Lateralization index but not contralateral suppression at adrenal vein sampling predicts improvement in blood pressure after adrenalectomy for primary aldosteronism.

Adrenal vein sampling (AVS) is essential in differentiating unilateral from bilateral sources of aldosterone excess in primary aldosteronism (PA). However, its ability to predict blood pressure (BP) improvement after adrenalectomy has not been well studied. This is a retrospective observational study of 119 patients who underwent AVS by sequential technique followed by adrenalectomy for PA at the Hospital of the University of Pennsylvania from 1997 to 2015. Median age was 52 years (interquartile range 44-59), 67% were male and median duration of hypertension was 10 (interquartile range 6-20) years. A total of 76% and 90% of patients experienced BP improvement at 0-6 months or at any time point after surgery, respectively. Lateralization index (LI) >8, but not the presence of contralateral suppression, was significantly associated with BP improvement after surgery by multivariate logistic regression analysis adjusted for potential confounders (odds ratio (95% confidence interval): 17.1 (1.7-171.6) and 6.39 (0.06-641.8), respectively). A prediction score was created by covariates that was significantly associated with BP improvement in logistic regression analysis (duration of hypertension, body mass index, preoperative systolic BP and number of antihypertensive medications). Receiver-operating characteristic curve analyses showed that the addition of LI >8 to the score increased its ability to predict BP improvement (area under the curve 0.73-0.80). In conclusion, LI is useful in predicting improvement in BP after adrenalectomy for PA. The results of this study suggest that patients with long-standing severe hypertension may still benefit from surgery if LI >8.

Lymph node evaluation and survival after curative-intent resection of duodenal adenocarcinoma: A matched cohort study.

BACKGROUND: Lymph node (LN) metastasis in patients with duodenal adenocarcinoma is associated with poor prognosis; however, the optimal extent of LN assessment and the interaction between LN assessment and adjuvant systemic therapy is poorly understood. METHODS: Resected non-metastatic duodenal adenocarcinoma patients (n = 1743) were identified in the National Cancer Database (1998-2011). Logistic regression analysis identified covariates associated with LN metastasis. The influence of increasing LN cut-off points on overall survival (OS) was analysed using the log-rank test and Cox proportional hazards modelling. Adjuvant chemotherapy (AC) and surgery alone cohorts were matched (1:1) by propensity scores based on the likelihood of nodal metastasis or survival hazard on Cox modelling. OS in the matched cohort was compared by Kaplan-Meier estimates. RESULTS: LN metastases were present in 865 (49.6%) patients. Increasing LN assessment was associated with an increased likelihood of nodal involvement (P = 0.008). In node-negative patients, increasing LN assessment was associated with a decreased risk of death, with the largest actuarial survival differences observed for ≥15 LN (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.48-0.82, P = 0.001). In the propensity score-matched cohort of node-negative patients, AC was associated with non-significant improvements in 5-year actuarial (66.1% versus 58.7%, HR 0.79, 95% CI 0.53-1.18, P = 0.249), and did not vary by adequacy of LN counts (<15 LNs: HR 0.79, 95% CI 0.51-1.24, P = 0.305; ≥15 LNs: HR 0.90, 95% CI 0.35-2.30, P = 0.900). CONCLUSIONS: The extent of LN identification has prognostic significance in resected node-negative duodenal adenocarcinoma, but cannot be implicated in the selection of node-negative patients for AC.

Preoperative radiotherapy in the management of retroperitoneal liposarcoma.

BACKGROUND: Histological subtype influences both prognosis and patterns of treatment failure in retroperitoneal sarcoma. Previous studies on the efficacy of neoadjuvant radiotherapy (NRT) have incorporated multiple histological types with heterogeneous tumour biology. The survival impact of NRT specifically for patients with retroperitoneal liposarcoma is poorly defined. METHODS: Patients who underwent resection with curative intent for retroperitoneal liposarcoma and who received NRT or surgery alone were identified in the US National Cancer Data Base (2004-2013). Cox regression was used to identify co-variables associated with overall survival. NRT and surgery-alone cohorts were matched 1 : 1 by propensity scores based on the survival hazard on Cox modelling. Overall survival was compared by Kaplan-Meier estimates. RESULTS: A total of 2082 patients with retroperitoneal liposarcoma were identified; 1908 underwent surgery alone and 174 received NRT before surgical resection. Median tumour size was 22·0 cm and 34·9 per cent of tumours were high grade. In the unmatched cohort, NRT was not associated with improved overall survival (χ2 = 3·49, P = 0·062). In the propensity score-matched cohort, NRT was associated with an improvement in survival (median overall survival 129·2 versus 84·3 months; P = 0·046; hazard ratio (HR) 1·54, 95 per cent c.i. 1·01 to 2·36). This effect appeared most pronounced for tumours with adjacent organ invasion (median overall survival not reached versus 63·8 months; P = 0·044; HR 1·79, 1·01 to 3·19). CONCLUSION: NRT improved survival in patients undergoing surgery for retroperitoneal liposarcoma, particularly those with high-risk pathological features.

