RESULTS: Of the 79 patients included in the cohort, 17 (22%) had PHT and 62 (78%) had nonPHT PCCs. PCC patients with > 2 of the examined predictive clinical parameters (preoperative weight loss [> 10% body weight], elevated preoperative hematocrit [> 50%], normal baseline heart rate [< 100 bpm], and normal plasma metanephrines [< 0.60 nmol/L]) were more likely to have PHT PCCs (AUC = 0.831, sensitivity = 0.882, specificity = 0.694, all p < 0.001). CONCLUSIONS: Widely available preoperative clinical parameters including indicators of erythropoiesis (hemoglobin, hematocrit, and red blood cell count), baseline heart rate, plasma metanephrines, and weight loss may be useful predictors of PHT PCCs and may help guide management of PCCs when genetic testing is unavailable/delayed.

International multicentre review of perioperative management and outcome for catecholamine-producing tumours.

BACKGROUND: Surgery for catecholamine-producing tumours can be complicated by intraoperative and postoperative haemodynamic instability. Several perioperative management strategies have emerged but none has been evaluated in randomized trials. To assess this issue, contemporary perioperative management and outcome data from 21 centres were collected. METHODS: Twenty-one centres contributed outcome data from patients who had surgery for phaeochromocytoma and paraganglioma between 2000 and 2017. The data included the number of patients with and without α-receptor blockade, surgical and anaesthetic techniques, complications and perioperative mortality. RESULTS: Across all centres, data were reported on 1860 patients with phaeochromocytoma or paraganglioma, of whom 343 underwent surgery without α-receptor blockade. The majority of operations (78·9 per cent) were performed using minimally invasive techniques, including 16·1 per cent adrenal cortex-sparing procedures. The cardiovascular complication rate was 5·0 per cent overall: 5·9 per cent (90 of 1517) in patients with preoperative α-receptor blockade and 0·9 per cent (3 of 343) among patients without α-receptor blockade. The mortality rate was 0·5 per cent overall (9 of 1860): 0·5 per cent (8 of 517) in pretreated and 0·3 per cent (1 of 343) in non-pretreated patients. CONCLUSION: There is substantial variability in the perioperative management of catecholamine-producing tumours, yet the overall complication rate is low. Further studies are needed to better define the optimal management approach, and reappraisal of international perioperative guidelines appears desirable.

ANTECEDENTES: La cirugía de los tumores productores de catecolaminas puede complicarse por la inestabilidad hemodinámica intraoperatoria y postoperatoria. Se han propuesto distintas estrategias de manejo perioperatorio, pero ninguna ha sido evaluada en ensayos aleatorizados. Para evaluar este tema, se han recogido los datos de los resultados y del manejo perioperatorio contemporáneo de 21 centros. MÉTODOS: Veintiún centros aportaron datos de los resultados de los pacientes operados por feocromocitoma y paraganglioma entre 2000-2017. Los datos incluyeron el número de pacientes con y sin bloqueo del receptor α, las técnicas quirúrgicas y anestésicas, las complicaciones y la mortalidad perioperatoria. RESULTADOS: Los centros en su conjunto aportaron datos de 1.860 pacientes con feocromocitoma y paraganglioma, de los cuales 343 pacientes fueron intervenidos sin bloqueo del receptor α. La gran mayoría (79%) de las cirugías se realizaron utilizando técnicas mínimamente invasivas, incluido un 17% de procedimientos con preservación de la corteza suprarrenal. La tasa de complicaciones cardiovasculares fue de 5,0% en total; 5,9% (90/1517) en pacientes con bloqueo preoperatorio de los receptores α y 0,9% (3/343) en pacientes no pretratados. La mortalidad global fue del 0,5% (9/1860); 0,5% (8/1517) en pacientes pretratados y 0,3% (1/343) en pacientes no tratados previamente. CONCLUSIÓN: Existe una variabilidad sustancial en el manejo perioperatorio de los tumores productores de catecolaminas, aunque la tasa global de complicaciones es baja. Este estudio brinda la oportunidad para efectuar comparaciones sistemáticas entre estrategias de prácticas terapéuticas variables. Se necesitan más estudios para definir mejor el enfoque de manejo óptimo y parece conveniente volver a evaluar las guías internacionales perioperatorias.

