Roger A. Graham

Local excision of rectal carcinoma

Sixteen published series were reviewed in which local excision was used as definitive treatment for patients with invasive rectal carcinoma located within 6 cm of the anal verge. Ninety-four percent of tumors were T1 or T2 adenocarcinomas with no identified regional metastases. Five-year cancer-specific survival was 89%. Local recurrence was 19%, although more than half of these patients were cured with additional surgery. These results were comparable with those for historical controls treated with abdominoperineal resection (APR). Four pathologic features of the surgical specimen were analyzed to assess their correlation with patient outcome. Positive surgical margins, poorly differentiated histology, and increasing depth of bowel wall invasion were associated with increased local recurrence and decreased survival. Tumor size greater than 3 cm was not a significant factor. When criteria for appropriate patient selection are followed, local excision may provide survival and recurrence rates comparable with those achieved with APR with less morbidity and operative mortality.

Mapping the cellular and molecular heterogeneity of normal and malignant breast tissues and cultured cell lines

IntroductionNormal and neoplastic breast tissues are comprised of heterogeneous populations of epithelial cells exhibiting various degrees of maturation and differentiation. While cultured cell lines have been derived from both normal and malignant tissues, it remains unclear to what extent they retain similar levels of differentiation and heterogeneity as that found within breast tissues.MethodsWe used 12 reduction mammoplasty tissues, 15 primary breast cancer tissues, and 20 human breast epithelial cell lines (16 cancer lines, 4 normal lines) to perform flow cytometry for CD44, CD24, epithelial cell adhesion molecule (EpCAM), and CD49f expression, as well as immunohistochemistry, and in vivo tumor xenograft formation studies to extensively analyze the molecular and cellular characteristics of breast epithelial cell lineages.ResultsHuman breast tissues contain four distinguishable epithelial differentiation states (two luminal phenotypes and two basal phenotypes) that differ on the basis of CD24, EpCAM and CD49f expression. Primary human breast cancer tissues also contain these four cellular states, but in altered proportions compared to normal tissues. In contrast, cultured cancer cell lines are enriched for rare basal and mesenchymal epithelial phenotypes, which are normally present in small numbers within human tissues. Similarly, cultured normal human mammary epithelial cell lines are enriched for rare basal and mesenchymal phenotypes that represent a minor fraction of cells within reduction mammoplasty tissues. Furthermore, although normal human mammary epithelial cell lines exhibit features of bi-potent progenitor cells they are unable to differentiate into mature luminal breast epithelial cells under standard culture conditions.ConclusionsAs a group breast cancer cell lines represent the heterogeneity of human breast tumors, but individually they exhibit increased lineage-restricted profiles that fall short of truly representing the intratumoral heterogeneity of individual breast tumors. Additionally, normal human mammary epithelial cell lines fail to retain much of the cellular diversity found in human breast tissues and are enriched for differentiation states that are a minority in breast tissues, although they do exhibit features of bi-potent basal progenitor cells. These findings suggest that collections of cell lines representing multiple cell types can be used to model the cellular heterogeneity of tissues.

Tumor-Derived Cyr61(CCN1) Promotes Stromal Matrix Metalloproteinase-1 Production and Protease-Activated Receptor 1–Dependent Migration of Breast Cancer Cells

Matrix metalloproteinases (MMPs) play a central role in remodeling the tumor-stromal microenvironment. We recently determined that stromal-derived MMP-1 also acts as a signaling molecule by cleaving protease-activated receptor 1 (PAR1) to cause breast cancer cell migration and invasion. Here, we show that ectopic PAR1 expression induces expression of the angiogenic factor Cyr61(CCN1) in breast cancer cells. The tumor-derived Cyr61 acts as an invasogenic signaling molecule that induces MMP-1 expression in adjacent stromal fibroblasts. Gene silencing of Cyr61 in breast cancer cells suppresses MMP-1 induction in stromal fibroblasts resulting in a major loss in migration of the cancer cells toward the fibroblasts. Cyr61-dependent loss of migration was complemented by exogenous MMP-1 and required the presence of the functional PAR1 receptor on the breast cancer cells. These results suggest that interrupting tumor-stromal cell communication by targeting Cyr61 may provide an alternative therapeutic approach for the treatment of invasive breast cancer.

Rapidly advancing necrotizing fasciitis caused by photobacterium (vibrio) damsela : A hyperaggressive variant

ObjectiveTo describe the first case of Vibrio damsela necrotizing fasciitis in New England, emphasizing the importance of very early operative intervention to achieve source control in this extremely aggressive infection. DesignCase report. SettingSurgical intensive care unit at Tufts-New England Medical Center in Boston, MA. PatientA 69-yr-old retired fisherman with rapidly progressive necrotizing fasciitis from Photobacterium (Vibrio) damsela infection and ensuing multiple-system organ failure. InterventionsSurgical debridement, ventilator support, vasopressors, continuous veno-venous hemofiltration, and blood product transfusions. Measurements and Main ResultsDeath. ConclusionsA high index of suspicion is necessary for the diagnosis of this specific pathogen and concordant infection. The willingness to surgically debride and amputate without hesitation at a very early point may be the only intervention capable of saving the lives of patients affected by Photobacterium (Vibrio) damsela.

