Phase I study of heat-deployed liposomal doxorubicin during radiofrequency ablation for hepatic malignancies.

PURPOSE: A phase I dose escalation study was performed with systemically delivered lyso-thermosensitive liposomal doxorubicin (LTLD). The primary objectives were to determine the safe maximum tolerated dose (MTD), pharmacokinetic properties, and dose-limiting toxicity (DLT) of LTLD during this combination therapy. MATERIALS AND METHODS: Subjects eligible for percutaneous or surgical radiofrequency (RF) ablation with primary (n = 9) or metastatic (n = 15) tumors of the liver, with four or fewer lesions as large as 7 cm in diameter, were included. RF ablation was initiated 15 minutes after starting a 30-minute intravenous LTLD infusion. Dose levels between 20 mg/m(2) and 60 mg/m(2) were evaluated. Magnetic resonance imaging, positron emission tomography, and computed tomography were performed at predetermined intervals before and after treatment until evidence of recurrence was seen, administration of additional antitumor treatment was performed, or a total of 3 years had elapsed. RESULTS: DLT criteria were met at 60 mg/m(2), and the MTD was defined as 50 mg/m(2). RF ablation was performed during the peak of the plasma concentration-time curve in an effort to yield maximal drug deposition. LTLD produced reversible, dose-dependent neutropenia and leukopenia. CONCLUSIONS: LTLD can be safely administered systemically at the MTD (50 mg/m(2)) in combination with RF ablation, with limited and manageable toxicity. Further evaluation of this agent combined with RF ablation is warranted to determine its role in the management of liver tumors.

Predictive Outcome Modeling of Preoperative Clinical Symptoms and Electrodiagnostic Data in Tarsal Tunnel Surgery.

Background The relationship between tarsal tunnel syndrome (TTS), electrodiagnostic (Edx) findings, and surgical outcome is unknown. Analysis of TTS surgical release outcome patient satisfaction and comparison to Edx nerve conduction studies (NCSs) is important to improve outcome prediction when deciding who would benefit from TTS release. Methods Retrospective study of 90 patients over 7 years that had tarsal tunnel (TT) release surgery with outcome rating and preoperative tibial NCS. Overall, 64 patients met study inclusion criteria with enough NCS data to be classified into one of the following three groups: (1) probable TTS, (2) peripheral polyneuropathy, or (3) normal. Most patients had preoperative clinical provocative testing including diagnostic tibial nerve injection, tibial Phalen's sign, and/or Tinel's sign and complaints of plantar tibial neuropathic symptoms. Outcome measure was percentage of patient improvement report at surgical follow-up visit. Results Patient-reported improvement was 92% in the probable TTS group ( n = 41) and 77% of the non-TTS group ( n = 23). Multivariate modeling revealed that three out of eight variables predicted improvement from surgical release, NCS consistent with TTS ( p = 0.04), neuropathic symptoms ( p = 0.045), and absent Phalen's test ( p = 0.001). The R 2 was 0.21 which is a robust result for this outcome measurement process. Conclusion The best predictors of improvement in patients with TTS release were found in patients that had preoperative Edx evidence of tibial neuropathy in the TT and tibial nerve plantar symptoms. Determining what factors predict surgical outcome will require prospective evaluation and evaluation of patients with other nonsurgical modalities.

A pilot feasibility study of TNFerade™ biologic with capecitabine and radiation therapy followed by surgical resection for the treatment of rectal cancer.

OBJECTIVE: The purpose of this pilot study was to evaluate the feasibility and tolerability of weekly intratumoral TNFerade™ injections combined with concurrent capecitabine and radiotherapy in the treatment of patients with locally advanced rectal cancer. METHODS: Patients with T3, T4, or N+ rectal cancer received radiotherapy to a total dose of 50.4-54 Gy in combination with capecitabine 937.5 mg/m(2) p.o. b.i.d. TNFerade™ at a dose of 4 × 10(10) particle units was injected into the rectal tumor on the first day of radiotherapy and weekly for a total of 5 injections. Surgery was performed 5-10 weeks after the completion of chemoradiation. RESULTS: Nine patients were enrolled in this pilot trial. The stage was cT2 in 2 patients, cT3 in 6 patients, cT4 in 1 patient, N- in 7 patients and N+ in 2 patients. Eight patients completed all treatments. Grade 3 hematologic toxicity was observed in 2 patients. There was no toxicity directly attributable to the injection procedure. A complete pathologic response was observed in 2 of 9 patients. CONCLUSIONS: This study demonstrates the feasibility of weekly intratumoral TNFerade™ injections during chemoradiotherapy for locally advanced rectal cancer. Pathologic responses with this combination compare favorably to published rates.

