Intraoperative pelvic brachytherapy for treatment of locally advanced or recurrent colorectal cancer.

BACKGROUND: The aim of this study was to evaluate the efficacy and morbidity of intraoperative radiation therapy (IORT) for advanced colorectal cancer. METHODS: All patients undergoing IORT for locally advanced rectal cancer from 2001-2009 were reviewed for cancer recurrence, survival, and procedure-related morbidity. Cumulative event rates were estimated using the method of Kaplan and Meier. RESULTS: Twenty-nine patients with locally advanced (n = 8) or recurrent (n = 21) rectal cancers were treated with IORT and resection. Surgical interventions included low anterior resection, abdominoperineal resection, pelvic exenteration, and a variety of non-anatomic resections of pelvic recurrences. R(0) resections were achieved in 16 patients, while R(1) resections were achieved in 10, and margins were grossly positive in 3 patients. IORT was delivered to all patients over a median area of 48 (42-72) cm(2) at a median dose of 12 (12-15) Gy. Local and overall recurrence rates were 24 % (locally advanced group) and 45 % (recurrent group). Median disease-free and overall survival were 25 and 40 months respectively at a median follow-up of 26 (18-42) months. The short-term (≤30 days) complication rate was 45 %. Eight patients developed local wound complications, 5 of which required operative intervention. Four patients developed intra-abdominal abscesses requiring drainage. Long-term (>30 days) complications were identified in 11 patients (38 %) and included long-term wound complications (n = 3), ureteral obstruction requiring stenting (n = 1), neurogenic bladder (n = 3), enteric fistulae (n = 2), small bowel obstruction (n = 1), and neuropathic pain (n = 1). CONCLUSIONS: Intraoperative brachytherapy is a viable IORT option during pelvic surgery for locally advanced or recurrent colorectal cancer but is associated with high postoperative morbidity. Whether intraoperative brachytherapy can improve local recurrence rates for locally advanced or recurrent colorectal cancer will require further prospective investigation.

A phase I multi-institutional study of systemic sorafenib in conjunction with regional melphalan for in-transit melanoma of the extremity.

BACKGROUND: Isolated limb infusion with melphalan (ILI-M) corrected for ideal body weight (IBW) is a well-tolerated treatment for patients with in-transit extremity melanoma with an approximate 29 % complete response (CR) rate. Sorafenib, a multi-kinase inhibitor, has been shown to augment tumor response to chemotherapy in preclinical studies. METHODS: A multi-institutional, dose-escalation, phase I study was performed to evaluate the safety and antitumor activity of sorafenib in combination with ILI-M. Patients with AJCC stage IIIB/IIIC/IV melanoma were treated with sorafenib starting at 400 mg daily for 7 days before and 7 days after ILI-M corrected for IBW. Toxicity, drug pharmacokinetics, and tumor protein expression changes were measured and correlated with clinical response at 3 months. RESULTS: A total of 20 patients were enrolled at two institutions. The maximum tolerated dose (MTD) of sorafenib in combination with ILI-M was 400 mg. Four dose-limiting toxicities occurred, including soft tissue ulcerations and compartment syndrome. There were three CRs (15 %) and four partial responses (20 %). Of patients with the Braf mutation, 83 % (n = 6) progressed compared with only 33 % without (n = 12). Short-term sorafenib treatment did alter protein expression as measured with reverse phase protein array (RPPA) analysis, but did not inhibit protein expression in the MAP kinase pathway. Sorafenib did not alter melphalan pharmacokinetics. CONCLUSION: This trial defined the MTD of systemically administered sorafenib in combination with ILI-M. Although some responses were seen, the addition of sorafenib to ILI-M did not appear to augment the effects of melphalan but did increase regional toxicity.

Interleukin-1 production in tumor cells of human melanoma surgical specimens.