Change in the pattern of adrenal venous sampling over time in patients with primary aldosteronism.

We report six patients with primary aldosteronism who had serial adrenal venous sampling. Patients with contralateral suppression of aldosterone to cortisol ratio compared with that in inferior vena cava developed lateralization over time whereas patients without contralateral suppression remained with a bilateral pattern.

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.

Vascularity and uptake of photosensitizer in small human tumor nodules: implications for intraperitoneal photodynamic therapy.

PURPOSE: i.p. spread of cancers is a common clinical problem, with limited treatment options leading to morbidity and death. i.p. photodynamic therapy (IP-PDT) combines maximal surgical debulking of gross tumor with intraoperative light delivery to the peritoneum after preoperative i.v. injection of photosensitizer to treat residual disease. An issue of concern in IP-PDT is the potential lack of photosensitizer uptake by residual small tumor nodules (STNs) < or =5 mm in maximum diameter and by microscopic residual disease caused by incomplete development of a vascular supply. This study examined the existence of vasculature and Photofrin (PF) uptake in STNs in 12 patients in a Phase II clinical trial for IP-PDT. EXPERIMENTAL DESIGN: Patients received PF 2.5 mg/kg i.v. 48 h before surgery. STNs obtained during surgery were cryosectioned, immunostained for platelet/endothelial cell adhesion molecule 1, and analyzed by light microscopy. Mean vascular densities in STNs were determined by counting microvessels within a x200 field (0.28 mm(2) area). Sections were also examined for PF uptake by fluorescence image analysis using an epifluorescence microscope and IPLab Spectrum software. RESULTS: Data obtained showed that tumors as small as 1 mm in diameter stained positive for platelet/endothelial cell adhesion molecule 1 and contained PF. A negative control from a patient not given PF showed no detectable fluorescence. The average of all mean vascular densities in STNs was determined to be 100 +/- 29. CONCLUSIONS: We conclude that STNs, as small as 1 mm in diameter, have a functional vasculature, because these tumors show PF uptake after i.v. delivery. Both properties are crucial for the treatment of residual STNs by IP-PDT after surgical debulking.

Parathyromatosis as cause of recurrent secondary hyperparathyroidism: a cytologic diagnosis.

Parathyromatosis is a rare cause of hyperparathyroidism. It can be divided into two types: primary and secondary. The pathologic lesion consists of multiple small nodules of hypercellular parathyroid tissue strewn in soft tissue (fat, skeletal muscle, fibrous tissue) of the neck. We present a case of parathyromatosis occurring in a patient with recurrent secondary hyperparathyroidism 4 yr after parathyroidectomy. The diagnosis was confirmed preoperatively by fine-needle aspiration of one of several neck masses.

Interinstitutional review of thyroid fine-needle aspirations: impact on clinical management of thyroid nodules.

Routine interinstitution pathology consultation can result in change in pathologic diagnosis in up to 10% of patients. In this study, we compared the outside cytopathologic diagnosis of thyroid fine-needle aspiration (FNA) specimens with the in-house diagnosis at the University of Pennsylvania Medical Center over an 18-mo period and its effect on patient management. One hundred ten (60%) diagnostic disagreements were identified among 183 patients. In 16 cases, the diagnosis was changed from benign to malignant, and in 12, the diagnosis was reversed from neoplastic/malignant to benign. Histologic follow-up was available in 109 cases; the overall accuracy of outside diagnosis was 73%, and that of inside diagnosis was 85%. In conclusion, we strongly recommend interinstitution cytology consultation on referred thyroid FNA cases, since our data showed a significant change in diagnosis, thus affecting patient management.

