Carlos Garberoglio

Association of reactive oxygen species levels and radioresistance in cancer stem cells.

The metabolism of oxygen, although central to life, produces reactive oxygen species (ROS) that have been implicated in processes as diverse as cancer, cardiovascular disease and ageing. It has recently been shown that central nervous system stem cells and haematopoietic stem cells and early progenitors contain lower levels of ROS than their more mature progeny, and that these differences are critical for maintaining stem cell function. We proposed that epithelial tissue stem cells and their cancer stem cell (CSC) counterparts may also share this property. Here we show that normal mammary epithelial stem cells contain lower concentrations of ROS than their more mature progeny cells. Notably, subsets of CSCs in some human and murine breast tumours contain lower ROS levels than corresponding non-tumorigenic cells (NTCs). Consistent with ROS being critical mediators of ionizing-radiation-induced cell killing, CSCs in these tumours develop less DNA damage and are preferentially spared after irradiation compared to NTCs. Lower ROS levels in CSCs are associated with increased expression of free radical scavenging systems. Pharmacological depletion of ROS scavengers in CSCs markedly decreases their clonogenicity and results in radiosensitization. These results indicate that, similar to normal tissue stem cells, subsets of CSCs in some tumours contain lower ROS levels and enhanced ROS defences compared to their non-tumorigenic progeny, which may contribute to tumour radioresistance.

Artificial dermis as an alternative for coverage of complex scalp defects following excision of malignant tumors

Background: Artificial dermis has been used successfully for coverage of full-thickness wounds with a well-vascularized surgical bed. However, the use of artificial dermis in the reconstruction of partial- and full-thickness scalp defects has not been well documented. Methods: Seven patients (six men and one woman; mean age, 70 ± 14 years) with partial-thickness (three patients) and full-thickness (four patients) soft-tissue defects of the scalp (mean defect area, 97 ± 58 cm2) following resection of recurrent malignant tumors and/or previous failed reconstructions underwent staged scalp reconstruction with a bilaminate skin substitute (Integra). After adequate débridement of scalp wounds, including burring the outer table of the calvaria down to bleeding bone for full-thickness defects, Integra was scored and applied unexpanded. A split-thickness skin graft (0.011 ± 0.0 inch in thickness) was placed on the operative site at postoperative day 36 ± 15 after removal of the silicone layer of the artificial dermis. Two patients required repeated applications of artificial dermis to compensate for contour deficits before skin grafting. Results: Clinically, all reconstructed areas showed well-vascularized neodermis before skin grafting. There was a 100 percent take of the skin grafts, with no infections or other complications noted. All reconstructive procedures were performed in less than 3 hours of combined operative time, with the last stage performed on an outpatient basis. Conclusions: Artificial dermis can be used successfully for reconstruction of complex scalp defects following oncologic resection, offering minimal donor-site morbidity, expedient operative time, and when needed, temporary quality closure until final pathologic results are known. Integra skin may offer another option for definitive management of extensive full-thickness scalp defects.

Outcomes in the Management of Appendicitis and Cholecystitis in the Setting of a New Acute Care Surgery Service Model: Impact on Timing and Cost

