Joseph A. Kuhn

Phase II Trial of Intratumoral Administration of ONYX-015, a Replication-Selective Adenovirus, in Patients With Refractory Head and Neck Cancer

PURPOSE To determine the safety, humoral immune response replication, and activity of multiple intratumoral injections of ONYX-015 (replication selective adenovirus) in patients with recurrent squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS This phase II trial enrolled patients with SCCHN who had recurrence/relapse after prior conventional treatment. Patients received ONYX-015 at a dose of 2 x 10(11) particles via intratumoral injection for either 5 consecutive days (standard) or twice daily for 2 consecutive weeks (hyperfractionated) during a 21-day cycle. Patients were monitored for tumor response, toxicity, and antibody formation. RESULTS Forty patients (30 standard and 10 hyperfractionated) received 533 injections of ONYX-015. Standard treatment resulted in 14% partial to complete regression, 41% stable disease, and 45% progressive disease rates. Hyperfractionated treatment resulted in 10% complete response, 62% stable disease, and 29% progressive disease rates. Treatment-related toxicity included mild to moderate fever (67% overall) and injection site pain (47% on the standard regimen, 80% on the hyperfractionated regimen). Detectable circulating ONYX-015 genome suggestive of intratumoral replication was identified in 41% of tested patients on days 5 and 6 of cycle 1; 9% of patients had evidence of viral replication 10 days after injection during cycle 1, and no patients had evidence of replication > or = 22 days after injection. CONCLUSION ONYX-015 can be safely administered via intratumoral injection to patients with recurrent/refractory SCCHN. ONYX-015 viremia is transient. Evidence of modest antitumoral activity is suggested.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the management of peritoneal surface malignancies of colonic origin: a consensus statement. Society of Surgical Oncology.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the management of peritoneal surface malignancies of colonic origin : a consensus statement

Pilot trial of genetically modified, attenuated Salmonella expressing the E. coli cytosine deaminase gene in refractory cancer patients.

We performed a pilot trial in refractory cancer patients to investigate the feasibility of intratumoral injection of TAPET-CD, an attenuated Salmonella bacterium expressing the E. coli cytosine deaminase gene. A total of three patients received three dose levels of TAPET-CD (3 × 106–3 × 107 CFU/m2) via intratumoral injection once every 28 days as long as progression of disease or intolerable toxicity was not observed. From days 4 to 14 of each 28 day cycle, patients also received 5-fluorocytosine (5-FC) at a dose of 100 mg/kg/day p.o. divided three times daily. Six cycles of treatment were administered. No significant adverse events clearly attributable to TAPET-CD were demonstrated. Two patients had intratumor evidence of bacterial colonization with TAPET-CD, which persisted for at least 15 days after initial injection. Conversion of 5-FC to 5-fluorouracil (5-FU) as a result of cytosine deaminase expression was demonstrated in these two patients. The tumor to plasma ratio of 5-FU for these two colonized patients was 3.0, demonstrating significantly increased levels of 5-FU at the site of TAPET-CD colonization and insignificant systemic spread of the bacteria. In contrast, the tumor to plasma ratio of 5-FU of the patient who did not show colonization of TAPET-CD was less than 1.0. These results support the principle that a Salmonella bacterium can be utilized as a delivery vehicle of the cytosine deaminase gene to malignant tissue and that the delivered gene is functional (i.e. able to convert 5-FC to 5-FU) at doses at or below 3 × 107 CFU/m2.

Preliminary Outcome Analysis in Patients With Breast Cancer and a Positive Sentinel Lymph Node Who Declined Axillary Dissection

