Leonard R. Henry

Clinical Implications of Fibroblast Activation Protein in Patients with Colon Cancer

Purpose: Human fibroblast activation protein (FAP)/seprase is a 97-kDa surface glycoprotein expressed on tumor associated fibroblasts in the majority of epithelial cancers including colon adenocarcinomas. FAP overexpression in human tumor cells has been shown to promote tumor growth in animal models, and clinical trials targeting FAP enzymatic activity have been initiated. The primary objective of this study was to evaluate the clinical significance of stromal FAP in human colon cancers by immunohistochemisty. Experimental Design: Sections of paraffin-embedded resected primary human colon cancer specimens from 1996 through 2001 within the Fox Chase Cancer Center tumor bank were stained with D8 antibody directed against FAP/seprase. Xenotransplanted human colorectal tumors in mice were examined similarly for stromal FAP in tumors of different sizes. Overall percentage of stromal FAP staining of the primary tumor was assessed semiquantitatively (0, 1+, 2+, 3+) and staining intensity was also graded (none, weak, intermediate, strong). Survival time and time to recurrence data were analyzed using Kaplan-Meier plots, log-rank tests, and Cox proportional hazards models. Results: One hundred thirty-eight patients with resected specimens were available for study (mean follow-up, 1,050 days) with 6 (4%) stage I, 52 (38%) stage II, 43 (31%) stage III, and 37 (27%) stage IV patients. FAP was detected in >93% of specimens. Semiquantitative staining was scored as 1+ in 28 (20%), 2+ in 52 (38%), and 3+ in 49 (35%). FAP staining intensity was graded as weak in 45 (33%), intermediate in 48 (35%), and dark in 36 (26%). Stromal FAP was found to correlate inversely with tumor stage (semiquantitative, P = 0.01; intensity, P = 0.009) and with tumor size of the tumor xenograft model (correlation coefficient, −0.61; P = 0.047), suggesting that stromal FAP may have a greater role in the early development of tumors. Furthermore, greater stromal FAP for patients with known metastatic disease was associated with a decreased survival. Conclusion: Our data indicate that patients whose colon tumors have high levels of stromal FAP are more likely to have aggressive disease progression and potential development of metastases or recurrence. This study affirms the rationale for ongoing clinical investigations using FAP as a therapeutic target to disrupt FAP-driven tumor progression in patients with metastatic disease. It also suggests that the effects of FAP inhibition should be investigated in earlier-stage tumors, given its high levels and potential effect earlier in the course of the disease.

Development of a clinical decision model for thyroid nodules

BackgroundThyroid nodules represent a common problem brought to medical attention. Four to seven percent of the United States adult population (10–18 million people) has a palpable thyroid nodule, however the majority (>95%) of thyroid nodules are benign. While, fine needle aspiration remains the most cost effective and accurate diagnostic tool for thyroid nodules in current practice, over 20% of patients undergoing FNA of a thyroid nodule have indeterminate cytology (follicular neoplasm) with associated malignancy risk prevalence of 20–30%. These patients require thyroid lobectomy/isthmusectomy purely for the purpose of attaining a definitive diagnosis. Given that the majority (70–80%) of these patients have benign surgical pathology, thyroidectomy in these patients is conducted principally with diagnostic intent. Clinical models predictive of malignancy risk are needed to support treatment decisions in patients with thyroid nodules in order to reduce morbidity associated with unnecessary diagnostic surgery.MethodsData were analyzed from a completed prospective cohort trial conducted over a 4-year period involving 216 patients with thyroid nodules undergoing ultrasound (US), electrical impedance scanning (EIS) and fine needle aspiration cytology (FNA) prior to thyroidectomy. A Bayesian model was designed to predict malignancy in thyroid nodules based on multivariate dependence relationships between independent covariates. Ten-fold cross-validation was performed to estimate classifier error wherein the data set was randomized into ten separate and unique train and test sets consisting of a training set (90% of records) and a test set (10% of records). A receiver-operating-characteristics (ROC) curve of these predictions and area under the curve (AUC) were calculated to determine model robustness for predicting malignancy in thyroid nodules.ResultsThyroid nodule size, FNA cytology, US and EIS characteristics were highly predictive of malignancy. Cross validation of the model created with Bayesian Network Analysis effectively predicted malignancy [AUC = 0.88 (95%CI: 0.82–0.94)] in thyroid nodules. The positive and negative predictive values of the model are 83% (95%CI: 76%–91%) and 79% (95%CI: 72%–86%), respectively.ConclusionAn integrated predictive decision model using Bayesian inference incorporating readily obtainable thyroid nodule measures is clinically relevant, as it effectively predicts malignancy in thyroid nodules. This model warrants further validation testing in prospective clinical trials.

Current Approaches and Challenges in Monitoring Treatment Responses in Breast Cancer

Monitoring response to treatment is a key element in the management of breast cancer that involves several different viewpoints from surgery, radiology, and medical oncology. In the adjuvant setting, appropriate surgical and pathological evaluation guides adjuvant treatment and follow up care focuses on detecting recurrent disease with the intention of improving long term survival. In the neoadjuvant setting, assessing response to chemotherapy prior to surgery to include evaluation for pathologic response can provide prognostic information to help guide follow up care. In the metastatic setting, for those undergoing treatment, it is crucial to determine responders versus non-responders in order to help guide treatment decisions. In this review, we present the current guidelines for monitoring treatment response in the adjuvant, neoadjuvant, and metastatic setting. In addition, we also discuss challenges that are faced in each setting.