FDG positron emission tomography in isolated limb perfusion therapy in patients with locally advanced melanoma: preliminary results.

PURPOSE: Isolated limb perfusion (ILP) with high-dose chemotherapy and tumor necrosis factor is being tested in clinical trials as a treatment for locally advanced extremity melanoma. The authors investigated the ability of F-18 fluorodeoxyglucose positron emission tomography (FDG PET) to determine the true extent of disease in patients with this condition, whose distribution of lesions differs from that seen in previous studies. METHODS: Nine patients with locally advanced melanoma were selected for imaging of the entire body and extremities using FDG PET from a group of participants in a clinical trial of ILP with melphalan +/- tumor necrosis factor. Scans were obtained without attenuation correction. Post-treatment scans were obtained in three patients 1 month after ILP. The findings in the FDG-PET scans were compared with those of a standard protocol (SP) that included anatomic images and physical examinations. RESULTS: Eighty lesions (74 malignant, 6 benign) were detected with FDG PET and the SP combined. Only malignant lesions were detected by both methods in the perfused limbs. Of the malignant lesions, FDG PET detected 65 lesions (sensitivity rate, 88%). In contrast, 48 lesions were detected with the SP (sensitivity rate, 65%). Twenty-six malignant lesions were seen only with FDG PET (35%), whereas nine malignant lesions were seen only with SP (12%). The six benign lesions included three false-positive mediastinal lymph nodes in one patient. The accuracy rates of FDG PET and the SP were 83% and 65%, respectively. These results are comparable to those seen in previous studies with patients who had disease confined primarily to the torso. All post-therapy FDG-PET scans showed a reduction in the number of visualized limb lesions, and diffuse uptake throughout the perfused limbs. The diffuse uptake correlated with post-therapy limb inflammation. CONCLUSIONS: Non-attenuation-corrected FDG PET is more sensitive than the SP in detecting the extent of disease in candidates for ILP. The FDG uptake associated with post-therapy inflammation may reduce the contrast resolution of this technique and must be evaluated further.

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.

Systemic IFN-beta gene therapy results in long-term survival in mice with established colorectal liver metastases.

Most patients succumbing to colorectal cancer fail with liver-predominant metastases. To make a clinical impact in this disease, a systemic or whole-liver therapy may be required, whereas most cancer gene therapy approaches are limited in their ability to treat beyond local disease. As a preclinical model for cancer gene therapy, recombinant adenovirus containing the human IFN-beta (hIFN-beta) cDNA was delivered systemically in nude mouse xenograft models of human colorectal cancer liver metastases. The vector targeted hepatocytes that produced high levels of hIFN-beta in the liver, resulting in a profound apoptotic response in the tumors and significant tumor regression. hIFN-beta gene therapy not only resulted in improved survival and long-term cure in a micrometastatic model, but provided similar benefits in a clinically relevant gross disease model. A similar recombinant adenovirus containing the murine IFN-beta (mIFN-beta) cDNA also resulted in a therapeutic response and improved survival in syngeneic mouse models of colorectal cancer liver metastases. Depletion studies demonstrate a contribution of natural killer cells to this therapeutic response. The toxicity of an adenoviral vector expressing murine IFN-beta in a syngeneic model is also presented. These encouraging results warrant further investigation of the use of cancer gene therapy for targeting metastatic disease.

Intra-arterial delivery of a recombinant adenovirus does not increase gene transfer to tumor cells in a rat model of metastatic colorectal carcinoma.

Hepatic artery infusion of adenoviral vectors has been shown to increase transduction of certain hepatocellular malignancies in preclinical studies. In addition, clinical trials have begun evaluating the efficacy of gene transfer of cytotoxic genes to metastatic colorectal tumors through hepatic artery infusion. Here we evaluate the extent of gene expression and therapeutic effect following various routes of administration of recombinant adenovirus in a rat model of metastatic colorectal carcinoma. We administered adenovirus (AdCMVlacZ) to rats with established colorectal metastases through infusion into the hepatic artery, intravenous infusion, or direct injection into a tumor. Intravenous administration resulted in transduction of hepatocytes, but not tumor cells. Hepatic arterial administration failed to substantially increase transduction of tumor cells. In addition, ligation of the hepatic artery following infusion of adenovirus or the addition of lipiodol infusion had no effect on the transduction of tumor cells. We administered AdCMVp53 by direct injection into tumors, intravenous administration, or hepatic artery infusion to evaluate the delivery of a therapeutic gene. Direct injection of AdCMVp53 into established hepatic colorectal metastases resulted in a therapeutic response in comparison with both hepatic arterial and intravenous infusion of vector. These preclinical studies fail to support a strategy of infusion through the hepatic artery of recombinant adenovirus targeting tumor cells in the treatment of colorectal cancer liver metastases.