To determine whether IL-1 alpha and/or IL-1 beta protein is expressed by human melanoma tumor in vivo, we first analyzed nine human melanoma cell lines and optimized the in situ detection of these proteins. Three of the melanoma cell lines stained positively for both IL-1 alpha and IL-1 beta using immunohistochemistry (IHC). THe specificity of IHC was confirmed by the ability of purified recombinant IL-1 alpha and IL-1 beta protein to abolish the staining after being adsorbed by their respective antibodies before use in IHC. The three positively staining cell lines were also the only lines to demonstrate IL-1 production by western blot analysis as well as IL-1 secretion by ELISA. Next we examined 29 surgically obtained melanoma tumor specimens (6 primary and 23 metastases) that had been formalin fixed and paraffin embedded. Using the same anti-IL-1 antibodies, 5 of 23 metastatic tumors stained positively. None of the 6 primary lesions stained for either IL-1 alpha or IL-1 beta. Comparison of staining pattern performed on serially sectioned tissue using preimmune serum and antibodies against S-100 protein, melanoma-associated antigen (HMB-45), and CD68 (kappa P1), which recognizes monocyte-macrophage cell lineage, demonstrates for the first time that IL-1 protein is produced by human melanoma tumor cells in vivo. These findings provide the basis for examination of what may be a previously unrecognized biologically distinct subset of patients.

Local ampullary resection with careful intraoperative frozen section evaluation for presumed benign ampullary neoplasms.

BACKGROUND: Frozen section evaluation has been reported to be inaccurate in detecting foci of adenocarcinoma within adenomas of the ampulla of Vater, leading many authors to advocate pancreaticoduodenectomy as the method of treatment for these neoplasms. The authors hypothesized that (1) ampullary resection is less morbid than pancreaticoduodenectomy, and (2) frozen section evaluation following ampullary resection is accurate and allows for a selective application of pancreaticoduodenectomy to those with carcinoma or benign lesions too large to be locally resected. METHODS: A retrospective review of a single-surgeon experience was conducted. Thirty-eight patients who underwent ampullary resection and pancreaticoduodenectomy (39 procedures) for benign and malignant ampullary neoplasms were identified. Our technique of step-frozen section analysis is described. RESULTS: Twenty-one ampullary resections were performed for preoperative diagnoses of benign (16) and malignant (5) ampullary neoplasms. Frozen section evaluation accurately predicted the final histology in all patients undergoing ampullary resection. Ampullary resection (vs pancreaticoduodenectomy) was associated with a statistically lower operative time (169 minutes vs 268 minutes), estimated blood loss (192 mL vs 727 mL), mean length of stay (10 days vs 25 days), and overall morbidity (29% vs 78%). CONCLUSIONS: Frozen section evaluation of ampullary neoplasms is accurate. Because ampullary resection is less morbid than pancreaticoduodenectomy and frozen section evaluation is accurate, ampullary resection with frozen section evaluation is our current approach to the treatment of small benign ampullary neoplasms.

Indeterminate fine-needle aspiration biopsy of the thyroid: identification of subgroups at high risk for invasive carcinoma.

BACKGROUND: We examined the various cytologic features of indeterminate thyroid fine-needle aspirates along with known clinical and radiologic risk factors to determine whether any parameters were predictive of malignancy. METHODS: Indeterminate fine-needle aspirates were prospectively categorized into four subgroups: (1) suspicious for papillary carcinoma, (2) follicular neoplasm, (3) Hürthle cell neoplasm, and (4) hypercellular follicular aspirates with colloid. Several clinical risk factors were examined, and subgroup comparisons were performed with Fisher's exact test. RESULTS: Of 571 fine-needle aspirate cytologic findings 104 were interpreted as indeterminate for malignancy, and 81 patients underwent thyroidectomy. Invasive cancer was diagnosed in 9 of 10 lesions cytologically suspicious for papillary carcinoma, 8 of 43 follicular neoplasms, 5 of 18 Hürthle cell neoplasms, and 0 of 10 hypercellular aspirates. Cytologic subgroup (p < 0.0001) and age of 50 years or older (p = 0.008) were the only significant predictors of malignancy. When used together, age of 50 years or older and a cytologic diagnosis of follicular or Hürthle cell neoplasm also identified a subgroup of patients at high risk (9 of 20) of invasive malignancy (p = 0.01). CONCLUSIONS: The majority of invasive cancers (18 of 22, 82%) were found in patients whose lesions were suspicious for papillary carcinoma or in patients 50 years or older with follicular or Hürthle cell neoplasms. The risk of carcinoma in these combined subgroups (18 of 30, 60%) warrants early surgical intervention.

