Tissue effects after stereotactic body radiotherapy using cyberknife for patients with abdominal malignancies.

AIMS: To report the tissue effects of treatment with single fraction stereotactic body radiotherapy (SBRT) using Cyberknife on malignant tumours of the abdomen and adjacent normal organs. MATERIALS AND METHODS: The data from four autopsies with unresectable pancreatic carcinoma and one lymph node excision from a case of recurrent neuroblastoma were reviewed for radiation-related tissue effects within the primary cancer and the normal organs within the radiation field. RESULTS: Cases of unresectable pancreatic carcinoma consistently showed radiation-induced changes in both the primary tumour and the adjacent, non-malignant colorectal tissue. An additional case of lymph nodes exposed to stereotactic radiation showed typical radiation-related changes, including lymphocyte depletion and capsular fibrosis. CONCLUSIONS: A myriad of radiation-related tissue effects are seen after SBRT with Cyberknife. The changes parallel those reported after conventionally fractionated radiotherapy and suggest that the pathophysiological mechanisms of radiation-induced normal tissue damage are similar for biologically equivalent single and fractionated doses of radiotherapy.

Reoperation for hyperparathyroidism in multiple endocrine neoplasia type 1.

BACKGROUND: Patients with multiple endocrine neoplasia type 1 and hyperparathyroidism often undergo multiple operations because of inadequate initial surgery, presence of supernumerary and ectopic glands, regrowth of remnant glands, or autograft hyperfunction. Management of this patient population is complex. METHODS: From January 1975 to December 2000 we performed 94 reoperative parathyroidectomies consisting of 79 neck reexplorations, 12 autograft removals, and 3 median sternotomies in 75 patients. Data were gathered by retrospective chart review and follow-up telephone interviews. RESULTS: Excluding autograft excision, reoperative surgery was successful (normocalcemia longer than 6 months) in 91%; autograft removal was successful in only 58%. With a median follow-up of 59 months, 64% of patients are currently free from hypercalcemia, and this outcome was not influenced by the total number of glands resected. The median time to recurrent hypercalcemia was 125 months. Thirty patients received an autograft after reoperation. The complication rate for all reoperations was 12%, including permanent recurrent laryngeal nerve injury in 2 patients (2.1%). CONCLUSIONS: Reoperative parathyroidectomy in patients with multiple endocrine neoplasia type 1 was safe and successful in the majority of patients; however, recurrent hyperparathyroidism is likely to develop in most individuals beyond 10 years of follow-up. The total number of glands accounted for after reoperation is not associated with successful outcome.

Iatrogenic pheochromocytomatosis: a previously unreported result of laparoscopic adrenalectomy.

BACKGROUND: Laparoscopic adrenalectomy is now regarded as the procedure of choice for treatment of small or benign adrenal tumors, including pheochromocytoma. However, long-term outcomes have not been critically assessed. We report here 3 cases of pheochromocytomatosis recurring 3 to 4 years after laparoscopic adrenalectomy. We postulate laparoscopic-induced seeding of tumor as the mechanism of recurrence. METHODS: We retrospectively reviewed the cases of 3 patients with documented biochemical and radiolabeled metaiodobenzylguanidine evidence of recurrent pheochromocytoma after prior presumed curative laparoscopic adrenalectomy. RESULTS: Original pheochromocytomas were 5.5 to 6.5 cm in diameter. At the time of laparoscopic adrenalectomy, tumors were not believed to be malignant, based on clinical or histopathologic data. However, on 3- to 4-year follow-up, each patient developed symptoms, elevated urinary catecholamine levels, and metaiodobenzylguanidine imaging consistent with recurrence. At reoperation, multiple small tumor nodules were found in the adrenal bed near the site of the initial laparoscopic resection. The original operative notes suggested some possible method of local seeding: tumor fragmentation and spillage or excessive tumor manipulation. CONCLUSIONS: Pheochromocytoma recurrence may occur as a result of local spillage of tumor during laparoscopic adrenalectomy. The relative risk of recurrence between open and laparoscopic resection needs to be assessed. Long-term follow-up will continue to be important, regardless of operative approach.

Pre-existing tumor-sensitized T cells are essential for eradication of established tumors by IL-12 and cyclophosphamide plus IL-12.