BACKGROUND The acute care surgery model is a novel notion in the provision of emergency general surgery. To date, several studies have analyzed the effects on patient health outcomes and timeliness of care for nontrauma patients within the scope of acute general surgery and emergencies, but none have assessed the cost benefits of this model. STUDY DESIGN A retrospective analysis of patients undergoing appendectomy or cholecystectomy in the setting of acute abdomen was performed to compare data from 2 cohorts, the traditional model from July 2009 to June 2010 and the acute care surgery model from July 2010 to June 2011. Categorical variables and comparison means were examined using chi-square and independent 2-tailed sample t-tests. RESULTS One hundred and seventy-five patients underwent appendectomy and 113 underwent cholecystectomy. The traditional model team staffed 82 appendectomies and 51 cholecystectomies, and the acute care surgery team staffed 93 and 62, respectively. In the appendectomy group, there was a statistically significant mean reduction of time to surgical evaluation (2.19 hours; p < 0.001) and time to the operating room (5.38 hours, p = 0.006), there were 7 fewer patients with complications (p = 0.06) and a reduced length of stay (1 day, p = 0.002) for the acute care surgery cohort. Similar statistically significant differences were observed in the cholecystectomy group in the acute care surgery cohort: surgical evaluation difference = 5.84 hours (p = 0.03), time to operating room difference = 25.37 hours (p = 0.002), 8 fewer patients with complications (p = 0.01), and length of stay difference was 2 days (p = 0.03) compared with the traditional model cohort. CONCLUSIONS The newly implemented acute care surgery model in our institution accomplished earlier treatment and shorter length of stay for the 2 most common causes of acute abdomen in our setting. Overall, the new model translated to better outcomes for patients and savings per case for the hospital.

Maltose absorption as an indicator of small-intestinal allograft rejection☆

Maltose and lactose absorption, which require an intact brush border for breakdown and absorption as glucose, was evaluated as a function test to monitor the integrity of the small-bowel graft. Using the rat model of accessory small-bowel transplantation, absorption tests (in the form of an oral glucose tolerance test) were performed on iso- and allografts with either portal (PP-A) or caval venous drainage (PC-A). In isografts the absorption of maltose was found to be reproducible and not influenced by the type of venous drainage. This was not the case with the use of lactose which thus was not studied further. Allografts with PC-A demonstrated a reduction in their capacity for maltose absorption on the fifth postoperative day, as the glucose peak at 30 min (T30) was significantly blunted in comparison to that for isografts with PC-A (167 mg% +/- 12 vs 204 mg% +/- 8). Functional impairment preceded histologic changes which did not arise before the sixth-to-seventh postoperative day in rats with PC-A. Allografts with PP-A absorbed maltose on the fifth postoperative day nearly as effectively as did isografts (T30 min: 185 mg% +/- 14 vs 213 mg% +/- 8). By the ninth postoperative day, the serum glucose curve after maltose administration was flattened for grafts with PC-A (T30 min: 137 mg% +/- 11) which were rejected acutely (hosts death) after 11.8 days +/- 0.45. A similar impairment of maltose absorption was not seen in the PP-A group (chronic graft rejection after 22.8 days +/- 1.8) until the 15th postoperative day.(ABSTRACT TRUNCATED AT 250 WORDS)

A technique of partial breast irradiation utilizing proton beam radiotherapy : Comparison with conformal X-ray therapy

Purpose:To develop a breast immobilization system and clinical technique to deliver partial breast irradiation with a proton beam and compare dose distributions using proton therapy and conformal x-rays. Methods:A clinical technique to provide reproducible breast immobilization was developed. Breast immobilization begins by fitting each patient with a treatment brassiere. Patients are placed prone in a cylindrical polyvinyl chloride shell with the upper and lower body being supported and immobilized with Vac-Lok foam bead cushions. The upper chest and breast areas are immobilized with two-part expandable foam. After a treatment planning computed tomography scan, the lumpectomy cavity is outlined, and a clinical target volume is generated by adding 1cm in all dimensions. A three-dimensional treatment plan is developed with treatment typically given with 2 to 4 separate proton beams. The dose administered is 40 cobalt Gray equivalents (CGE) delivered in 10 daily fractions of 4 CGE with multiple fields treated each day. Proton and conformal x-ray plans were compared using dose-volume histogram analysis to determine volumes of normal breast tissue and skin treated with each technique. Results:An institutional review board–approved clinical trial was developed using this technique, and 20 patients have completed treatment. All subjects were able to undergo the immobilization procedure and daily treatments without significant discomfort, and no treatment interruptions were encountered. There was no evidence of respiratory motion identified on treatment planning CT images or on daily set-up radiographs. Acute toxicity has been limited to occasional radiation dermatitis (Radiation Therapy Oncology Group grade 1–2). Proton plans were compared with 2 methods of photon partial breast irradiation, including reduced tangential fields and five-field conformal techniques. Ten treatment plans with dose-volume histogram analysis revealed that the use of proton beams provided a significant reduction in doses to the ipsilateral breast and skin while eliminating doses to the heart and lung tissues. Conclusions:A simple immobilization procedure provides accurate and reproducible breast positioning while simultaneously eliminating respiratory motion. The procedure has been well tolerated by the first 20 patients. Protons can provide substantial normal tissue protection compared with the use of conformal x-rays when used for partial breast treatment. We plan to continue enrollment and analyze long-term toxicity, local control, and survival.