Carcinoids of unknown origin: comparative analysis with foregut, midgut, and hindgut carcinoids.

BACKGROUND: Carcinoids are rare neuroendocrine tumors typically arising in the gastrointestinal tract. A significant percentage of these tumors present as metastatic disease of unknown primary site. The aim of this study was to better define the functional and clinical characteristics of carcinoids of unknown primary (CUP) site. METHODS: This study examines the hormonal activity, clinical characteristics, and survival of 434 patients with carcinoids originating in the foregut, midgut, hindgut, or unknown location. The 143 patients with CUP were compared with the other groups with regard to presenting characteristics, diagnostic tests and therapeutic modalities used, hormonal activity, and survival. RESULTS: The hormone levels (urinary 5-hydroxyindoleacetic acid and serotonin, serum and platelet serotonin) of CUP were not significantly different from midgut carcinoids with metastatic disease. Although survival with CUP was shorter than with carcinoids with identified primaries (10-year survivals of 22% vs 62%, 50%, and 48% for foregut, midgut, and hindgut, respectively), the survival curve for CUP was quite similar to that of patients with midgut carcinoids with distant disease (10-year survival of 22% vs 28%). CONCLUSIONS: CUP are similar to midgut carcinoids presenting with metastatic disease with regard to hormone production and survival. Like other carcinoids, CUP can be an indolent disease process with gradual progression over decades.

Foregut carcinoids: a clinical and biochemical analysis.

BACKGROUND: Gastrointestinal foregut carcinoids make up a small percentage (3% to 6%) of all reported carcinoids. Because these tumors are so uncommon, comparisons between the subtypes have been difficult. The goal of this study was to compare the hormonal and clinical characteristics of gastric, duodenal, and pancreatic carcinoids. METHODS: A prospective database of approximately 750 carcinoid patients seen by one author over 25 years was reviewed, and the 104 patients with gastric (33), duodenal (17), or pancreatic (54) carcinoids were selected as the subgroup for analysis. These patients were compared with regard to hormone levels, clinical course, treatment, and survival. RESULTS: Duodenal carcinoids exhibited significantly lower serotoninergic hormone levels than did the gastric and pancreatic carcinoids (urine 5-hydroxyindoleacetic acid [mg/24 h], 5 +/- 1 vs 16 +/- 5 and 47 +/- 12, respectively, P = .03). Pancreatic carcinoids presented with more advanced stage (distant metastases 87% vs 42% and 20% for gastric and duodenal, respectively) and had worse outcomes than patients with gastric and duodenal tumors with 10-year survivals of 10%, 59%, and 58%, respectively (P = .003). CONCLUSIONS: Pancreatic carcinoids produce higher levels of serotoninergic hormones and have a significantly higher stage and worse outcome than other foregut carcinoids. This study demonstrates that the organ of origin is an important determinant of hormonal activity and clinical course for patients with foregut carcinoids.

Management of node-positive melanoma in the era of sentinel node biopsy.

Regional lymph node metastasis is a powerful predictor of decreased overall survival from malignant melanoma. However, the therapeutic value of elective node dissections and the role of adjuvant therapy for node-positive disease have been highly controversial. Sentinel lymph node biopsy has reshaped the debate by allowing for staging of the regional lymph nodes with less morbidity and greater accuracy. This review summarizes the current consensus on the management of node-positive melanoma in the era of sentinel lymph node biopsy.

The role of laparoscopy in the management of suspected pancreatic and periampullary malignancies.

