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.

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.

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.

Optimization for the blockade of epidermal growth factor receptor signaling for therapy of human pancreatic carcinoma.

We determined the optimal administration schedule of a novel epidermal growth factor receptor (EGFR) protein tyrosine kinase inhibitor (PKI), PKI 166 (4-(R)-phenethylamino-6-(hydroxyl)phenyl-7H-pyrrolo[2.3-d]-pyrimidine), alone or in combination with gemcitabine (administered i.p.) for therapy of L3.6pl human pancreatic carcinoma growing in the pancreas of nude mice. Seven days after orthotopic implantation of L3.6pl cells, the mice received daily oral doses of PKI 166. PKI 166 therapy significantly inhibited phosphorylation of the EGFR without affecting EGFR expression. EGFR phosphorylation was restored 72 h after cessation of therapy. Seven days after orthotopic injection of L3.6pl cells, groups of mice received daily or thrice weekly oral doses of PKI 166 alone or in combination with gemcitabine. Treatment with PKI 166 (daily), PKI 166 (3 times/week), or gemcitabine alone produced a 72%, 69%, or 70% reduction in the volume of pancreatic tumors in mice, respectively. Daily oral PKI 166 or thrice weekly oral PKI 166 in combination with injected gemcitabine produced 97% and 95% decreases in volume of pancreatic cancers and significant inhibition of lymph node and liver metastasis. Daily oral PKI 166 produced a 20% decrease in body weight, whereas treatment 3 times/week did not. Decreased microvessel density, decreased proliferating cell nuclear antigen staining, and increased tumor cell and endothelial cell apoptosis correlated with therapeutic success. Collectively, our results demonstrate that three weekly oral administrations of an EGFR tyrosine kinase inhibitor in combination with gemcitabine are sufficient to significantly inhibit primary and metastatic human pancreatic carcinoma.

A matrix metalloproteinase inhibitor prevents processing of tumor necrosis factor alpha (TNF alpha) and abrogates endotoxin-induced lethality.

Excessive tumor necrosis factor alpha (TNF alpha) production in response to Gram-negative bacteremia or endotoxemia can often lead to hypotension, shock, and increased mortality. Current approaches used to block the deleterious effects of exaggerated TNF alpha production rely on monoclonal antibodies or immunoadhesins that bind TNF alpha and thus prevent the interaction with its cellular receptors. This report examines whether a previously described inhibitor of matrix metalloproteinases, GM-6001, can inhibit TNF alpha processing and release and attenuate endotoxin-induced mortality. In human peripheral blood mononuclear cells stimulated in vitro with 1 microgram/mL endotoxin, GM-6001 at concentrations > 5 micrograms/mL blocked release of TNF alpha, but did not affect the release of either IL-1 beta or IL-6. GM-6001 also inhibited the release of soluble TNF receptor (p75) from peripheral blood mononuclear cells stimulated with endotoxin and/or TNF alpha. To confirm the role of secreted TNF alpha in endotoxic shock-induced mortality, C57BL/6 mice were challenged with either endotoxin alone (500 micrograms/mouse) or endotoxin (100 ng/mouse) plus D-galactosamine (8 mg/mouse). GM-6001 pretreatment (100 mg/kg) significantly attenuated the 90-minute plasma TNF alpha response in both models and improved survival in mice treated with low-dose endotoxin plus D-galactosamine. However, plasma IL-1 beta and IL-6 concentrations at 90 min after endotoxin treatment were unaffected by GM-6001 following lethal endotoxin challenge, confirming the in vivo specificity of this matrix metalloproteinase inhibitor for TNF alpha processing. These findings demonstrate that a novel inhibitor of matrix metalloproteinases can prevent the release of TNF alpha both in vitro and in vivo, and can abrogate the harmful sequelae of endotoxemic shock.

Nonfunctioning islet cell carcinoma of the pancreas: survival results in a contemporary series of 163 patients.