The antitumor immune response activated by IL-12, especially by a combination of cyclophosphamide and IL-12 (Cy+IL-12), is clinically significant in certain experimental tumor models, in that a number of well-established (10-20 mm in diameter) s.c. tumors are completely eradicated. Furthermore, Cy+IL-12 treatment is also able to eradicate well-established grossly detectable experimental lung metastases and advanced ascites tumors. Despite the dramatic antitumor effects seen in some tumor models, Cy+IL-12 fails to induce regression of other established tumors. Characterization of tumor immunogenicity shows that all tumors responding to IL-12 and Cy+IL-12 treatments are immunogenic tumors, in that an antitumor immune response is detectable in tumor-bearing hosts upon tumor establishment. In contrast, none of the nonimmunogenic tumor responds to IL-12 and Cy+IL-12 treatments. Analysis of cellular requirements for successful tumor rejection through an adoptive cell transfer approach reveals that the presence of tumor-sensitized, but not naive, T cells is essential for tumor rejection by IL-12 and Cy+IL-12. Transfer of these tumor-sensitized T cells must be conducted before, but not after, IL-12 treatment in order for tumor rejection to occur. The requirement of sensitized T cells is also tumor specific. In mice bearing immunogenic tumors, the presence of pre-existing tumor-sensitized T cells is demonstrated by adoptive cell transfer experiments using purified spleen T cells from these mice. Results from our study show that Cy+IL-12-based immunotherapy of cancer may be highly effective and that pre-existing tumor-sensitized T cells are essential for the success of the therapy.

Intraoperative ultrasound and preoperative localization detects all occult insulinomas; discussion 1025-6.

HYPOTHESIS: Preoperative invasive localization procedures with intraoperative ultrasound (IOUS) can result in successful surgical treatment of occult insulinomas when noninvasive imaging study results are equivocal or negative. DESIGN: Prospective study. SETTING: Tertiary care university hospital. PATIENTS: Thirty-seven consecutive patients with a biochemical diagnosis of insulinoma without multiple endocrine neoplasia (MEN). INTERVENTION: All patients underwent portal venous sampling (PVS) (n = 22) or calcium angiogram (n = 15) followed by surgery with palpation and IOUS (n = 37). MAIN OUTCOME MEASURE: Portal venous sampling, calcium angiogram, palpation, and IOUS were compared for accurate localization of insulinoma. RESULTS: All patients were cured of hypoglycemia after surgery. Portal venous sampling correctly localized tumors in 17 (77%) of 22 patients. Calcium angiogram was correct in 13 (87%) of 15 patients. Palpation identified 24 (65%) of 37 tumors, and IOUS found 35 (95%) of 37 tumors. The 2 tumors missed by IOUS were located in the tail of the pancreas and were resected based on regional localization alone. CONCLUSIONS: Intraoperative ultrasound is the single best localization study, but it will miss some tumors that regional localization can identify. Combining both modalities allowed surgical cure of all insulinomas in our study. Therefore, we recommend both IOUS and regional localization for insulinoma when preoperative imaging studies are equivocal.

Comparison of surgical results in patients with advanced and limited disease with multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome.

OBJECTIVE: To determine the role of surgery in patients with Zollinger-Ellison syndrome (ZES) and multiple endocrine neoplasia type 1 (MEN1) with either limited or advanced pancreatic endocrine tumors (PETs). SUMMARY BACKGROUND DATA: The role of surgery in patients with MEN1 and ZES is controversial. There have been numerous previous studies of surgery in patients with PETs; however, there are no prospective studies on the results of surgery in patients with advanced disease. METHODS: Eighty-one consecutive patients with MEN1 and ZES were assigned to one of four groups depending on the results of imaging studies. Group 1 (n = 17) (all PETs smaller than 2.5 cm) and group 3 (n = 8) (diffuse liver metastases) did not undergo surgery. All patients in group 2A (n = 17; single PET 2.5-6 cm [limited disease]) and group 2B (n = 31; two or more lesions, 2.5 cm in diameter or larger, or one lesion larger than 6 cm) underwent laparotomy. Tumors were preferably removed by simple enucleation, or if not feasible resection. Patients were reevaluated yearly. RESULTS: Pancreatic endocrine tumors were found in all patients at surgery, with groups 2A and 2B having 1.7 +/- 0.4 and 4.8 +/- 1 PETs, respectively. Further, 35% of the patients in group 2A and 88% of the patients in group 2B had multiple PETs, 53% and 84% had a pancreatic PET, 53% and 68% had a duodenal gastrinoma, 65% and 71% had lymph node metastases, and 0% and 12% had liver metastases. Of the patients in groups 2A and 2B, 24% and 58% had a distal pancreatectomy, 0% and 13% had a hepatic resection, 0% and 6% had a Whipple operation, and 53% and 68% had a duodenal resection. No patient was cured at 5 years. There were no deaths. The early complication rate, 29%, was similar for groups 2A and 2B. Mean follow-up from surgery was 6.9 +/- 0.8 years, and during follow-up liver metastases developed in 6% of the patients in groups 2A and 2B. Groups 1, 2A, and 2B had similar 15-year survival rates (89-100%); they were significantly better than the survival rate for group 3 (52%). CONCLUSIONS: Almost 40% of patients with MEN1 and ZES have advanced disease without diffuse distant metastases. Despite multiple primaries and a 70% incidence of lymph node metastases, tumor can be removed with no deaths and complication rates similar to those in patients with limited disease. Further, despite previous studies showing that patients with advanced disease have decreased survival rates, in this study the patients with advanced tumor who underwent surgical resection had the same survival as patients with limited disease and patients without identifiable tumor. This suggests that surgical resection should be performed in patients with MEN1 who have ZES and advanced localized PET.