Local excision of rectal carcinoma: a safe alternative for more advanced tumors?

Local excision of rectal carcinoma has primarily been limited to patients with small (≤3 cm), early rectal carcinoma. We wanted to determine whether local excision (transanal or transacral), when combined with selective chemoradiation therapy, would be adequate treatment for patients with larger (>3 cm) and more advanced T3 and N1 tumors.

Broadband Optical Mammography: Chromophore Concentration and Hemoglobin Saturation Contrast in Breast Cancer

This study reports the optical characterization and quantitative oximetry of human breast cancer using spectrally-resolved images collected with a broadband, continuous-wave optical mammography instrument. On twenty-six cancer patients, we collected two-dimensional optical mammograms and created maps of the concentrations of hemoglobin, water, and lipids, as well as the oxygen saturation of hemoglobin. For each cancerous breast, we analyzed the difference between the tumor region (as identified by x-ray and optical mammography) and the remainder of breast tissue. With respect to the surrounding tissue, we found that cancer regions have significantly higher concentrations of total hemoglobin (+2.4±0.4 μM) and water (+7±1% v/v), and significantly lower lipid concentration (8±2% v/v) and oxygen saturation of hemoglobin (5±1%). We also found a significant correlation between the tumor optical contrast and the grade of breast cancer as quantified by the Nottingham histologic score; this demonstrates how optical signatures may be representative of metabolic and morphological features, as well as the aggressive potential of the tumor.

Local excision of rectal carcinoma - Early results with combined chemoradiation therapy using 5-fluorouracil and leucovorin

PURPOSE: This study was undertaken to evaluate the treatment morbidity, functional outcome, and recurrence risk of patients undergoing local excision and combined chemoradiation therapy for rectal carcinoma. METHODS: Eighteen patients underwent local excision of their rectal carcinoma. Four patients underwent local excision alone (T1-2, N0-X, low risk), 10 patients underwent local excision with postoperative chemoradiation therapy using 5-fluorouracil and leucovorin (T1-2, N0-X, high risk), and 4 patients underwent local excision, chemoradiation therapy, and six months of additional 5-fluorouracil and leucovorin (T3 or N1). RESULTS: Of the four patients undergoing local excision alone, there was no treatment morbidity or alteration in functional outcome. Of the 14 patients receiving chemoradiation therapy, three reported early Grade 3–4 toxicity manifested by cystitis, proctitis, or perineal skin desquamation. At six months, two patients reported persistent rectal urgency and occasional fecal incontinence, and 11 patients reported increasing stool frequency (average, 3: range, 2–8). The six months of additional 5-fluorouracil and leucovorin were well tolerated and did not appear to further affect functional outcome. There were no local recurrences, although one patient developed distant mestastatic disease. CONCLUSION: This treatment regimen, while generally well tolerated, is associated with significant acute toxicity in certain patients. We have identified specific causative factors which can be modified to decrease acute morbidity, including the elimination of leucovorin during the combined chemoradiation therapy.

NEAR-INFRARED, BROAD-BAND SPECTRAL IMAGING OF THE HUMAN BREAST FOR QUANTITATIVE OXIMETRY: APPLICATIONS TO HEALTHY AND CANCEROUS BREASTS

We have examined ten human subjects with a previously developed instrument for near-infrared diffuse spectral imaging of the female breast. The instrument is based on a tandem, planar scan of two collinear optical fibers (one for illumination and one for collection) to image a gently compressed breast in a transmission geometry. The optical data collection features a spatial sampling of 25 points/cm2 over the whole breast, and a spectral sampling of 2 points/nm in the 650–900 nm wavelength range. Of the ten human subjects examined, eight are healthy subjects and two are cancer patients with unilateral invasive ductal carcinoma and ductal carcinoma in situ, respectively. For each subject, we generate second-derivative images that identify a network of highly absorbing structures in the breast that we assign to blood vessels. A previously developed paired-wavelength spectral method assigns oxygenation values to the absorbing structures displayed in the second-derivative images. The resulting oxygenation images feature average values over the whole breast that are significantly lower in cancerous breasts (69 ± 14%, n = 2) than in healthy breasts (85 ± 7%, n = 18) (p < 0.01). Furthermore, in the two patients with breast cancer, the average oxygenation values in the cancerous regions are also significantly lower than in the remainder of the breast (invasive ductal carcinoma: 49 ± 11% vs 61 ± 16%, p < 0.01; ductal carcinoma in situ: 58 ± 8% vs 77 ± 11%, p < 0.001).