BACKGROUND: The natural history of nonfunctioning islet cell carcinoma of the pancreas is poorly defined. We therefore reviewed our institutional experience during a period of 12 years to define more clearly the natural history of this disease as a basis for individual therapeutic recommendations. METHODS: The records of all patients who had histologically or cytologically confirmed nonfunctioning islet cell carcinoma of the pancreas were retrospectively reviewed. Patients were grouped by extent of disease at diagnosis and by initial treatment. Survival distributions were estimated by Kaplan-Meier analysis. RESULTS: One hundred sixty-three patients with nonfunctioning islet cell carcinoma of the pancreas were identified. The overall median survival duration was 3.2 years. The median survival was 7.1 years in patients with localized disease who underwent a potentially curative resection and 5.2 years in those with locally advanced, unresectable, nonmetastatic disease (P = .04). Patients with metastatic disease that could not be resected had a median survival of 2.1 years. CONCLUSIONS: Patients with completely resected localized disease had a long median survival. Patients with nonmetastatic but unresectable locally advanced disease also had a surprisingly long median survival; major treatment-related morbidity may be hard to justify in this subgroup. The short median survival in patients with metastatic disease suggests that the frequent practice of observation in this patient subgroup needs to be reexamined and that continued investigation of regional and systemic therapies with novel agents is warranted.

Pharmacokinetics, immunogenicity, and efficacy of dimeric TNFR binding proteins in healthy and bacteremic baboon.

Immunogenicity, pharmacokinetics, and therapeutic efficacy of three novel dimeric soluble tumor necrosis factor (TNF)-receptor I constructs [TNF-binding protein (bp)] were evaluated in 28 baboons, 12 of which were healthy and 16 were challenged with a lethal Escherichia coli bacteremia. The three constructs differed only in the number of extracellular domains of the TNF receptor I and were dimerized with polyethylene glycol. Although all three constructs had generally similar pharmacokinetics when administered to a naive animal, they differed quantitatively in their immunogenicity. Antibodies were detected more frequently, and titers were significantly higher (P < 0.05) in both healthy and septic baboons that received the 4.0-domain TNF-bp construct, compared with animals receiving the 2.6-domain construct. When the TNF-bp constructs were administered a second time (21 days later), the half-lives of the three constructs were significantly shorter in animals that had an antibody response after the first injection. In contrast, all three TNF-bp constructs were equally effective at improving outcome, blocking a systemic TNF-alpha response, and attenuating the cytokine responses when administered at a dose of 1.0 mg/kg body wt 1 h before a lethal E. coli infusion. The findings suggest that immunogenicity of TNF-bp constructs can be altered by changing the number of functional domains, without affecting their capacity to neutralize TNF-alpha and to abrogate TNF-mediated pathology.

Prospective evaluation of the giant prosthetic reinforcement of the visceral sac for recurrent and complex bilateral inguinal hernias.

BACKGROUND: Recurrent and complex bilateral inguinal hernias are associated with a high recurrence rate. This study evaluates prospectively the efficacy and safety of giant prosthetic reinforcement of the visceral sac (GPRVS) in a group of patients at high risk for recurrence. METHODS: Sixty-four patients with 124 inguinal hernias (60 bilateral and 4 unilateral) underwent repair using a large polyester mesh based on Stoppa's preperitoneal technique. Mean age was 61 years (63 men and 1 woman), and 69% had one or more comorbid medical conditions. RESULTS: Factors predicating a high risk for recurrence included large hernia size (> or =5 cm; 31%, 20 of 64), failure of one or more previous repairs (39%, 25 of 64), and chronic obstructive pulmonary disease (28%, 18 of 64). Mean operative time was 115 minutes (range 45 to 235). Mean length of stay was 3+/-3 days. There were 2 major and 15 minor complications, no mesh infections, and no death. Follow-up was obtained in 95% (61 of 64). After a mean follow-up of 24 months, the recurrence rate was 1% (1 of 124) per inguinal hernia repaired or 2% (1 of 64) per patient. CONCLUSION: GPRVS is a safe and effective addition to the surgeon's armamentarium to treat selected patients with recurrent or complex bilateral inguinal hernias.