Laparoscopic evaluation of patients with suspected periampullary malignancies has been utilized more frequently in recent years. Its exact role with regard to staging and surgical bypass for palliation have yet to be clearly defined. To better define the role of laparoscopy in the evaluation and palliation of periampullary malignancy, a retrospective review of the Duke experience was carried out. Fifty-three patients with suspected pancreatic or periampullary malignancies were referred for surgical evaluation at Duke University Medical Center between 1993 and 1995. All patients underwent CT scanning and lesions were classified as resectable or unresectable based on previously established criteria. Patients either underwent laparoscopic evaluation (n = 30; 11 with laparoscopic palliation) or proceeded directly to celiotomy (n = 23). Charts were reviewed for postoperative course including complications, length of stay, and hospital costs. Although laparoscopy had a sensitivity of 93.3% for metastatic disease, CT scans accurately staged 86.8% of patients missing only one patient with peritoneal/hepatic disease. Based on these results, laparoscopy may not be beneficial for every patient with a suspected pancreatic malignancy. Retrospectively an attempt was made to determine which patients benefited from laparoscopy and which patients are best served by proceeding directly to open exploration. From these data we devised an algorithm that outlines an efficient and cost-effective approach for this patient population.

Staging of pancreatic cancer before and after neoadjuvant chemoradiation.

Neoadjuvant chemoradiation therapy is used at many institutions for treatment of localized adenocarcinoma of the pancreas. Accurate staging before neoadjuvant therapy identifies patients with distant metastatic disease, and restaging after neoadjuvant therapy selects patients for laparotomy and attempted resection. The aims of this study were to (1) determine the utility of staging laparoscopy in candidates for neoadjuvant therapy and (2) evaluate the accuracy of restaging CT following chemoradiation. Staging laparoscopy was performed in 98 patients with radiographically potentially resectable (no evidence of arterial abutment or venous occlusion) or locally advanced (arterial abutment or venous occlusion) adenocarcinoma of the pancreas. Unsuspected distant metastasis was identified in 8 (18%) of 45 patients with potentially resectable tumors and 13 (24%) of 55 patients with locally advanced tumors by CT. Neoadjuvant chemoradiation therapy and restaging CT were completed in a total of 103 patients. Thirty-three patients with potentially resectable tumors by restaging CT underwent surgical exploration and resections were performed in 27 (82%). Eleven (22%) of 49 patients with locally advanced tumors by restaging CT were resected, with negative margins in 55%; the tumors in these 11 patients had been considered locally advanced because of arterial involvement on restaging CT. Staging laparoscopy is useful for the exclusion of patients with unsuspected metastatic disease from aggressive neoadjuvant chemoradiation protocols. Following neoadjuvant chemoradiation, restaging CT guides the selection of patients for laparotomy but may overestimate unresectability to a greater extent than does prechemoradiation CT.

Complications of pancreaticoduodenectomy after neoadjuvant chemoradiation in patients with and without preoperative biliary drainage.

BACKGROUND: It has been suggested that preoperative biliary drainage increases the risk of infectious complications of pancreaticoduodenectomy. AIMS: The aim of this study was to assess complications related to biliary stents/drains and postoperative morbidity in patients undergoing neoadjuvant chemoradiotherapy for periampullary cancer. PATIENTS: One hundred and eighty-four patients with periampullary neoplasms were prospectively selected for neoadjuvant external beam radiation therapy and 5-fluorouracil-based chemotherapy between 1995 and 2002. METHODS: The data were retrospectively completed and analysed with respect to biliary drainage, efficacy and complications of endoscopic biliary stents and postoperative morbidity. Patients who had undergone a surgical biliary bypass were excluded. RESULTS: Data were completed in 168 patients. One hundred and nineteen patients were treated with endoscopic biliary stents, 18 patients had a percutaneous biliary drain and 31 patients did not require biliary drainage. Hospitalisation for stent-related complications was necessary in 15% of the patients with endoscopic biliary stents. Seventy-two patients underwent pancreaticoduodenectomy. There was no significant difference in the rate of wound infections, intra-abdominal abscesses and overall complications between the groups with and without preoperative biliary drainage. CONCLUSIONS: Postoperative infectious complications are common in patients both with and without preoperative biliary drainage. A statistically significant difference in complication rates was not observed between these groups.

Asystole as a neurologic sign.