Preliminary report of photodynamic therapy for intraperitoneal sarcomatosis.

INTRODUCTION: Sarcomatosis is the disseminated intraperitoneal spread of sarcoma. It is a condition for which there is no effective treatment. Photodynamic therapy (PDT) is a cancer treatment modality that uses a photosensitizing agent and laser light to kill cells. We report our preliminary Phase II clinical trial experience using PDT for the treatment of intraperitoneal sarcomatosis. METHODS: From May 1997 to December 1998 eleven patients received twelve PDT treatments for intraperitoneal sarcomatosis. Photofrin (PF) 2.5 mg/kg was administered intravenously 48 hours before surgical debulking to a maximum residual tumor size of less than 5 mm. Light therapy was administered at a fluence of 2.5 J/cm2 of 532 nm green light to the mesentery and serosa of the small bowel and colon; 5 J/cm2 of 630 nm red light to the stomach and duodenum; 7.5 J/cm2 of red light to the surface of the liver, spleen, and diaphragms; and 10 J/cm2 of red light to the retroperitoneal gutters and pelvis. Light fluence was measured with an on-line light dosimetry system. Response to treatment was evaluated by abdominal CT scan at 3 and 6 months, diagnostic laparoscopy at 3 to 6 months, and clinical examination every 3 months. RESULTS: Adequate tumor debulking required an omentectomy in eight patients (73%), small bowel resection in seven patients (64%), colon resection in four patients (36%), splenectomy in one patient (9%), and a left spermatic cord resection in one patient. Five patients (45%) have no evidence of disease at follow-up (range, 1.7-17.3 months), including patients at 13.8 and 17.3 months examined by CT. Two patients (18%) died from disease progression. Four patients (36%) are alive with disease progression. Toxicities related to PDT included substantial postoperative fluid shifts with volume overload, transient thrombocytopenia, and elevated liver function tests. One patient suffered a postoperative pulmonary embolism complicated by adult respiratory distress syndrome (ARDS). CONCLUSIONS: Debulking surgery with intraperitoneal PDT for sarcomatosis is feasible. Preliminary response data suggest prolonged relapse-free survival in some patients. Additional follow-up with more patients will be necessary for full evaluation of the added benefit of PDT and aggressive surgical debulking in these patients.

The impact of a multidisciplinary breast cancer center on recommendations for patient management: the University of Pennsylvania experience.

BACKGROUND: Advances in the diagnosis and treatment of breast carcinoma have led to a multidisciplinary approach to management for patients with breast carcinoma. To assess the effect of this approach, the authors performed an evaluation for a cohort of patients examined in a multidisciplinary breast cancer center. METHODS: An analysis was performed for the records of 75 consecutive women with 77 breast lesions examined in consultation in a multidisciplinary breast cancer center between January and June 1998. Each patient's case was evaluated by a panel consisting of a medical oncologist, surgical oncologist, radiation oncologist, pathologist, diagnostic radiologist, and, when indicated, plastic surgeon. A comprehensive history and physical examination was performed, and the relevant mammograms, pathology slides, and medical records were reviewed. Treatment recommendations made before this evaluation were compared with the consensus recommendations made by the panel. RESULTS: For the 75 patients, the multidisciplinary panel disagreed with the treatment recommendations from the outside physicians in 32 cases (43%), and agreed in 41 cases (55%). Two patients (3%) had no treatment recommendation before consultation. For the 32 patients with a disagreement, the treatment recommendations were breast-conservation treatment instead of mastectomy (n = 13; 41%) or reexcision (n = 2; 6%); further workup instead of immediate definitive treatment (n = 10; 31%); treatment based on major change in diagnosis on pathology review (n = 3; 9%); addition of postmastectomy radiation treatment (n = 3; 9%); or addition of hormonal therapy (n = 1; 3%). CONCLUSIONS: The multidisciplinary breast cancer evaluation program provided an integrated program in which individual patients were evaluated by a team of physicians and led to a change in treatment recommendation for 43% (32 of 75) of the patients examined. This multidisciplinary program provided important second opinions for many patients with breast carcinoma.