Factors predictive of the status of sentinel lymph nodes in melanoma patients from a large multicenter database.

BackgroundNumerous predictive factors for cutaneous melanoma metastases to sentinel lymph nodes have been identified; however, few have been found to be reproducibly significant. This study investigated the significance of factors for predicting regional nodal disease in cutaneous melanoma using a large multicenter database.MethodsSeventeen institutions submitted retrospective and prospective data on 3463 patients undergoing sentinel lymph node (SLN) biopsy for primary melanoma. Multiple demographic and tumor factors were analyzed for correlation with a positive SLN. Univariate and multivariate statistical analyses were performed.ResultsOf 3445 analyzable patients, 561 (16.3%) had a positive SLN biopsy. In multivariate analysis of 1526 patients with complete records for 10 variables, increasing Breslow thickness, lymphovascular invasion, ulceration, younger age, the absence of regression, and tumor location on the trunk were statistically significant predictors of a positive SLN.ConclusionsThese results confirm the predictive significance of the well-established variables of Breslow thickness, ulceration, age, and location, as well as consistently reported but less well-established variables such as lymphovascular invasion. In addition, the presence of regression was associated with a lower likelihood of a positive SLN. Consideration of multiple tumor parameters should influence the decision for SLN biopsy and the estimation of nodal metastatic disease risk.

Papillary Carcinoma of the Breast: An Overview

Papillary carcinoma of the breast represents ~0.5% of all newly diagnosed cases of breast cancer. The prevalence of both invasive and in situ papillary carcinoma seems to be greater in older postmenopausal women and, in relative terms, in males. Histologic features of the tumor include cellular proliferations surrounding fibrovascular cores, with or without invasion. In this review, characteristics of both in situ and invasive disease are outlined. Immunohistochemical analyses of papillary carcinoma suggest the utility of markers such as smooth muscle myosin heavy chain, calponin, p63, and high molecular weight keratins, which can characterize the myoepithelial cell layer. With respect to radiographic evaluation of papillary carcinoma, ultrasonography is the most extensively studied imaging modality, though magnetic resonance mammography has potential utility. Available data suggest improved outcome for papillary carcinoma as compared to invasive ductal carcinoma. Treatment-related information for patients with papillary carcinoma is limited, and patterns noted in available series suggest a variable approach to this disease. The scarcity of information underscores the need for further treatment- and outcome-related studies in papillary carcinoma of the breast.

Partial Breast Radiation Therapy With Proton Beam: 5-Year Results With Cosmetic Outcomes