Cassava flour slurry as a low-cost alternative to commercially available gel for obstetrical ultrasound: a blinded non-inferiority trial comparison of image quality.

OBJECTIVE: To evaluate the quality of ultrasound images obtained with cassava flour slurry (CFS) compared with conventional gel in order to determine objectively whether CFS could be a true low-cost alternative. DESIGN: Blinded non-inferiority trial. SETTING: Obstetrical ultrasound unit in an academic medical centre. POPULATION OR SAMPLE: Women with a singleton pregnancy, undergoing anatomy ultrasounds. METHODS: Thirty pregnant women had standard biometry measures obtained with CFS and conventional gel. Images were compared side-by-side in random order by two blinded sonologists and rated for image resolution, detail and total image quality using a 10-cm visual analogue scale. Ratings were compared using paired t-tests. Participant and sonographer experience was measured using five-point Likert scales. MAIN OUTCOME MEASURES: Image resolution, detail, and total image quality. Participant experience of gel regarding irritation, messiness, and ease of removal. RESULTS: We found no significant difference between perceived image quality obtained with CFS (mean = 6.2, SD = 1.2) and commercial gel (mean = 6.4, SD = 1.2) [t (28) = -1.1; P = 0.3]. Images were not rated significantly differently for either reviewer in any measure, any standardized image or any view of a specific anatomic structure. All five sonographers rated CFS as easy to obtain clear images and easy for patient and machine cleanup. Only one participant reported itching with CFS. CONCLUSIONS: CFS produces comparable image quality to commercial ultrasound gel. The dissemination of these results and the simple CFS recipe could significantly increase access to ultrasound for screening, monitoring and diagnostic purposes in resource-limited settings. FUNDING: This study was internally funded by our department. TWEETABLE ABSTRACT: Low-cost homemade cassava flour slurry creates images equal to commercial ultrasound gel, improving access.

The Bethesda system for reporting thyroid cytopathology: a single-center experience over 5 years.

BACKGROUND: The Bethesda System for Reporting Thyroid Cytopathology (BSRTC) was developed to refine fine-needle aspiration (FNA) cytology definitions and improve clinical management. This study evaluates the impact of the BSRTC 5 years after its adoption at a single institution. METHODS: A total of 1,625 patients undergoing thyroidectomy in the pre-BSRTC (Group 1: July 2007-January 2009) and post-BSRTC (Group 2: February 2009-September 2013) periods were reviewed. Cytologic diagnoses in Group 1 included non-diagnostic, benign, follicular neoplasm, suspicious for malignancy and malignant. Atypia/follicular lesion of undetermined significance (AUS/FLUS) was included in Group 2. The proportions of each FNA category and malignancy rate per cytologic diagnosis were compared. RESULTS: Fifty-four percent (187/347) of Group 1 patients had a preoperative FNA versus 61 % (777/1278) in Group 2 (p = 0.02). Group 1 FNA results included 3 % non-diagnostic, 48 % benign, 17 % follicular, 13 % suspicious for cancer, and 19 % cancer. Group 2 results included 3 % non-diagnostic, 36 % benign, 9 % follicular, 8 % suspicious for malignancy, 18 % malignant and 26 % AUS/FLUS. In Group 2, the proportions of benign, follicular and suspicious for malignancy FNAs decreased significantly (p < 0.05). In Group 2, there were more indeterminate FNA diagnoses overall (30 vs. 43 %; p < 0.001). The rate of cancer in suspicious for cancer FNA lesions increased from 44 to 65 % (p = 0.07). The AUS/FLUS malignancy rate was 15 %. CONCLUSIONS: Since the adoption of the BSRTC at our institution, the proportion of indeterminate FNAs has increased; however, the diagnostic accuracy of the suspicious for cancer category improved. We recommend periodic review of the utilization and malignancy rates per cytologic category at each institution to help tailor clinical management.

Utilization and impact of repeat biopsy for follicular lesion/atypia of undetermined significance.