Efficacy and safety of continuous low-irradiance photodynamic therapy in the treatment of chest wall progression of breast cancer.

BACKGROUND Photodynamic therapy (PDT) is a binary therapy using a drug and high-energy light source. PDT is approved for several premalignant and malignant conditions. Recent in-vitro and animal data suggest that enhanced tumor-specific cytotoxicity can be achieved with far less collateral damage to normal surrounding tissues if PDT is administered continuously at a lower dose rate for extended periods of time. Based on these promising preclinical data, we conducted a Phase I clinical trial of continuous low-irradiance photodynamic therapy (CLIPT) using 630 nm laser energy and intravenously administered porforin sodium as the photosensitizer. We determined the maximum tolerated dose (MTD) of CLIPT on skin and tumor response in subjects with cutaneous and subcutaneous metastatic nodules who had failed radiation and surgery. METHODS Patients with cutaneous and/or subcutaneous metastatic nodules that had failed radiation and surgery were offered enrollment into the trial. The initial study design planned for sequential cohorts of six subjects to be treated at increasing laser intensity, starting at 100 J/cm(2) administered continuously over 24 h (10(-2) dose rate compared with standard PDT). Dose-limiting toxicity was defined as partial or full-thickness necrosis of the surrounding tumor-free, previously irradiated skin. The MTD was defined as the highest laser energy at which ≤33% of subjects experienced the dose-limiting toxicity. Subjects received intravenous porfirmer sodium 0.8 mg/kg 48 h before commencing CLIPT. Response rates and quality of life measures were assessed. RESULTS Nine subjects were enrolled with chest wall progression of breast cancer following mastectomy. All had failed prior surgery and electron-beam radiation therapy. The initial two subjects were treated at 100 J/cm(2) and developed partial thickness skin necrosis. Dose reduction was therefore instituted, and the next cohort was treated at 50 J/cm(2). None of the subsequent seven subjects suffered partial or full thickness necrosis, thus establishing the MTD at 50 J/cm(2) over 24 h (0.5 mW irradiance). Six of the nine subjects (67%) had either a complete or partial clinical response. Of note, two subjects had significant regression of tumor nodules distant from the treatment field. Of the eight subjects whose terminal deoxynucleotidyl transferase dUTP nick end labeling assay results were available, 8 (100%) demonstrated histologic response to treatment as evidenced by either tumor apoptosis or regression. Quality of life measures were improved following treatment-particularly bleeding and pain from the tumor nodules. CONCLUSIONS The MTD of CLIPT was established at 50 J/cm(2) administered continuously over 24 h. These preliminary data suggest CLIPT may be an effective, low-morbidity therapeutic modality in the treatment of cutaneous and subcutaneous metastases of breast cancer following mastectomy. Further evaluation in a larger cohort is warranted to better assess efficacy and optimize the intervention.

Optical Mammography in Patients with Breast Cancer Undergoing Neoadjuvant Chemotherapy: Individual Clinical Response Index

RATIONALE AND OBJECTIVES We present an optical mammography study that aims to develop quantitative measures of pathologic response to neoadjuvant chemotherapy (NAC) in patients with breast cancer. Such quantitative measures are based on the concentrations of oxyhemoglobin ([HbO2]), deoxyhemoglobin ([Hb]), total hemoglobin ([HbT]), and hemoglobin saturation (SO2) in breast tissue at the tumor location and at sequential time points during chemotherapy. MATERIALS AND METHODS Continuous-wave, spectrally resolved optical mammography was performed in transmission and parallel-plate geometry on 10 patients before treatment initiation and at each NAC administration (mean number of optical mammography sessions: 12, range: 7-18). Data on two patients were discarded for technical reasons. The patients were categorized as responders (R, >50% decrease in tumor size), or nonresponders (NR, <50% decrease in tumor size) based on imaging and histopathology results. RESULTS At 50% completion of the NAC regimen (therapy midpoint), R (6/8) demonstrated significant decreases in SO2 (-27% ± 4%) and [HbT] (-35 ± 4 µM) at the tumor location with respect to baseline values. By contrast, NR (2/8) showed nonsignificant changes in SO2 and [HbT] at therapy midpoint. We introduce a cumulative response index as a quantitative measure of the individual patients response to therapy. At therapy midpoint, the SO2-based cumulative response index had a sensitivity of 100% and a specificity of 100% for the identification of R. CONCLUSIONS These results show that optical mammography is a promising tool to assess individual response to NAC at therapy midpoint to guide further decision making for neoadjuvant therapy.