Prognostic value of initial fasting serum gastrin levels in patients with Zollinger-Ellison syndrome.

PURPOSE: To assess the value of the initial fasting serum gastrin (FSG) at presentation in patients with Zollinger-Ellison Syndrome (ZES) in predicting primary tumor characteristics and survival. PATIENTS AND METHODS: A total of 239 patients were treated for ZES between December 1981 and September 1998, with a mean follow-up of 9.1 +/- 0.6 years. At initial evaluation, 86 patients (36%) had mild (0 to 499 pg/mL), 61 (25.5%) had moderate (500 to 1,000 pg/mL), and 92 (38.5%) had severe (> 1,000 pg/mL) elevations in FSG. Primary tumor location and size, presence of lymph node or hepatic metastases, and survival were analyzed based on the level of initial FSG. RESULTS: In patients with sporadic ZES, but not in those with multiple endocrine neoplasia type 1 (MEN-1) and ZES, there was a significant relationship between the level of initial FSG and tumor size and location of primary tumor, frequency of lymph node and liver metastases, and survival. The median 5- and 10-year survival decreased with increasing initial FSG (P <.001) in patients with sporadic ZES; MEN-1 patients lived longer than sporadic ZES patients (P =.012), and survival in this group was not associated with the level of initial FSG. Multivariate analysis showed that factors independently associated with death from disease in patients with sporadic ZES were liver metastases (P =.0001), a pancreatic site (P =.0027), and primary tumor size (P =.011) but not initial FSG (P >.30). CONCLUSION: The severity of FSG at presentation is associated with size and site of tumor and the presence of hepatic metastases, factors that are significant independent predictors of outcome. The level of FSG at presentation may be useful in planning the nature and extent of the initial evaluation and management in patients with sporadic ZES.

A high-resolution radiation hybrid map of the human genome draft sequence.

We have constructed a physical map of the human genome by using a panel of 90 whole-genome radiation hybrids (the TNG panel) in conjunction with 40,322 sequence-tagged sites (STSs) derived from random genomic sequences as well as expressed sequences. Of 36,678 STSs on the TNG radiation hybrid map, only 3604 (9.8%) were absent from the unassembled draft sequence of the human genome. Of 20,030 STSs ordered on the TNG map as well as the assembled human genome draft sequence and the Celera assembled human genome sequence, 36% of the STSs had a discrepant order between the working draft sequence and the Celera sequence. The TNG map order was identical to one of the two sequence orders in 60% of these discrepant cases.

Gastrinoma.

Gastrinoma treatment has evolved considerably in the last 20 years. In particular, the advent of effective acid-reducing pharmacologic agents has changed the primary morbidity of this disease entity from one of acid hypersecretion to one of tumor growth and spread. Thus, while symptoms can be temporized using histamine receptor antagonists, proton pump inhibitors, or somatostatin analogs, cure can be effected only by surgical means. Recent advances in operative techniques and pre- and intra-operative imaging studies, including routine duodenotomy, somatostatin-receptor scintigraphy, and intraoperative ultrasound, have allowed for identification and subsequent resection of more than 95% of gastrinoma tumors. Most experts agree that all sporadic cases of localized gastrinoma should be excised. In addition, debulking of metastatic tumor may improve symptoms and survival when cure cannot be ascertained. There is, however, some controversy as to the surgical approach for gastrinoma found in the setting of multiple endocrine neoplasia, type 1. Because of the usual multiplicity and particular indolence of these tumors, two primary strategies have emerged: aggressive approaches have been advocated in an effort to eradicate all present and potential tumor; and less aggressive, or nonoperative, approaches have been suggested because it is unclear whether intervention offers survival or disease-free benefit in this population. We advocate surgical intervention for patients with gastrinoma and multiple endocrine neoplasia, type 1 when tumors exceed 2.5 cm in size. This tumor size has been associated with a higher likelihood of hepatic metastases, which ultimately affects survival. The role of adjuvant therapies for gastrinoma remains limited.