BACKGROUND: The Bethesda System for Reporting Thyroid Cytopathology (BSRTC) created a new diagnostic category,follicular lesion/atypia of undetermined significance(FLUS/AUS). The recommended management of FLUS/AUS lesions is repeat biopsy to re-classify the lesion and guide therapy. Prior surgical studies suggest a higher than expected malignancy rate for FLUS/AUS. The present study evaluates a large institutional experience with all FLUS/AUS lesions analyzing use and impact of repeat biopsy. METHODS: A total of 322 patients with FLUS/AUS cytology have been retrospectively identified since adoption of the BSRTC (2/2009­6/2012). Patient demographics, the results of clinical follow-up, repeat biopsy, or surgical pathology results were evaluated. RESULTS: Among the 322 patients, 16 had concurrent cytology of higher acuity and were excluded. For the remaining 306 patients, 101 (33 %) underwent repeat biopsy, yielding 49 (48.5 %) with FLUS/AUS, 43 (42.5 %)with benign cytology, and 9 (9 %) with higher acuity cytology. Among the 205 patients without repeat biopsy,117 (57 %) chose thyroidectomy, and 88 (43 %) are being observed. Overall, 170/306 (55.6 %) patients underwent surgery to remove the index lesion, yielding a malignancy rate of 16.5 %. In contrast, the malignancy rate for the entire cohort was 28/306 (9 %). CONCLUSIONS: Repeat biopsy was underutilized in FLUS/AUS cases. Repeat biopsy allows a significant proportion of FLUS/AUS patients without other indications for surgery to move to surveillance. In patients who have indications for thyroidectomy regardless of FLUS/AUS results,repeat biopsy does not appear necessary. Malignancy and thyroidectomy rates were similar among patients who did or did not have a repeat biopsy. Further data must be obtained to determine the long-term outcomes for surveillance of FLUS/AUS lesions in patients who do not undergo surgical removal.

Exploring the muscle architecture effect on the mechanical behaviour of mouse rotator cuff muscles.

Incorporating detailed muscle architecture aspects into computational models can enable researchers to gain deeper insights into the complexity of muscle function, movement, and performance. In this study, we employed histological, multiphoton image processing, and finite element method techniques to characterise the mechanical dependency on the architectural behaviour of supraspinatus and infraspinatus mouse muscles. While mechanical tests revealed a stiffer passive behaviour in the supraspinatus muscle, the collagen content was found to be two times higher in the infraspinatus. This effect was unveiled by analysing the alignment of fibres during muscle stretch with the 3D models and the parameters obtained in the fitting. Therefore, a strong dependence of muscle behaviour, both active and passive, was found on fibre orientation rather than collagen content.

The utility of parathyroid autofluorescence as an adjunct in thyroid and parathyroid surgery 2023.

Thyroid and parathyroid surgery requires careful dissection around the vascular pedicle of the parathyroid glands to avoid excessive manipulation of the tissues. If the blood supply to the parathyroid glands is disrupted, or the glands are inadvertently removed, temporary and/or permanent hypocalcemia can occur, requiring post-operative exogenous calcium and vitamin D analogues to maintain stable levels. This can have a significant impact on the quality of life of patients, particularly if it results in permanent hypocalcemia. For over a decade, parathyroid tissue has been noted to have unique intrinsic properties known as "fluorophores," which fluoresce when excited by an external light source. As a result, parathyroid autofluorescence has emerged as an intra-operative technique to help with identification of parathyroid glands and to supplement direct visualization during thyroidectomy and parathyroidectomy. Due to the growing body of literature surrounding Near Infrared Autofluorescence (NIRAF), we sought to review the value of using autofluorescence technology for parathyroid detection during thyroid and parathyroid surgery. A literature review of parathyroid autofluorescence was performed using PubMED. Based on the reviewed literature and expert surgeons' opinions who have used this technology, recommendations were made. We discuss the current available technologies (image vs. probe approach) as well as their limitations. We also capture the opinions and recommendations of international high-volume endocrine surgeons and whether this technology is of value as an intraoperative adjunct. The utility and value of this technology seems promising and needs to be further defined in different scenarios involving surgeon experience and different patient populations and conditions.