The functional impact on voice of sternothyroid muscle division during thyroidectomy

BackgroundPost-thyroidectomy voice dysfunction may occur in the absence of laryngeal nerve injury. Strap muscle division has been hypothesized as one potential contributor to dysphonia.MethodsVocal-function data, prospectively recorded before and after thyroidectomy from two high-volume referral institutions, were utilized. Patient-reported symptoms, laryngoscopic, acoustic, and aerodynamic parameters were recorded at 2 weeks and 3 months postoperatively. Patients with and without sternothyroid muscle division during surgery were compared for voice changes. Patients with laryngeal nerve injury, sternohyoid muscle division, arytenoid subluxation or no early postoperative follow-up evaluation were excluded. Differences between study groups and outcomes were compared using t-tests and rank-sum tests as appropriate.ResultsOf 84 patients included, 45 had sternothyroid division. Distribution of age, gender, extent of thyroidectomy, specimen size, and laryngeal nerve identification rates did not differ significantly between groups. There was a significant predilection for or against sternothyroid muscle division according to medical center. No significant difference in reported voice symptoms was observed between groups 2 weeks or 3 months after thyroidectomy. Likewise, acoustic and aerodynamic parameters did not differ significantly between groups at these postoperative study time points.ConclusionSternothyroid muscle division is occasionally employed during thyroidectomy to gain superior pedicle exposure. Division of this muscle does not appear to be associated with adverse functional voice outcome, and should be utilized at surgeon discretion during thyroidectomy.

Induction Cisplatin and Paclitaxel Followed by Combination Chemoradiotherapy with 5-Fluorouracil, Cisplatin, and Paclitaxel Before Resection in Localized Esophageal Cancer: A Phase II Report

BackgroundMultimodality therapy for esophageal cancer holds promise for improving outcome in this lethal disease. On the basis of encouraging data from a phase I trial, we conducted a phase II study of preoperative chemotherapy, followed by concurrent chemoradiotherapy and surgery.MethodsPatients with clinically staged resectable esophageal cancer were treated with induction cisplatin and paclitaxel, followed by 45 Gy of external beam radiation with concurrent infusional 5-fluorouracil and weekly cisplatin and paclitaxel. Four to eight weeks after multimodality induction, esophagectomy was performed in suitable patients. Study end points were survival, pathologic complete response, and toxicity.ResultsTwenty-one patients were enrolled with a median age of 58 years, and all patients were clinically staged II or III. Sixteen (76.2%) patients completed the trial, of whom four (25%) had a pathologic complete response. One patient died from postoperative complications. Grade 3 or 4 toxicity was observed in 76% of patients, and dose-limiting toxicity was seen in 6 of the first 14 patients, thus necessitating a planned dose reduction of paclitaxel. At a median follow-up of 30 months, 13 patients remain alive. The 2-year disease-specific survival for the study population was 78%.ConclusionsThis regimen of multimodality therapy before resection resulted in an encouraging 2-year survival rate but a disappointing rate of pathologic complete response and was toxic, necessitating a predetermined paclitaxel dose reduction. The incorporation of taxanes into induction strategies for esophageal cancer seems promising, but the optimal schedule remains undefined.

Standard versus pH-adjusted and lidocaine supplemented radiocolloid for patients undergoing sentinel-lymph-node mapping and biopsy for early breast cancer (PASSION-P trial): a double-blind, randomised controlled trial

BACKGROUND Sentinel-lymph-node (SLN) mapping and biopsy maintains staging accuracy in early breast cancer and identifies patients for selective lymphadenectomy. SLN mapping requires injection of technetium-99m-sulfur colloid-an effective but sometimes painful method, for which better pain-management strategies are needed. In this randomised, double-blind trial, we compared degree of pain between standard radiocolloid injection and pH-adjusted and lidocaine-supplemented formulations for patients undergoing SLN mapping for breast cancer. METHODS Between Jan 13, 2006, and April 30, 2009, 140 patients with early breast cancer were randomly assigned in a 1:1:1:1 fashion to receive the standard topical 4% lidocaine cream and injection of [(99m)Tc]Tc-sulfur colloid (n=35), or to one of three other study groups: topical placebo cream and injection of Tc-sulfur colloid containing either sodium bicarbonate (n=35), 1% lidocaine (n=35), or sodium bicarbonate and 1% lidocaine (n=35). The randomisation sequence was computer generated, and all patients and investigators were masked to treatment allocation. The primary endpoint was patient-reported breast pain immediately after radioisotope injection, using the Wong-Baker FACES pain rating scale and McGill pain questionnaire, analysed in the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT00940199. FINDINGS 19 of the 140 patients enrolled were excluded from analysis: nine declined study participation or sought care elsewhere, nine did not undergo SLN mapping because of disease extent or a technical problem, and one had unreliable data. There were no adverse events. Mean pain scores on the Wong-Baker scale (0-10) were: 6.0 (SD 2.6) for those who received standard of practice, 4.7 (3.0) for those who received radiocolloid plus bicarbonate, 1.6 (1.4) for those who received radiocolloid plus 1% lidocaine, and 1.6 (1.3) for those who received radiocolloid plus bicarbonate and 1% lidocaine (p<0.0001). Mean pain rating, according to the McGill questionnaire (0-78), was 17.5 (SD 11.8) for the standard-of-care group, 15.4 (14.4) for the sodium bicarbonate group, 4.6 (4.5) for the 1% lidocaine group, and 3.4 (5.1) for the sodium bicarbonate plus 1% lidocaine group (p<0.0001). SLN identification rates for each group were: 96% for the standard of care, 97% for sodium bicarbonate, 90% for 1% lidocaine, and 90% for sodium bicarbonate plus 1% lidocaine group (p=0.56). INTERPRETATION For centres that use radiocolloid injections for SLN mapping in patients with early breast cancer, the addition of 1% lidocaine to the radioisotope solution can improve patient comfort, without compromising SLN identification. FUNDING US Military Cancer Institute, the Clinical Breast Care Project, and the Army Regional Anesthesia and Pain Management Initiative.