Inhibition of growth and metastasis of human pancreatic cancer growing in nude mice by PTK 787/ZK222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases.

Since vascular endothelial growth factor (VEGF) plays a major role in tumor angiogenesis, we determined whether blockage of VEGF receptor signaling using a novel tyrosine kinase inhibitor (PTK 787) decreases the growth and metastasis of human pancreatic carcinoma growing orthotopically in nude mice. Human pancreatic L3.6pl cells were injected into the pancreas of nude mice. Seven days later, groups of mice were given daily oral administrations of PTK 787 alone, twice weekly i.p. injections of gemcitabine, or combination therapy. The mice were necropsied when control mice became moribund (day 35). Therapy with PTK 787 alone, gemcitabine alone, or the combination of both agents produced respectively 60%, 70%, and 81% inhibition in the volume of pancreatic cancers. The combination therapy significantly decreased the incidence of lymph node and liver metastasis, leading to a significant increase in survival. Microvessel density (MVD) was significantly decreased in tumors treated with either PTK 787 alone or PTK 787 plus gemcitabine. MVD directly correlated with tumor cell proliferation and inversely correlated with apoptosis of tumor cells and associated endothelial cells. Collectively, our results demonstrate that blockade of VEGF-R signaling may provide an additional approach to the therapy of pancreatic cancer.

Unusual presentation of hemoptysis in a 78-year-old with previous Nissen fundoplication.

A 78-year-old individual, who had a previous transthoracic Nissen fundoplication 20 years earlier, presented to our institution with hemoptysis. Initial workup included chest roentgenogram, upper gastrointestinal series, and upper endoscopy, all of which were nondiagnostic. A repeat upper endoscopy diagnosed a gastrobronchial fistula by revealing a large gastric ulcer that penetrated into the lung parenchyma. The patient underwent surgery for takedown of the fistula. One of the most common symptoms associated with gastrobronchial fistula is hemoptysis, although insidious cough, recurrent pneumonia, or gastrointestinal bleeding are also observed. The most useful diagnostic study is an upper gastrointestinal series, which must be read with a high index of suspicion. Gastrobronchial fistula is most commonly a long-term complication from hiatal hernia repair. The most frequently used procedure for repair of this disorder is the Nissen fundoplication. This can be done from either an abdominal or transthoracic approach. When the procedure is done such that the gastric wrap is left above the diaphragm, serious complications can occur. These include gastric ulceration, gastric herniation with gastric outlet obstruction, slippage or perforation of the wrap, and gastrobronchial fistula. Because of these serious complications, the Nissen fundoplication with the wrap left above the diaphragm should only be used in certain situations, such as obesity and shortened esophagus.

Utility of breast sentinel lymph node biopsy using day-before-surgery injection of high-dose 99mTc-labeled sulfur colloid.

BACKGROUND: In sentinel lymph node (SLN) biopsy for breast cancer, many centers use same-day preoperative injection of technetium 99mTc-labeled sulfur colloid and intraoperative injection of blue dye for localization of SLNs. Same-day sulfur colloid injections can be problematic because of the variability in sulfur colloid migration times, which can lead to ineffective use of operating room time, and low SLN-to-background radioactivity ratios. We examined the utility of day-before-surgery injections of high dose 99mTc-labeled sulfur colloid injections. METHODS: The day before surgery, high-dose 99mTc-labeled sulfur colloid was injected peritumorally, and a lymphoscintigram was obtained. Intraoperatively, after injection of blue dye, a gamma probe was used to localize SLNs. Nodes that were stained blue or were highly radioactive were considered SLNs and were removed. RESULTS: Lymphoscintigraphy demonstrated drainage in 107 patients (91%). Transcutaneous localization of the SLN was possible in 104 patients (89%). In three patients, all of whom had no drainage demonstrated on lymphoscintigraphy, no SLN was identified at surgery (97.5% success rate for SLN identification). A mean of 2.3 SLNs per patient were identified. Twenty-five patients (21%) had at least one histologically positive SLN. In 23 of these patients, the positive SLN was the SLN with the most radioactivity, and in the remaining two patients, the positive SLN was both blue-stained and hot. CONCLUSION: Day-before-surgery injection of high-dose 99mTc-labeled sulfur colloid results in high rates of transcutaneous and intraoperative identification of SLNs. The delay between injection and surgery did not appear to promote significant passage of sulfur colloid to second-echelon nodes.