The Americas: paving the road toward global measles eradication.

BACKGROUND: The Region of the Americas set a goal of interrupting endemic measles virus transmission by the end of 2000. This decision was primarily based on rapid decreases in measles disease burden in pioneering countries that implemented Pan American Health Organization-recommended vaccination and surveillance strategies. Review of these strategies may inform measles elimination efforts in other regions. METHODS: Results from the implementation of the measles elimination strategy in the Americas were compiled and analyzed over a 30-year period, which was divided into 4 phases: the early years of the Expanded Program on Immunization (1980-1986); the start-up phase for elimination (1987-1994); the elimination phase (1995-2002); and the postelimination phase (2003-2010). Factors that contributed to elimination and the challenges confronted during the postelimination phase are discussed. RESULTS: An analysis of vaccination strategies over time highlights the transition from monovalent measles vaccine to the incorporation of measles-mumps-rubella vaccine administered in the routine program. Regional vaccination coverage increased during the period 1987-2010, sustained at ≥90% since 1998. Measles elimination efforts led to the implementation of 157 national vaccination campaigns, vaccinating a total of 440 million persons. Endemic measles virus transmission was interrupted in 2002. After elimination, measles importations and associated outbreaks occurred. Measles incidence has remained at <1 case per 1 million population since 2002. CONCLUSIONS: The success of measles elimination strategies in the Americas suggests that global measles eradication is attainable.

Spheroscope: A custom-made miniaturized microscope for tracking tumour spheroids in microfluidic devices.

3D cell culture models consisting of self-assembled tumour cells in suspension, commonly known as tumour spheroids, are becoming mainstream for high-throughput anticancer drug screening. A usual measurable outcome of screening studies is the growth rate of the spheroids in response to treatment. This is commonly quantified on images obtained using complex, expensive, optical microscopy systems, equipped with high-quality optics and customized electronics. Here we present a novel, portable, miniaturized microscope made of low-cost, mass-producible parts, which produces both fluorescence and phase-gradient contrast images. Since phase-gradient contrast imaging is based on oblique illumination, epi-illumination is used for both modalities, thus simplifying the design of the system. We describe the system, characterize its performance on synthetic samples and show proof-of-principle applications of the system consisting in imaging and monitoring the formation and growth of lung and pancreas cancer tumour spheroids within custom made microfluidic devices.

Semi-supervised labelling of the femur in a whole-body post-mortem CT database using deep learning.

A deep learning pipeline was developed and used to localize and classify a variety of implants in the femur contained in whole-body post-mortem computed tomography (PMCT) scans. The results provide a proof-of-principle approach for labelling content not described in medical/autopsy reports. The pipeline, which incorporated residual networks and an autoencoder, was trained and tested using n = 450 full-body PMCT scans. For the localization component, Dice scores of 0.99, 0.96, and 0.98 and mean absolute errors of 3.2, 7.1, and 4.2 mm were obtained in the axial, coronal, and sagittal views, respectively. A regression analysis found the orientation of the implant to the scanner axis and also the relative positioning of extremities to be statistically significant factors. For the classification component, test cases were properly labelled as nail (N+), hip replacement (H+), knee replacement (K+) or without-implant (I-) with an accuracy >97%. The recall for I- and H+ cases was 1.00, but fell to 0.82 and 0.65 for cases with K+ and N+. This semi-automatic approach provides a generalized structure for image-based labelling of features, without requiring time-consuming segmentation.

Halton sampling for autofocus.

Reliable autofocusing is a critical part of any automated microscopy system: by precisely positioning the sample in the focal plane, the acquired images are sharp and can be accurately segmented and quantified. The three main components of an autofocus algorithm are a contrast function, an optimization algorithm and a sampling strategy. The latter has not been given much attention in the literature. It is however a very important part of the autofocusing algorithm, especially in high content and high throughput image-based screening. It deals with the problem of sampling the focus surface as sparsely as possible to reduce bleaching and computation time while with sufficient detail as to permit a faithful interpolation. We propose a new strategy that has higher performance compared to the classical square grid or the hexagonal lattice, which is based on the concept of low discrepancy point sets and in particular on the Halton point set. We tested the new algorithm on nine different focus surfaces, each under 24 different combinations of Signal-to-Noise ratio (SNR) and sampling rate, obtaining that in 88% of the tested conditions, Halton sampling outperforms its counterparts.