Background:This retrospective study was designed to provide a preliminary outcome analysis in patients with positive sentinel nodes who declined axillary dissection.Methods:A review was conducted of patients who underwent lumpectomy and sentinel lymph node excision for invasive disease between January 1998 and July 2000. Those who were found to have sentinel lymph node metastasis without completion axillary dissection were selected for evaluation. Follow-up included physical examination and mammography.Results:Thirty-one patients were identified who met inclusion criteria. Primary invasive cell types included infiltrating ductal carcinoma, infiltrating lobular carcinoma, and mixed cellularity. Most primary tumors were T1. Nodal metastases were identified by hematoxylin and eosin stain and immunohistochemistry. Twenty-seven of the metastases were microscopic (<2 mm), and the remaining four were macroscopic. All patients received adjuvant systemic therapy. With a mean follow-up of 30 months, there have been no patients with axillary recurrence on physical examination or mammographic evaluation.Conclusions:We have presented patients with sentinel lymph nodes involved by cancer who did not undergo further axillary resection and remain free of disease at least 1 year later. This preliminary analysis supports the inclusion of patients with subclinical axillary disease in trials that randomize to observation alone.

Optimizing Outcomes in Bariatric Surgery: Outpatient Laparoscopic Gastric Bypass

Background:Roux-en-Y gastric bypass (RYGB) is an effective treatment of severe obesity and one of the fastest growing surgical procedures in the United States. Methods:A single institution prospective database of patients undergoing outpatient laparoscopic (lap) RYGB over a 3-year period was reviewed. Study end points included hospital discharge within 23 hours, 30-day hospital readmission rate, early (<30 day) and late complication rates, and 30-day perioperative mortality. Variables assessed included surgeon experience, patient demographics, comorbidities, operative time, Roux limb pathway, intraoperative steroid bolus, and use of dexmedetomidine. Results:Two thousand consecutive patients undergoing outpatient lap RYGB were identified, and 84% (n = 1669) were discharged within 23 hours. Of these, 1.7% (n = 34) were readmitted within 30 days. The overall early and late complication rates were 1.9% (n = 38) and 4.3% (n = 86), respectively. The 30-day mortality rate was 0.1% (n = 2), and neither patient was discharged before death. Univariate analysis demonstrated surgeon experience (<50 cases), age (<56 years), body mass index (<60 kg/m2), weight (400 lbs), comorbidities (<5), and intraoperative steroid bolus as predictive of successful outpatient discharge. Multivariate analysis revealed surgeon experience, comorbidities, body mass index, and steroid bolus as predictive variables. Conclusions:These data suggest that outpatient lap RYGB can be performed with acceptable perioperative complication rates, hospital readmission, and mortality rates. Surgeon experience, careful patient selection, and the use of intraoperative steroid bolus predicted optimal patient outcomes.

The contribution of malabsorption to the reduction in net energy absorption after long-limb Roux-en-Y gastric bypass

BACKGROUND Roux-en-Y gastric bypass (RYGB) restricts food intake, and when the Roux limb is elongated to 150 cm, the procedure is believed to induce malabsorption. OBJECTIVE Our objective was to measure total reduction in intestinal absorption of combustible energy after RYGB and the extent to which this was due to restriction of food intake or malabsorption of ingested macronutrients. DESIGN Long-limb RYGB was performed in 9 severely obese patients. Dietary intake and intestinal absorption of fat, protein, carbohydrate, and combustible energy were measured before and at 2 intervals after bypass. By using coefficients of absorption to measure absorptive function, equations were developed to calculate the daily gram and kilocalorie quantities of ingested macronutrients that were not absorbed because of malabsorption or restricted food intake. RESULTS Coefficients of fat absorption were 92 ± 1.3% before bypass, 72 ± 5.5% 5 mo after bypass, and 68 ± 8.7% 14 mo after bypass. There were no statistically significant effects of RYGB on protein or carbohydrate absorption coefficients, although protein coefficients decreased substantially in some patients. Five months after bypass, malabsorption reduced absorption of combustible energy by 124 ± 57 kcal/d, whereas restriction of food intake reduced energy absorption by 2062 ± 271 kcal/d. Fourteen months after bypass, malabsorption reduced energy absorption by 172 ± 60 kcal/d compared with 1418 ± 171 kcal/d caused by restricted food intake. CONCLUSION On average, malabsorption accounted for ≈6% and 11% of the total reduction in combustible energy absorption at 5 and 14 mo, respectively, after this gastric bypass procedure.

A prospective phase II trial of ONYX-015 adenovirus and chemotherapy in recurrent squamous cell carcinoma of the head and neck (the Baylor experience).