The authors present a case of asystole occurring during dural closure following craniotomy with the patient in the supine position. This 22-year-old woman had a left parietal lobe tumor resected with bipolar cautery. Standard intraoperative monitoring with a left radial arterial line and a right internal jugular central venous catheter was used during the surgery. The anesthetic course was complicated by intraoperative bleeding that responded to three units of fresh frozen plasma. Prior to closure, the operative site appeared dry and intact. After closure, asystole occurred suddenly and resolved with evacuation of 500 ml of blood. It is speculated that the asystole was preceded by an acute increase in intracranial pressure and a subsequent secondary brainstem compression.

Cyclosporine and experimental skin allografts: long-term survival in rats treated with low maintenance doses.

Although cyclosporine (CsA) is a powerful immunosuppressive agent in organ transplantation, its efficacy in skin transplantation has not been examined completely. We have tested it as primary immunosuppression in a rat skin allograft model. Histoincompatible Brown-Norway skin grafts are rejected in untreated Lewis hosts within 9 +/- 1 days but survive for 22 +/- 3, 34 +/- 2, or 41 +/- 8 days after 7, 14, or 21 days of CsA treatment (15 mg/kg per day subcutaneously), respectively (p less than 0.001). Animals treated daily for 4 weeks died from drug toxicity; however, an initial 2-week course followed by a low maintenance dose (15 mg/kg every fourth day) produced indefinite (greater than 150 days) graft acceptance without side effects. The long-surviving grafts were supple, grew long hair, and showed normal histology. When the drug was stopped at any time during this maintenance period, early signs of rejection (hair loss, epidermal breakdown, and localized ulceration) occurred, which could be reversed completely by a short CsA "pulse" (15 mg/kg per day for 7 days). These experimental data support the potential application of CsA immunosuppression in human skin allotransplantation.

Ral activation promotes melanomagenesis.

Up to one-third of human melanomas are characterized by an oncogenic mutation in the gene encoding the small guanosine triphosphatase (GTPase) NRAS. Ras proteins activate three primary classes of effectors, namely, Rafs, phosphatidyl-inositol-3-kinases (PI3Ks) and Ral guanine exchange factors (RalGEFs). In melanomas lacking NRAS mutations, the first two effectors can still be activated through an oncogenic BRAF mutation coupled with a loss of the PI3K negative regulator PTEN. This suggests that Ras effectors promote melanoma, regardless of whether they are activated by oncogenic NRas. The only major Ras effector pathway not explored for its role in melanoma is the RalGEF-Ral pathway, in which Ras activation of RalGEFs converts the small GTPases RalA and RalB to an active guanosine triphosphate-bound state. We report that RalA is activated in several human melanoma cancer cell lines harboring an oncogenic NRAS allele, an oncogenic BRAF allele or wild-type NRAS and BRAF alleles. Furthermore, short hairpin RNA (shRNA)-mediated knockdown of RalA, and to a lesser extent of RalB, variably inhibited the tumorigenic growth of melanoma cell lines having these three genotypes. Thus, as is the case for Raf and PI3 K signaling, Rals also contribute to melanoma tumorigenesis.

Future directions in regional treatment strategies for melanoma and sarcoma.

Hyperthermic isolated limb perfusion (HILP) with melphalan and more recently isolated limb infusion (ILI) with melphalan +/- dactinomycin are common treatment modalities for both in-transit melanoma of the extremity and advanced extremity sarcoma. In order to further optimize treatment, future research should focus on selection of appropriate patients, verification of a technique that produces consistent results while maintaining acceptable toxicity, and development of novel strategies and agents. Development of these novel agents and strategies has potential to not only improve the efficacy of regional chemotherapy but may also help guide future strategies for systemic treatment.

Reoperative pancreaticoduodenectomy.