Influence of dietary macronutrient composition on adiposity and cellularity of different fat depots in Wistar rats.

The aim of this study was to investigate the role of dietary macronutrient content on adiposity parameters and adipocyte hypertrophy/hyperplasia in subcutaneous and visceral fat depots from Wistar rats using combined histological and computational approaches. For this purpose, male Wistar rats were distributed into 4 groups and were assigned to different nutritional interventions: Control group (chow diet); high-fat group, HF (60% E from fat); high-fat-sucrose group, HFS (45% E from fat and 17% from sucrose); and high-sucrose group, HS (42% E from sucrose). At day 35, rats were sacrificed, blood was collected, tissues were weighed and fragments of different fat depots were kept for histological analyses with the new softwareAdiposoft. Rats fed with HF, HFS and HS diets increased significantly body weight and total body fat against Control rats, being metabolic impairments more pronounced on HS rats than in the other groups. Cellularity analyses usingAdiposoft revealed that retroperitoneal adipose tissue is histologically different than mesenteric and subcutaneous ones, in relation to bigger adipocytes. The subcutaneous fat pad was the most sensitive to the diet, presenting adipocyte hypertrophy induced by HF diet and adipocyte hyperplasia induced by HS diet. The mesenteric fat pad had a similar but attenuated response in comparison to the subcutaneous adipose tissue, while retroperitoneal fat pad only presented adipocyte hyperplasia induced by the HS diet intake after 35 days of intervention. These findings provide new insights into the role of macronutrients in the development of hyperplastic obesity, which is characterized by the severity of the clinical features. Finally, a new tool for analyzing histological adipose samples is presented.

Protective effect of PCV vaccine against experimental pneumococcal challenge in adults is primarily mediated by controlling colonisation density.

Widespread use of Pneumococcal Conjugate Vaccines (PCV) has reduced vaccine-type nasopharyngeal colonisation and invasive pneumococcal disease. In a double-blind, randomised controlled trial using the Experimental Human Pneumococcal Challenge (EHPC) model, PCV-13 (Prevenar-13) conferred 78% protection against colonisation acquisition and reduced bacterial intensity (AUC) as measured by classical culture. We used a multiplex qPCR assay targeting lytA and pneumococcal serotype 6A/B cpsA genes to re-assess the colonisation status of the same volunteers. Increase in detection of low-density colonisation resulted in reduced PCV efficacy against colonisation acquisition (29%), compared to classical culture (83%). For experimentally colonised volunteers, PCV had a pronounced effect on decreasing colonisation density. These results obtained in adults suggest that the success of PCV vaccination could primarily be mediated by the control of colonisation density. Studies assessing the impact of pneumococcal vaccines should allow for density measurements in their design.

Intra-operative parathyroid hormone monitoring in patients with parathyroid cancer.

BACKGROUND: Intra-operative parathyroid hormone (PTH) monitoring (IPM) is 97% accurate in predicting postoperative eucalcemia in sporadic primary hyperparathyroidism (SPHPT). However, its usefulness in parathyroid cancer has not been demonstrated. This study reports IPM accuracy during surgical resections for parathyroid cancer. METHODS: Eight of 556 consecutive patients with SPHPT underwent parathyroidectomy using IPM and had parathyroid cancer. Operative success was defined as eucalcemia > six months and operative failure/persistent cancer as hypercalcemia within six months of parathyroidectomy. The IPM criterion for operative success was defined as a >50% decrease of peripheral PTH levels from the highest either pre-incision or pre-excision values, 10 minutes after resection. RESULTS: In eight patients, 11 operations were performed. Ten operations (91%) resulted in >50% intra-operative PTH decrease. However, in only seven (70%) of these resections, eucalcemia was achieved for >6 months with five of these seven (71%) procedures being initial en bloc resections. The remaining 3/10 (30%) operations with >50% intra-operative PTH decrease resulted in operative failures. In the last operation, intraoperative parathormone monitoring (IPM) correctly predicted operative failure. IPM sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy in predicting outcome were 100, 40, 70, 100, and 75%, respectively. CONCLUSIONS: IPM with the criterion of >50% PTH drop from the highest level is less accurate in predicting operative success in parathyroid cancer when compared to SPHPT. A >50% intra-operative PTH level decrease in patients with parathyroid cancer, particularly in reoperative cases, is less predictive of complete resection. The initial recognition of this disease followed by proper resection remains essential in the treatment of parathyroid cancer.