Exogenously administered interleukin-10 decreases pulmonary neutrophil infiltration in a tumor necrosis factor-dependent murine model of acute visceral ischemia.

INTRODUCTION: Visceral ischemia and reperfusion associated with thoracoabdominal aortic aneurysm (TAAA) repair results in lung injury, which appears to be mediated in part by proinflammatory cytokines. The purpose of this study was to determine the effect of exogenous administration of the antiinflammatory cytokine, recombinant human IL-10 (rhIL-10), on proinflammatory cytokine production (IL-6 and TNF alpha) and pulmonary neutrophil infiltration after acute visceral ischemia-reperfusion. METHODS: Two hours before 25 minutes of supraceliac aortic occlusion, 80 C57BL/6 mice (20 to 22 g) received an intraperitoneal injection of rhIL-10 (0.2 microgram [n = 20], 2 micrograms [n = 20], 5 micrograms [n = 25], or 20 micrograms [n = 15]), and 16 mice received murine anti-IL-10 IgM 200 micrograms. Twenty-five additional mice underwent visceral ischemia-reperfusion without treatment (controls), and 16 mice underwent laparotomy without aortic occlusion (sham). RESULTS: Pretreatment with exogenous rhIL-10 resulted in significant reductions in lung neutrophil infiltration with 0.2 microgram, 2 micrograms, and 5 micrograms per mouse of rhIL-10 compared with lung neutrophil levels in control mice that underwent acute visceral ischemia-reperfusion alone (p < 0.05). In addition, serum TNF alpha was detected in 50% of control mice and in 75% of mice that received murine anti-IL-10, but in none of the mice that received rhIL-10 (2 micrograms per mouse) or the mice that underwent sham operative procedures (p < 0.05 by chi 2 analysis). CONCLUSION: Exogenous IL-10 limits pulmonary neutrophil recruitment and the appearance of TNF alpha in this model of visceral ischemia-reperfusion injury. Thus the use of exogenous IL-10 may offer a novel therapeutic approach to decrease the complications that are associated with TAAA repair.

Inhibition of transforming growth factor alpha stimulation of human squamous cell carcinoma of the head and neck with anti-TGF-alpha antibodies and tyrphostin.

BACKGROUND: Transforming growth factor alpha (TGF-alpha) and its receptor (EGF-R) may regulate normal and malignant epithelial cell growth by an autocrine mechanism. We investigated the role of TGF-alpha in regulating head and neck SCC tumor growth. METHODS: TGF-alpha and EGF-R levels were measured in 7 SCC cell lines and 14 SCC biopsies by RIA, Scatchard, and Western analysis. TGF-alpha autocrine stimulation of DNA synthesis in SCC cell lines was assessed by incubation with TGF-alpha neutralizing antibodies and tyrphostin AG 1478, a selective and potent inhibitor of EGF-R kinase. RESULTS: All SCC cell lines synthesized TGF-alpha and expressed elevated EGF-R levels compared to normal keratinocytes. Twelve of the 14 SCC biopsies contained TGF-alpha protein and 8 had specific EGF-R. Exogenous TGF-alpha or EGF significantly increased DNA synthesis in 4 of 5 SCC cell lines. TGF-alpha neutralizing antibodies or tyrphostin AG 1478 reduced DNA synthesis in the two SCC cell lines (FaDu and SCC9) tested. CONCLUSIONS: These results indicate that SCC cell lines and tumors usually synthesize TGF-alpha, have elevated levels of EGF-R, and are mitogenically stimulated by a TGF-alpha autocrine system. Selective inhibition of the TGF-alpha system by EGF-R kinase inhibitors or TGF-alpha neutralizing antibodies may be useful strategies for treating SCC that overexpress TGF-alpha and its receptor.