Preclinical evaluation of motexafin lutetium-mediated intraperitoneal photodynamic therapy in a canine model.

Intraperitoneal photodynamic therapy (IP PDT) is an experimental cancer treatment in clinical development for the treatment of peritoneal carcinomatosis and sarcomatosis. A canine study of motexafin lutetium (Lu-Tex)-mediated IP PDT was performed to evaluate normal tissue toxicities of this treatment in the presence and absence of a bowel resection and to assess the feasibility of measuring Lu-Tex fluorescence in abdominal tissues. Thirteen dogs were treated with Lu-Tex (0.2-2 mg/kg) i.v. 3 h before laparotomy and 730-nm light delivery (fluences, 0.5-2.0 J/cm2; average fluence rate <150 mW/cm2). Laparoscopy was performed 7-10 days after the procedure to assess acute toxicities. In situ fluorescence spectra were obtained from various abdominal tissues before and after light delivery using a fiber array probe with fixed-source detector distances. Lu-Tex-mediated IP PDT was well tolerated at the doses of drug and light studied. Bowel toxicity was not observed in animals treated with a bowel resection before PDT. Mild transient liver function test abnormalities without associated clinical sequelae were observed. No gross PDT-related abnormalities were observed at laparoscopy or necropsy; however, thickening in the glomerular capillary wall and the mesangium were noted microscopically in the kidneys of seven dogs. No renal function abnormalities were found. Analysis of the fluorescence spectra from intra-abdominal tissues suggests that measurements of Lu-Tex in situ are feasible and may provide a way of assessing photosensitizer concentration in vivo without the need for a biopsy. These results support the continued development of Lu-Tex as a candidate photosensitizer for IP PDT.

Isolated hepatic perfusion for unresectable hepatic metastases from colorectal cancer.

BACKGROUND: Unresectable colorectal liver metastases are a significant clinical problem. Isolated hepatic perfusion (IHP) is a regional treatment technique that delivers high dose chemotherapy, biologic agents, and hyperthermia via a completely isolated vascular recirculating perfusion circuit as a means of regionally treating liver tumors. This study presents our results of IHP with tumor necrosis factor (TNF) plus melphalan or IHP with melphalan alone followed by infusional floxuridine (FUDR) and leucovorin in patients with advanced or refractory unresectable hepatic colorectal metastases. METHODS: Fifty-one patients with unresectable colorectal hepatic metastases underwent a 60-minute IHP with 1.5 mg/kg melphalan and hyperthermia (39 degrees C to 40 degrees C). Thirty-two patients received IHP with 1 mg TNF with melphalan and 19 patients had IHP with melphalan alone followed by monthly hepatic intra-arterial infusional (HAI) FUDR (0.2 mg/kg/day) and leucovorin (15 mg/M(2)/day) for 14 days monthly for up to 12 months. Twenty-six patients failed 1 or more previous treatment regimens for established hepatic metastases and 27 had greater than 25% hepatic replacement (PHR) by tumor. Patients were monitored for response, toxicity, and survival. RESULTS: There was 1 perioperative death (2%), and only 2 patients (4%) had measurable perfusate leak during IHP (both less than 4%). In the 32 patients treated with IHP alone there were no detectable systemic TNF or melphalan levels during perfusion. The overall objective radiographic response rate (all partial [PR]) was 76% (38 of 50 assessable patients) with a median duration of 10.5 months (range, 2 to 21 months). Twenty-four of 31 patients (77%) had a PR after IHP alone and 14 of 19 (74%) after IHP with postperfusion HAI. Median duration of response was 8.5 months after IHP alone and 14.5 months after IHP and HAI; median survival was 16 and 27 months, respectively. There were 18 PRs in 26 patients (69%) whose prior therapy had failed and 18 PRs in 27 patients (67%) with PHR of 25 or greater. CONCLUSIONS: IHP can be performed with acceptably low morbidity and has significant antitumor activity in patients with unresectable hepatic metastases from colorectal cancer including those with refractory disease or PHR of 25 or greater. HAI appears to prolong the duration of response after IHP, and this combined treatment strategy deserves additional clinical evaluation as a therapeutic modality in this setting.