OBJECTIVE: The preoperative diagnostic strategy and operative technique for reoperative pancreaticoduodenectomy were outlined and operative mortality, perioperative morbidity, and early survival data in carefully selected patients undergoing reoperation for pancreatic cancer were analyzed. SUMMARY BACKGROUND DATA: Many patients with localized, nonmetastatic cancer of the pancreas undergo exploratory surgery with limited preoperative assessment of resectability. Frequently, pancreaticoduodenectomy is not performed because cytologic or histologic proof of diagnosis is lacking, or tumor resectability is questioned. Many patients are denied reoperation and a potentially curative resection because of the unacceptable morbidity and mortality believed to accompany pancreaticoduodenectomy in the reoperative setting. METHODS: Twenty-three patients who had undergone previous surgery for palliation or diagnosis of a pancreatic head mass were reoperated on after a standardized preoperative imaging evaluation consisting of chest radiography, computed tomography, and visceral angiography. A standardized operative technique was used on all patients, but was modified based on altered anatomy from the initial operation. RESULTS: Based on preoperative imaging studies, 19 of the 23 patients believed to have resectable tumors underwent laparotomy for planned pancreaticoduodenectomy; resection was accomplished in 14 patients. Seven of the fourteen patients required extended resections that included the superior mesenteric vein, right colon, or both. There was no perioperative mortality, and early complications occurred in 3 of the 14 resected patients. Four patients underwent planned palliative procedures. Four of ten patients who underwent resection for adenocarcinoma are without evidence of disease at a median follow-up of 26 months. CONCLUSIONS: Reoperative pancreaticoduodenectomy can be performed safely and may result in prolonged survival in carefully selected patients with resectable, localized pancreatic cancer.

Malignant melanoma of the mucous membranes: a review of 119 cases.

BACKGROUND: Melanomas arising from the mucous membranes lining the respiratory, digestive, and genitourinary tracts are rare. Women are more commonly affected than are men, mainly because there is no male counterpart for vulvovaginal lesions. The mainstay of therapy is surgery, with little current use of adjuvant modalities in primary therapy. These lesions usually are advanced at initial presentation; consequently, the prognosis is poor, with 5-year survivals well below 50% in most series. METHODS: One hundred and nineteen patients with primary mucosal melanoma were reviewed. They represented 1.1% of the 10,393 melanoma patients seen at Duke University between 1970 and 1995. All data were obtained from the patients' clinic charts and computerized databases. RESULTS: There were 43 tumors arising from the head and neck region, 46 from the urogenital tract, and 30 from the anorectum. A female predominance was observed, with a female-to-male ratio of 2.7:1. All but five of the patients underwent resection with curative intent. Regional or distant metastases, or both, were encountered in 36 patients at the time of presentation. In patients with head and neck and urogenital tumors, local recurrences accounted for most of the treatment failures, whereas systemic recurrences were more common with tumors arising in the anorectum. The age and gender of the patient, anatomic site of origin of the tumor, clinical stage at initial presentation, and ulceration of the primary all clearly affected prognosis. Overall, the probabilities of being alive 1, 5, and 10 years after diagnosis were 80%, 29%, and 15%, respectively. CONCLUSIONS: Widely accepted classification systems are needed so that results from separate institutions can be compared adequately. Multi-institutional trials could help in delineating standardized therapeutic protocols and in establishing the potential roles of emerging modalities in the treatment of this subtype of melanoma.

Measurement of direct and indirect forms of anti-HIV-1 ADCC: implications for other retroviral disease.

Among the varied cytotoxic immune reactivities elicited as a result of HIV-1 infection are two forms of non-MHC restricted cytotoxicity--namely, indirect and direct ADCC. Since these reactivities are directed at both HIV-1 infected as well as gp120 coated targets, there is a potential for anti-HIV-1 ADCC to play both a beneficial as well as a pathogenic role in the natural history of HIV-1 disease. Resolution of these issues will be of great importance to the development of future preventive and interventive therapeutic strategies for AIDS. The direct and indirect forms of ADCC described herein are, most probably, not unique to HIV-1. In theory, any viral disease, retroviral or otherwise, in which high titers of anti-envelope antibodies persist in an environment rich in Fc-receptor bearing effector NK/K cells would be likely to have some component of direct ADCC as part of the host anti-viral response. With this in mind it is imperative that those researchers involved in characterizing cellular anti-viral cytotoxicities do not mistake direct ADCC for another form of CTL activity. These two highly potent reactivities operate independently and are subject to different control mechanisms, both positive and negative, anti-viral ADCC has too long been regarded as a strictly in vitro phenomenon with no in vivo counterpart. Our studies demonstrating direct forms of ADCC in infected patients will hopefully have some impact in forcing a careful re-evaluation of this extremely important issue.