PURPOSE We updated our previous report of a phase 2 trial using proton beam radiation therapy to deliver partial breast irradiation (PBI) in patients with early stage breast cancer. METHODS AND MATERIALS Eligible subjects had invasive nonlobular carcinoma with a maximal dimension of 3 cm. Patients underwent partial mastectomy with negative margins; axillary lymph nodes were negative on sampling. Subjects received postoperative proton beam radiation therapy to the surgical bed. The dose delivered was 40 Gy in 10 fractions, once daily over 2 weeks. Multiple fields were treated daily, and skin-sparing techniques were used. Following treatment, patients were evaluated with clinical assessments and annual mammograms to monitor toxicity, tumor recurrence, and cosmesis. RESULTS One hundred subjects were enrolled and treated. All patients completed the assigned treatment and were available for post-treatment analysis. The median follow-up was 60 months. Patients had a mean age of 63 years; 90% had ductal histology; the average tumor size was 1.3 cm. Actuarial data at 5 years included ipsilateral breast tumor recurrence-free survival of 97% (95% confidence interval: 100%-93%); disease-free survival of 94%; and overall survival of 95%. There were no cases of grade 3 or higher acute skin reactions, and late skin reactions included 7 cases of grade 1 telangiectasia. Patient- and physician-reported cosmesis was good to excellent in 90% of responses, was not changed from baseline measurements, and was well maintained throughout the entire 5-year follow-up period. CONCLUSIONS Proton beam radiation therapy for PBI produced excellent ipsilateral breast recurrence-free survival with minimal toxicity. The treatment proved to be adaptable to all breast sizes and lumpectomy cavity configurations. Cosmetic results appear to be excellent and unchanged from baseline out to 5 years following treatment. Cosmetic results may be improved over those reported with photon-based techniques due to reduced breast tissue exposure with proton beam, skin-sparing techniques, and the dose fractionation schedule used in this trial.

Partial breast irradiation delivered with proton beam: results of a phase II trial.

BACKGROUND AND PURPOSE A phase II trial sought to determine the safety and efficacy of proton beam irradiation to deliver partial breast radiotherapy after lumpectomy for early-stage breast cancer. PATIENTS AND METHODS Eligible patients included women with invasive nonlobular carcinoma ≤ 3 cm. Surgical therapy included lumpectomy with negative margins and negative axillary lymph nodes on sampling. Postoperative proton radiotherapy to the surgical bed with an additional 1-cm margin was delivered by 40 Gy in 10 fractions over a 2-week course. Patients received systemic therapy as recommended after proton treatment. Patients had clinical evaluations every 6 months and annual mammograms. RESULTS Fifty patients were enrolled; median follow-up was 48 months. All patients completed the prescribed treatment. Acute toxicities were limited to mild radiation dermatitis. Late skin toxicities included 3 grade 1 telangiectasias. There were no posttreatment infections or ulcerations and no cases of fat necrosis, rib fractures, radiation pneumonitis, or cardiac events. Actuarial 5-year overall survival and disease-free survival rates were 96% and 92%, respectively. No local failures occurred. Ipsilateral breast cancer developed in 1 patient 5.5 years after treatment. Dose-volume histogram analysis showed near-complete elimination of dose to the contralateral breast, lung, and heart. CONCLUSION Proton partial breast radiotherapy appeared to be a feasible method of treatment and provided excellent disease control within the ipsilateral breast. Treatment-related toxicity was minimal and no technical limitations prevented treatment delivery. The incidence of posttreatment complications may be less than that reported when using more invasive techniques; comparative trials should be considered.

Pathological complete response after neoadjuvant chemotherapy with trastuzumab-containing regimen in gastric cancer: a case report.

We report a 49-year-old Chinese male with locally advanced gastric adenocarcinoma achieving pathological complete response after neoadjuvant chemotherapy with trastuzumab-containing regimen. He underwent esophagogastroduodenoscopy in September 2009, which revealed a 2-cm gastric ulcer on the lesser curvature proximal to angularis. Biopsy of gastric ulcer showed moderately differentiated adenocarcinoma with overexpression of human epidermal growth factor receptor 2 (HER2) by immunohistochemistry and fluorescence in situ hybridization. Further workups with endoscopic ultrasound, computed tomography and positron emission tomography staged his cancer as T3N1M0. He received 3 cycles of neoadjuvant chemotherapy consisting of trastuzumab, oxaliplatin, docetaxel and capecitabine without severe toxicities except grade 2 diarrhea near the completion of cycle 3 requiring discontinuation of capecitabine. Afterwards, he received total gastrectomy with extended D2 lymph node dissections showing pathological complete response. He went on to receive 3 more cycles of chemotherapy postoperatively. The role of trastuzumab as a part of perioperative therapy in gastric cancer overexpressing HER2 is worth further investigation.