Hypoxia in human intraperitoneal and extremity sarcomas.

PURPOSE: The presence of hypoxia, measured by needle electrodes, has been shown to be associated with poor patient outcome in several human tumor types, including soft tissue sarcomas. The present report emphasizes the evaluation of hypoxia in soft tissue sarcomas based upon the binding of the 2-nitroimidazole drug EF5 (2-[2-nitro-1H-imidazol-1-yl]-N-(2,2,3,3,3-pentafluoropropyl) acetamide). EF5 has previously been shown to be predictive of radiation response in animal tumors and in in vitro studies. We have also previously reported studies of EF5 binding in human squamous cell tumors. Using fluorescent immunohistochemical techniques, we provide data on the presence and distribution of EF5 binding, as a surrogate for hypoxia, in human spindle cell tumors. METHODS AND MATERIALS: Patients with spindle cell tumors who were scheduled for tumor surgery were asked to participate in the Phase I trial of EF5. Approximately 48 h preoperatively, EF5 was administered i.v. at doses between 9 and 21 mg/kg. Binding in frozen sections of biopsied tissues was determined using monoclonal antibodies labeled with the green-excited, orange-emitting fluorescent dye, Cy3. Calibration studies were performed in vitro by incubating fresh tumor tissue cubes obtained from each patient with EF3 (an analog of EF5) under hypoxic conditions ("reference binding"). The goal of these calibration studies was to quantify the maximal binding levels possible in individual patient's tissues. The relationship between binding (in situ based on EF5 binding) and reference binding (in vitro based on EF3 binding) was determined. RESULTS: Eight patients were studied; 3 of these patients had gastrointestinal stromal tumors (GIST). The incubation of tumor tissue cubes in EF3 under hypoxic conditions demonstrated that all tumors bound drug to a similar extent. Reference binding showed a 3.2-fold variation in median fluorescence (113-356) on an absolute fluorescence scale, calibrated by a Cy3 dye standard. In situ binding in the brightest tumor section varied by a factor of 25.4 between the lowest and highest binding tumor (7.5-190.2). Heterogeneity of highest binding was greater between tumors than within individual tumors. A correspondence between EF5 binding and Eppendorf needle electrode studies was seen in the 5 patients with non-GISTs. CONCLUSION: Inter- and intratumoral heterogeneity of EF5 binding in spindle cell tumors has been documented. Patterns of binding consistent with diffusion limited hypoxia are present in human spindle cell neoplasms.

Phase II trial of debulking surgery and photodynamic therapy for disseminated intraperitoneal tumors.

BACKGROUND: Photodynamic therapy (PDT) combines photosensitizer drug, oxygen, and laser light to kill tumor cells on surfaces. This is the initial report of our phase II trial, designed to evaluate the effectiveness of surgical debulking and PDT in carcinomatosis and sarcomatosis. METHODS: Fifty-six patients were enrolled between April 1997 and January 2000. Patients were given Photofrin (2.5 mg/kg) intravenously 2 days before tumor-debulking surgery. Laser light was delivered to all peritoneal surfaces. Patients were followed with CT scans and laparoscopy to evaluate responses to treatment. RESULTS: Forty-two patients were adequately debulked at surgery; these comprise the treatment group. There were 14 GI malignancies, 12 ovarian cancers and 15 sarcomas. Actuarial median survival was 21 months. Median time to recurrence was 3 months (range, 1-21 months). The most common serious toxicities were anemia (38%), liver function test (LFT) abnormalities (26%), and gastrointestinal toxicities (19%), and one patient died. CONCLUSIONS: Photofrin PDT for carcinomatosis has been successfully administered to 42 patients, with acceptable toxicity. The median survival of 21 months exceeds our expectations; however, the relative contribution of surgical resection versus PDT is unknown. Deficiencies in photosensitizer delivery, tissue oxygenation, or laser light distribution leading to recurrences may be addressed through the future use of new photosensitizers.