Perspective on RET proto-oncogene and thyroid cancer.

Much is yet to be learned about cancer and its genetic basis. The discovery of the RET proto-oncogene and its role in tumorigenesis have improved our understanding of thyroid cancer. It is clear that RET is responsible for MEN 2A, MEN 2B, FMTC, and PTC. Although the physical and genetic map of the RET proto-oncogene has been elucidated, the precise mechanism of neoplastic transformation and how it affects phenotypic variability is not completely understood. From the precise mapping of RET arose a highly reliable method of DNA analysis for presymptomatic detection of disease allele carriers. The understanding of the role of the RET proto-oncogene in MEN syndromes has led to a new paradigm in surgical practice: the recommendation for surgery based solely on genetic testing.

Habituation of cutaneomuscular reflexes recorded from the first dorsal interosseous and triceps muscle in man.

Cutaneomuscular reflexes have been recorded from the first dorsal interosseous muscle during a sustained abduction of the index finger of 20 subjects (25 recordings) following stimulation of the digital nerves at the following frequencies: 2 Hz, 3 Hz, 5 Hz, 7 Hz and 9 Hz, presented in random order. Five hundred stimuli were given at each frequency. EMG was rectified and consecutive batches of 100 sweeps of each set of 500 responses were averaged time locked to the stimulus. All reflex components, E1, I1 and E2, exhibit habituation with the E1 component habituating the most and the I1 component the least. There was considerable variation in the rate of habituation between subjects. The rate of habituation was independent of the frequency of stimulation. Reflex responses were recorded from the triceps brachii muscle in eight subjects; this reflex response habituated at a faster rate than the E2 component recorded from the first dorsal interosseous muscle. These results are discussed in relation to the choice of stimulus parameters for the clinical testing of cutaneous reflexes. We conclude that it is important to consistently average the same number of responses.

Duodenopancreatic resections in patients with multiple endocrine neoplasia type 1.

OBJECTIVE: To review the authors' 7-year experience with a surgical approach for pancreatic and duodenal neuroendocrine tumors (NETs) in patients with multiple endocrine neoplasia type 1 (MEN 1) designed to remove all gross tumor with limited complications, preserving pancreatic function. SUMMARY BACKGROUND DATA: MEN 1 is an autosomal dominant familial neoplasia syndrome characterized by the development of NETs of the duodenum and pancreas. Some tumors are clinically insignificant or follow a benign course, although a subset pursues a malignant, lethal natural history; the risk of surgical management must be appropriate to the disease course. METHODS: The clinical, biochemical, genetic, and pathologic data were retrospectively reviewed for 21 consecutive MEN 1 patients undergoing pancreatic resection for NETs between 1993 and 1999 at one institution. Age at operation, presenting symptoms, results of preoperative and intraoperative localization studies, major and minor complications, and pathology, including metastases, were analyzed. RESULTS: The surgical approach was selected based on the location and size of the tumors. Five patients required pancreaticoduodenectomy, 11 patients underwent non-Whipple pancreatic resections, and 5 underwent simple enucleation of benign NETs. The incidence of regional lymph node metastases was 33%. CONCLUSIONS: Major pancreatic procedures can be performed safely in most patients with MEN 1 and NETs. Because NETs are the most common MEN 1-related cause of death in the authors' kindreds, an aggressive surgical approach, including early intervention before malignant spread and major pancreatic resection where indicated, appears justified.

Multiple endocrine neoplasia type 2B--genetic basis and clinical expression.

Multiple endocrine neoplasia (MEN) type 2B is a heritable endocrine disorder characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, multiple mucosal neuromas, and a marfanoid habitus. Intestinal ganglioneuromatosis, corneal nerve thickening and skeletal abnormalities are also often present. The disease is inherited in an autosomal dominant fashion and is caused by a single mutation in the RET proto-oncogene, with a methionine to threonine substitution at codon 918. The MTC in MEN 2B presents at an earlier age and tends to be more aggressive than the MTC in MEN 2A. It is multicentric and bilateral and occurs as young as age 3, with early lymph node metastases. Pheochromocytoma is also often bilateral but is rarely malignant. If pheochromocytoma is detected, adrenalectomy should precede thyroidectomy to avoid intraoperative catecholamine crisis. Patients at risk for MEN 2B should undergo genetic screening in infancy. Total thyroidectomy should be performed on all patients positive for RET mutations even prior to the onset of clinical symptoms.