Resection of Isolated Pelvic Recurrences After Colorectal Surgery: Long-Term Results and Predictors of Improved Clinical Outcome

BackgroundRecurrence in the pelvis after resection of a rectal or rectosigmoid cancer presents a dilemma. Resection offers the only reasonable probability for cure, but at the cost of marked perioperative morbidity and potential mortality. Clinical decision making remains difficult.MethodsPatients who underwent resection with curative intent for isolated pelvic recurrences after curative colorectal surgery from 1988 through 2003 were reviewed retrospectively. Clinical and pathological factors, salvage operations, and complications were recorded. The primary measured outcome was overall survival. Univariate and multivariate analyses were conducted to identify prognostic factors of improved outcome.ResultsNinety patients underwent an attempt at curative resection of a pelvic recurrence; median follow-up was 31 months. Complications occurred in 53% of patients. Operative mortality occurred in 4 (4.4%) of 90 patients. Median overall survival was 38 months, and estimated 5-year survival was 40%. A total of 51 of 86 patients had known recurrences (15 local, 16 distant, 20 both). Multivariate analysis revealed that preoperative carcinoembryonic antigen level and final margin status were statistically significant predictors of outcome.ConclusionsThe resection of pelvic recurrences after colorectal surgery for cancer can be performed with low mortality and good long-term outcome; however, morbidity from such procedures is high. Low preoperative carcinoembryonic antigen and negative margin of resection predict improved survival.

Current Approaches and Challenges in Early Detection of Breast Cancer Recurrence

Early detection of breast cancer recurrence is a key element of follow-up care and surveillance after completion of primary treatment. The goal is to improve survival by detecting and treating recurrent disease while potentially still curable assuming a more effective salvage surgery and treatment. In this review, we present the current guidelines for early detection of recurrent breast cancer in the adjuvant setting. Emphasis is placed on the multidisciplinary approach from surgery, medical oncology, and radiology with a discussion of the challenges faced within each setting.

Hydronephrosis Does Not Preclude Curative Resection of Pelvic Recurrences After Colorectal Surgery

BackgroundIn one third of patients who die of rectal cancer, a pelvic recurrence after resection represents isolated disease for which re-resection may provide cure. These extensive resections can carry high morbidity. Proper patient selection is desirable but difficult. Hydronephrosis has been documented previously to portend a poor prognosis, and some consider it a contraindication to attempted resection. It was our goal to review our experience and either confirm or refute these conclusions.MethodsWe performed a retrospective analysis of 90 patients resected with curative intent for pelvic recurrence at our center from 1988 through 2003. Seventy-one records documented the preoperative presence or absence of hydronephrosis. Clinical and pathologic data were recorded. The groups with and without hydronephrosis were compared.ResultsThere were 15 patients with hydronephrosis in this study and 56 without. Although patients with hydronephrosis had shorter overall survival, disease-free survival, and rate of local control, none of these differences was statistically significant. Patients in the hydronephrosis group were younger and had higher-stage primary tumors and larger recurrent tumors. Subsequently, they underwent more extensive resections and were more likely to be treated with adjuvant therapies. There was no difference in the rate of margin-negative resections between the groups.ConclusionsHydronephrosis correlates with younger patients with larger recurrent tumors undergoing more extensive operations and multimodality therapy but does not preclude curative (R0) resection or independently affect overall survival, disease-free survival, or local control. We believe that it should not be considered a contraindication to attempting curative resection.

Future Directions for the Early Detection of Recurrent Breast Cancer

The main goal of follow-up care after breast cancer treatment is the early detection of disease recurrence. In this review, we emphasize the multidisciplinary approach to this continuity of care from surgery, medical oncology, and radiology. Challenges within each setting are briefly addressed as a means of discussion for the future directions of an effective and efficient surveillance plan of post-treatment breast cancer care.