Intraoperative Assessment of Parathyroid Viability using Laser Speckle Contrast Imaging.

Post-surgical hypoparathyroidism and hypocalcemia are known to occur after nearly 50% of all thyroid surgeries as a result of accidental disruption of blood supply to healthy parathyroid glands, which are responsible for regulating calcium. However, there are currently no clinical methods for accurately identifying compromised glands and the surgeon relies on visual assessment alone to determine if any gland(s) should be excised and auto-transplanted. Here, we present Laser Speckle Contrast Imaging (LSCI) for real-time assessment of parathyroid viability. Taking an experienced surgeon's visual assessment as the gold standard, LSCI can be used to distinguish between well vascularized (n = 32) and compromised (n = 27) parathyroid glands during thyroid surgery with an accuracy of 91.5%. Ability to detect vascular compromise with LSCI was validated in parathyroidectomies. Results showed that this technique is able to detect parathyroid gland devascularization before it is visually apparent to the surgeon. Measurements can be performed in real-time and without the need to turn off operating room lights. LSCI shows promise as a real-time, contrast-free, objective method for helping reduce hypoparathyroidism after thyroid surgery.

Analysis of large versus small pheochromocytomas: operative approaches and patient outcomes.

BACKGROUND: Laparoscopic adrenalectomy for small pheochromocytomas, although challenging, is widely accepted. However, its application to pheochromocytomas larger than 6 cm is questioned due to concerns of malignancy and case complexity. Our aim was to examine the impact of pheochromocytoma tumor size (>/=6 cm vs <6 cm) on operative approach and postoperative patient outcomes. METHODS: A retrospective review of adrenalectomies performed at 3 university hospitals over 1 decade was analyzed. All pheochromocytomas were identified and then divided based on size into large (>/=6 cm) and small (<6 cm) groups. We examined patient and tumor demographics, pathologic diagnosis, operative approach (laparoscopic vs open), postoperative complications, and biochemical cure rates. Data were analyzed using the Student t test and Fisher exact test with a P value <.05 considered significant. RESULTS: From 1995 to 2005, 65 pheochromocytomas were resected. Of the total, 38% (n = 25) tumors were >/=6 cm and 62% (n = 40) were <6 cm. For the large tumors, 1 out of 25 (4%) was malignant, whereas no small tumors were malignant. There was no statistically significant increased risk of malignancy in tumors >/=6 cm in size (P = .31). Initial operative approach was based on surgeon preference. Of the adrenalectomies performed, 88% were laparoscopic, with 3 of 25 (12%) large tumors requiring conversion from laparoscopic to open for intraoperative bleeding. None of the small tumors required conversion. No major postoperative complications (eg, stroke or myocardial infarction) occurred in either group. Minor complications (eg, wound infections and hematomas) were noted in 16% of large tumors and 12.5% of small tumors (P = .45). A total of 96% (24 of 25) patients with large tumors and 100% with small tumors showed postoperative biochemical cure. Tumor recurrence was noted in 1 patient with a tumor <6 cm. CONCLUSIONS: Pheochromocytomas >/=6 cm pose a challenge for laparoscopic resection, and concerns have been raised about the validity of this operative approach. This study demonstrates that there is no significant difference in the rate of malignancy for pheochromocytomas >/=6 cm versus <6 cm. There also were no significant differences identified in complication rates, postoperative biochemical cures, or tumor recurrence rates between these groups. Laparoscopic resection of pheochromocytomas can be safely accomplished regardless of size in centers with surgeons experienced in these procedures.