Frequency of Electrodiagnostically Measurable Berrettini Anastomosis.

PURPOSE: Ulnar sensory palmar crossover to digit three (D3), the Berrettini anastomosis, is measurable in routine electrodiagnostic nerve conduction studies. The crossover is reported as occurring in 60% of anatomic dissections, but the frequency of measurable ulnar crossover to D3 and its potential as a nerve conduction pitfall is not established. The purpose of this article was to present descriptive statistics regarding the frequency of measurable Berrettini anastomosis in nerve conduction studies. METHODS: A retrospective chart review and data analysis was completed on 248 patients representing 411 extremities with a main outcome measure of ulnar sensory stimulated nerve conduction simultaneous waveform recording on D3 and digit four (D4). Consistent electrodiagnostic technique with waveform recording data analysis in a private practice and independent university waveform verification was completed on sequential patients referred for upper extremity electrodiagnostic testing. RESULTS: Measurable ulnar stimulated D3 sensory nerve action potentials were demonstrated in 34% of patients with amplitudes of 27%, the simultaneously recorded corresponding ulnar D4 amplitudes representing electrophysiological evidence of ulnar sensory crossover. CONCLUSIONS: The Berrettini anastomosis can frequently be seen as a small amplitude sensory nerve action potential response, but at times can be observed with an amplitude greater than 10 µV. It is possible that patients with an absent or significantly delayed median nerve response may have simultaneous inadvertent spread of stimulus to ulnar axons measurable on D3 that may be interpreted as a falsely normal response. All electromyographers need to be aware of this potential pitfall.

Electrodiagnostic Evidence of Berrettini Anastomosis.

PURPOSE: Cadaveric palmar dissections reveal an ulnar sensory crossover (Berrettini anastomosis) to the third common palmar nerve so frequently that this crossover is considered a normal part of the anatomy. No literature has documented electrophysiologic evidence of the Berrettini anastomosis (BA). Presentation of third digit ulnar sensory crossover waveforms. METHODS: Retrospective chart review case series. Clinical office. Nerve conduction waveforms and data. RESULTS: Ulnar stimulation sensory crossover waveforms to digit three consistent with BA are presented. CONCLUSIONS: Third digit BA is measurable in routine electrodiagnostic nerve conduction study in some patients. The observed BA latency is the same and the amplitude is smaller (25% to 33%) than the ulnar sensory response. The clinical significance of the BA sensory response is unclear. The presence of a BA in severe carpal tunnel syndrome may give a small amplitude normal latency sensory response that could be misinterpreted and lead to a false negative result.

Phase I study of hepatic arterial melphalan infusion and hepatic venous hemofiltration using percutaneously placed catheters in patients with unresectable hepatic malignancies.

PURPOSE: We conducted a phase I study of a 30-minute hepatic artery infusion of melphalan via a percutaneously placed catheter and hepatic venous hemofiltration using a double balloon catheter positioned in the retrohepatic inferior vena cava to shunt hepatic venous effluent through an activated charcoal filter and then to the systemic circulation. The purpose of the study was to demonstrate feasibility in an initial cohort and subsequently determine the maximum tolerated dose and dose-limiting toxicity of melphalan. PATIENTS AND METHODS: The initial cohort (n = 12) was treated with 2.0 mg/kg of melphalan before dose escalation to 3.5 mg/kg (n = 16). Total hepatic drug delivery, systemic levels, and percent filter efficiency were determined. Patients were assessed for hepatic and systemic toxicity and response. RESULTS: A total of 74 treatments were administered to 28 patients. Twelve patients with primary and metastatic hepatic tumors received 30 treatments (mean, 2.5 per patient) at an initial melphalan dose of 2.0 mg/kg. At 3.5 mg/kg, a dose-limiting toxicity (neutropenia and/or thrombocytopenia) was observed in two of six patients. Transient grade 3/4 hepatic and systemic toxicity was seen after 19% and 66% of treatments, respectively. An overall radiographic response rate of 30% was observed in treated patients. In the 10 patients with ocular melanoma, a 50% overall response rate was observed, including two complete responses. CONCLUSION: Delivery of melphalan via this system is feasible, with limited, manageable toxicity and evidence of substantial antitumor activity; 3 mg/kg is the maximum safe tolerated dose of melphalan administered via this technique.