AbstractBackground: The E1-b attenuated adenovirus, ONYX-015 (Onyx Pharmaceuticals, Richmond, CA), has demonstrated antitumoral activity in patients with recurrent squamous cell carcinoma of the head and neck. This study evaluated the effects of intratumoral ONYX-015 injection combined with systemic chemotherapy. Methods: Inclusion criteria included: (1) recurrent squamous cell carcinoma of the head and neck, not surgically salvageable, (2) target tumor amenable to direct injection, and (3) no prior chemotherapy for recurrent disease. Patients received ONYX-015 (1010 plaque-forming units) intratumorally for 5 days, cisplatin (80 mg/m2) on day 1, and 5-fluorouracil (800–1000 mg/m2) on days 1–5. This cycle was repeated every 3 weeks. Serial physical examination and computed tomography were used to assess tumor size and treatment response. Results: Fourteen patients were enrolled, and nine patients were evaluable for response at the time of enrollment. The mean age of the evaluable patients was 60.8 years (range, 46–71 years). Mean maximum tumor diameter was 4.8 cm (range, 1.9–10.5 cm). Treatment-related toxicity included nausea (n=7, 77.8%), vomiting (n=5, 55.6%), mucositis (n=5, 55.6%), pain at the injection site (n=5, 55.6%), constipation (n=4, 44.4%), and fatigue (n=4, 44.4%). Locoregional tumor control was obtained in all nine patients (100%) (mean observation time, 157 days). Complete clinical response was seen in three patients (33.3%), partial response was seen in three patients (33.3%), minor response was seen in one patient (11.1%), and two patients (22.2%) had stable disease. Median time to local progression of disease has not been reached (range, 35–356 days). Conclusions: ONYX-015 adenovirus plus systemic cisplatin and 5-fluorouracil provides antitumor activity and local tumor control in patients with recurrent squamous cell carcinoma of the head and neck. This novel treatment approach offers hope for patients with limited treatment alternatives and provides the foundation for a phase III clinical trial.

Radiation safety with breast sentinel node biopsy

BACKGROUND Sentinel lymph node biopsy with Technetium 99m sulfur colloid (Tc99m) is an evolving technique that offers the potential for improved staging of breast cancer with decreased morbidity. However, the use of radioactive materials in the operating room generates significant concern about radiation exposure. The purpose of this study was to evaluate radiation exposure to operating room personnel, pathologist, and equipment from specimens during breast sentinel lymph node biopsy. METHODS Twenty patients were injected with 0.7 to 1.1 mCi of Tc99m sulfur colloid 1.5 to 3 hours before sentinel lymph node biopsy. A calibrated Geiger counter was used to measure dose rates from the breast injection site before skin incision (n = 20), lumpectomy specimens (n = 8), and sentinel nodes (n = 20) at distances of 3, 30, and 300 cm. This represented exposure to the surgeons hands, surgeons torso, and scrub nurse, respectively. Exposure to the pathologists hands and torso was represented as dose-rate measurements from lumpectomy and nodal specimens. The operative instruments, trash receptacles, suction canisters, pathology slides, and cryostat machines were measured at 3 cm at the conclusion of each procedure. Specimens or equipment emitting radiation doses equal to background levels (0.04 mRem/h) were exempt from special handling and disposal. RESULTS The highest exposure rate was to the surgeons hands from the breast injection site before skin incision (34.25 mRem/h). Exposure to the surgeons torso measured 1.33 mRem/h, and exposure to the scrub nurses torso measured 0.15 mRem/h from the injection site. Exposure to the pathologists hands was 18.62 and 0.06 mRem/h from the lumpectomy specimen and sentinel node, respectively. Exposure to the pathologists torso measured 0.34 and 0.04 mRem/h from the lumpectomy specimen and sentinel node, respectively. One hundred percent of lumpectomy specimens measured above the exempt level. Thirty-two of 46 (70%) sentinel lymph nodes emitted radiation equal to the exempt background level. Seventeen of 20 trash receptacles (85%) and 4 of 12 (33%) suction canisters measured equal to background levels. All operative instruments, pathology slides, and cryostat machines were equal to background levels. CONCLUSIONS Radiation exposure to operating room personnel, pathologists, and operative equipment during a breast sentinel node biopsy using Tc99m is minimal. A primary surgeon can perform 2,190 hours, a scrub nurse 33,333 hours, and a pathologist 14,705 hours of procedural work before surpassing Occupational Safety and Health Administration limits. Operative instruments, pathology slides, and cryostat machines do not require special handling. All lumpectomy specimens should be stored for decontamination until the dose rate equals background levels. Intraoperative dose-rate monitoring allows selective decontamination of nodal specimens, trash receptacles, and suction canisters, which decreases disposal time and cost.