Recent advances in carcinoid pathogenesis, diagnosis and management.

Carcinoid tumors usually present as diagnostic dilemmas due to obscure or nonspecific symptomatology. Advances in molecular biology are allowing the investigation of molecular markers of aggressiveness, better serum tumor markers, as well as the molecular pathogenesis of carcinoid heart disease. Somatostatin receptor scintigraphy (SRS) and whole body positron emission tomography (PET) are providing much improved sensitivity in localization of both primary and metastatic tumors. Long acting depot somatostatin analogues are combining effectiveness and ease of use for medical management of carcinoid syndrome. An additional benefit may be tumor growth suppression.

Intra-operative procedures to localize endocrine tumours of the pancreas and duodenum.

Somatostatin receptor scintigraphy is the best imaging method to identify the presence of neuroendocrine gastroenteropancreatic tumours. Nevertheless, a well structured surgical approach incorporating specific intra-operative methods can localize those tumours that cannot be readily detected by this imaging technique. In the case of gastrinoma, standard palpation allows duodenal tumour detection in approximately 60% of cases, endoscopic transillumination, in more than 80%. Furthermore, adding duodenotomy, 95-97% duodenal tumours can be localized. Intraoperative ultrasound, instead, does not add much to standard palpation in duodenal gastrinoma localization. For insulinoma detection, among the intra-operative methods, inspection gives the poorest results, identifying the lesion in only 20% of cases. Palpation offers better results, localizing 60-80% of insulinomas. The introduction of intra-operative ultrasound has revolutionized the ability to find pancreatic insulinoma, allowing the surgeon to identify the insulinoma in nearly every patient.

Results of heterotopic parathyroid autotransplantation: a 13-year experience.

BACKGROUND: The reported success of heterotopic parathyroid autotransplantation (HPA) in patients with primary hyperparathyroidism varies from 20% to 60%. The purpose of this study was to evaluate our results with HPA to help define its role in this patient group. METHODS: Between July 1985 and June 1998, 44 patients underwent 51 HPA procedures at our institution. Twenty to 25 fragments of parathyroid tissue measuring 1 to 3 mm3 each were placed into the forearm musculature. HPA results were scored as nonfunctional (requiring calcium and vitamin D), partially functional (normocalcemia on calcium alone), fully functional (normocalcemia without supplementation), or hyperfunctional (hypercalcemia without supplementation). RESULTS: Follow-up data were available for 39 patients who underwent 46 autografts (20 immediate and 26 cryopreserved). With a median follow-up of 35 months, 19 autografts (41%) were nonfunctional; 9 autografts (20%) were partially functional; 15 autografts (33%) were fully functional, and 3 autografts (7%) were hyperfunctional. Full function was observed in 35% of immediate and 31% of delayed autografts. CONCLUSIONS: One third of parathyroid autografts develop full function, and an additional one fifth develop partial function. Recurrent hyperparathyroidism is uncommon. No benefit was observed from immediate versus delayed HPA, and the modest success rate of HPA suggests that improvements in technique are warranted.

Clinical use of the Odstock dropped foot stimulator: its effect on the speed and effort of walking.

OBJECTIVE: To assess the clinical effectiveness of the Odstock dropped foot stimulator by analysis of its effect on physiological cost index (PCI) and speed of walking. This functional electrical stimulation (FES) device stimulates the common peroneal nerve during the swing phase of gait. DESIGN: A retrospective study of patients who had used the device for 4 1/2 months. SUBJECTS: One hundred fifty-one patients with a dropped foot resulting from an upper motor neuron lesion. SETTING: A medical physics and biomedical engineering department of a district general hospital specializing in the clinical application of FES and a neurophysiotherapy department at a separate hospital. MAIN OUTCOME MEASURES: Changes in walking speed and effort of walking, as measured by PCI over a 10-meter course. RESULTS: There was a 92.7% compliance with treatment. Stroke patients showed a mean increase in walking speed of 27% (p<.01) and reduction in PCI of 31% (p<.01) with stimulation, and changes of 14% (p<.01) and 19% (p<.01), respectively, while not using the stimulator. Multiple sclerosis patients gained similar orthotic benefit but no "carry-over." CONCLUSIONS: The measured differences in walking with and without stimulation were statistically significant in the stroke and multiple sclerosis groups. In this study use of the stimulator improved walking. Those with stroke demonstrated a short-term "carry-over" effect.