Phase I and pharmacokinetic studies of CYT-6091, a novel PEGylated colloidal gold-rhTNF nanomedicine.

PURPOSE: A novel nanomedicine, CYT-6091, constructed by simultaneously binding recombinant human tumor necrosis factor alpha (rhTNF) and thiolyated polyethylene glycol to the surface of 27-nm colloidal gold particles, was tested in a phase I dose escalation clinical trial in advanced stage cancer patients. EXPERIMENTAL DESIGN: CYT-6091, whose dosing was based on the amount of rhTNF in the nanomedicine, was injected intravenously, and 1 cycle of treatment consisted of 2 treatments administered 14 days apart. RESULTS: Doses from 50 µg/m(2) to 600 µg/m(2) were well tolerated, and no maximum tolerated dose (MTD) was reached, as the highest dose exceeded the target dosage of 1-mg rhTNF per treatment, exceeding the previous MTD for native rhTNF by 3-fold. The first 2 patients on the study, each receiving 50 µg/m(2), did not receive any prophylactic antipyretics or H2 blockade. A predicted, yet controllable fever occurred in these patients, so all subsequently treated patients received prophylactic antipyretics and H2 blockers. However, even at the highest dose rhTNF's dose-limiting toxic effect of hypotension was not seen. Using electron microscopy to visualize nanoparticles of gold in patient biopsies of tumor and healthy tissue showed that patient biopsies taken 24 hours after treatment had nanoparticles of gold in tumor tissue. CONCLUSIONS: These data indicate that rhTNF formulated as CYT-6091 may be administered systemically at doses of rhTNF that were previously shown to be toxic and that CYT-6091 may target to tumors. Future clinical studies will focus on combining CYT-6091 with approved chemotherapies for the systemic treatment of nonresectable cancers.

The utility of routine transcervical thymectomy for multiple endocrine neoplasia 1-related hyperparathyroidism.

BACKGROUND: Operation for multiple endocrine neoplasia (MEN)1-related hyperparathyroidism (HPT) includes a neck exploration with resection of 3.5 or 4 parathyroid glands and transcervical thymectomy (TCT). We reviewed our experience with initial operation for primary HPT to determine the outcome and utility of routine TCT. METHODS: All patients with MEN1 who underwent initial neck exploration from 1993 to 2007 under an institutional review board-approved protocol were reviewed. RESULTS: We identified 66 patients with initial operation for HPT in MEN1. In 34 patients, 4 glands were found; in 32 patients, <4 glands were found. In 2 of the 34 (6%) and 17 of the 32 (53%), intrathymic parathyroid tissue was found on permanent pathology. No thymic carcinoid tissue was found in any specimen. CONCLUSION: These data highlight the importance of performing TCT when <4 entopic parathyroid glands are found at first operation.

Clinical, genetic and radiographic analysis of 108 patients with von Hippel-Lindau disease (VHL) manifested by pancreatic neuroendocrine neoplasms (PNETs).

BACKGROUND: von Hippel-Lindau (vHL) disease is an autosomal dominant syndrome associated with neoplasms in multiple organs, which includes the pancreas. Here, we report the greatest single center experience in patients with vHL pancreatic endocrine neoplasm (PNETs). METHODS: Between December 1998 and November 2006, 633 patients with vHL were evaluated and those with PNETs were enrolled on a prospective protocol. RESULTS: Overall, 108 vHL patients had PNETs (17%). Nine patients had metastatic disease (8.3%) from their PNET. Patients with lesions greater than 3 cm (n = 25) were more likely to develop metastases than patients with lesions less than 3 cm (n = 83) (P < .005). Thirty-nine patients underwent resection. Germline sequencing showed that 78% of patients with metastases (7/9) had exon 3 mutations compared with 46% of patients without metastases (32/98; P < .01). Tumor doubling time was calculated for the largest PNET. The group with metastases had an average tumor doubling time of 337 days (range, 180-463 days) compared with 2630 days (range, 103-9614 days) for those without metastases (P < .0001). CONCLUSIONS: By implementing a system of selective operative resection based on defined criteria, vHL patients with PNETs can be managed safely. For patients with small primary lesions (<3 cm), without a mutation of exon 3 and slow tumor doubling time (>500 days), a nonoperative approach may be appropriate for these nonfunctional neoplasms.