The role of computed tomography in the diagnosis of acute appendicitis.

BACKGROUND Routine contrast-enhanced computed tomography (CECT) has been described as an accurate diagnostic imaging modality in patients with acute appendicitis. However, most patients with acute appendicitis can be diagnosed by clinical findings and physical exam alone. The role of CECT in patients suspected of having appendicitis but with equivocal clinical exams remains ill defined. METHODS One hundred and seven consecutive patients who were thought to have appendicitis but with equivocal clinical findings and/or physical exams were imaged by CECT over a 12-month period. Oral and intravenous contrast-enhanced, spiral abdominal and pelvic images were obtained using 7-mm cuts. CECT images were interpreted by a board-certified radiologist. Main outcome measures included CECT sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy in the diagnosis of acute appendicitis, comparing CECT with ultrasound, and determining the impact of CECT on the clinical management of this patient population. RESULTS A group of 107 patients consisting of 44 males (41%) and 63 females (59%) with a median age of 33 years (range 13 to 89 years) were imaged with CECT to evaluate suspected appendicitis. Of the 107 CECTs performed, 11 false-positive and 3 false-negative readings were identified, resulting in a sensitivity of 92%, specificity of 85%, PPV of 75%, NPV of 95%, and an overall accuracy of 90%. Forty-three patients were imaged with ultrasound and CECT, and CECT had significantly better sensitivity and accuracy (30% versus 92% and 69% versus 88%, P<0.01). With regard to clinical management, 100% (36/36) of patients with appendicitis, and 4.2% (3/71) of patients without appendicitis underwent appendectomy. Therefore, the overall negative appendectomy rate was 7.6% (3/39). CONCLUSIONS CECT is a useful diagnostic imaging modality for patients suspected of having acute appendicitis but with equivocal clinical findings and/or physical exams. CECT is more sensitive and accurate than ultrasound and is particularly useful in excluding the diagnosis of appendicitis in those without disease.

Cryosurgical ablation of hepatic tumors

BACKGROUND Cryosurgical ablation of hepatic tumors relies on nonspecific tissue necrosis due to freezing as well as microvascular thrombosis. Patients with selected primary and metastatic hepatic malignancies who are not candidates for surgical resection are afforded potentially curative benefit using this technique. METHODS Forty patients underwent cryosurgery for hepatic malignancy related to colorectal metastasis (n = 27), hepatocellular carcinoma (n = 8), metastatic breast (n = 2), metastatic neuroendocrine (n = 2), and metastatic ovarian carcinoma (n = 1). Intraoperative ultrasound (IOUS) was used in all patients to help locate the tumor and guide the cryosurgical trocar to the lesions. RESULTS Indications for cryosurgical ablation included bilobar and centrally located disease, poor medical risk, insufficient hepatic reserve, and involved margin after wedge resection. Major complications included hepatic parenchyma cracking requiring transfusion in 5 patients, 1 postoperative biliary stenosis, and 1 inferior vena cava injury. There were 3 postoperative deaths from non-hepatic-related events. Based on Kaplan-Meier analysis the estimated overall survival for patients with hepatocellular carcinoma (60% at 18 months) was compared with patients with colorectal metastases (30% at 18 months). Nine patients (23%) are currently free of disease with an average follow-up of 17.7 months. The pattern of failure was identified at the site of cryosurgical ablation in 2 of 88 lesions. CONCLUSIONS Cryosurgical ablation of selected hepatic malignancies is a safe and viable treatment for patients not amenable to surgical resection.