Improvement in the health-related quality-of-life symptoms of hyperparathyroidism is durable on long-term follow-up.

BACKGROUND: Subjective symptoms such as decreased energy, chronic fatigue, and depression are associated with hyperparathyroidism. Studies have shown that these symptoms are improved during short-term follow-up after parathyroidectomy. This study evaluates the durability of this subjective improvement in quality-of-life symptoms in a large population of patients with follow-up greater than 1 year after operation. METHODS: Between 2002 and 2005, 258 patients underwent parathyroidectomy, 100 (81 females and 19 males) of whom were available for this study. The patients were evaluated with a survey based on the Health Outcomes Institute Health Status Questionnaire. Some answers were quantified on a 1 to 6 scale, while others consisted of "yes" or "no" responses. Patients completed a questionnaire prior to parathyroidectomy and postoperatively at 1 month, 3 to 6 months, and 1 to 2 years or greater intervals. Statistical analysis was used to detect changes attributable to parathyroidectomy. A P value <.05 was considered statistically significant. RESULTS: At 1-month follow-up, patients' perceptions of their overall health, energy level, and mood significantly improved. At 6-month follow-up, significant improvements in muscle strength, health, endurance, and relief of anxiety were documented. At the interval of 1 to 2 years, overall health, energy level, endurance, and relief of anxiety were improved. There was no significant decrement in the quality of life in these patients after parathyroidectomy. CONCLUSIONS: Parathyroidectomy for hyperparathyroidism is associated with significant lasting improvement in subjective symptoms. The potential durable improvement in these quality-of-life symptoms is a valid indication for parathyroidectomy.

In vivo intracellular signaling as a marker of antiangiogenic activity.

Alterations in endothelial cell (EC) signaling could serve as a marker of effective antiangiogenic therapy. We determined the effect of an antiangiogenic tyrosine kinase inhibitor, SU6668, on tumor EC signaling in liver metastases in mice. In vitro immunofluorescence verified that pretreatment of ECs with SU6668 before exposure to VEGF decreased in vitro phosphorylation of Erk and Akt. Using double-fluorescence immunohistochemistry, phosphorylated Erk and Akt were constitutively expressed in ECs in liver metastases in untreated mice, but SU6668 blocked activation of these signaling intermediates. Determining the activation status of the Erk and Akt signaling pathways in tumor ECs may serve as a surrogate marker for the effectiveness of antiangiogenic regimens.

Blockade of the epidermal growth factor receptor signaling by a novel tyrosine kinase inhibitor leads to apoptosis of endothelial cells and therapy of human pancreatic carcinoma.

We determined whether down-regulation of the epidermal growth factor-receptor (EGF-R) signaling pathway by oral administration of a novel EGF-R tyrosine kinase inhibitor (PKI166) alone or in combination with gemcitabine (administered i.p.) can inhibit growth and metastasis of human pancreatic carcinoma cells implanted into the pancreas of nude mice. Therapy beginning 7 days after orthotopic injection of L3.6pl human pancreatic cancer cells reduced the volume of pancreatic tumors by 59% in mice treated with gemcitabine only, by 45% in those treated with PKI166 only, and by 85% in those given both drugs. The combination therapy also significantly inhibited lymph node and liver metastasis, which led to a significant increase in overall survival. EGF-R activation was significantly blocked by therapy with PKI166 and was associated with significant reduction in tumor cell production of VEGF and IL-8, which in turn correlated with a significant decrease in microvessel density and an increase in apoptotic endothelial cells. Collectively, our results demonstrate that oral administration of an EGF-R tyrosine kinase inhibitor decreased growth and metastasis of human pancreatic cancer growing orthotopically in nude mice and increased survival. The therapeutic effects were mediated in part by inhibition of tumor-induced angiogenesis attributable to a decrease in production of proangiogenic molecules by tumor cells and increased apoptosis of tumor-associated endothelial cells.