Oncoplastic reconstruction of central lumpectomy defects using the medial pillar island flap.

PURPOSE: This report presents the medial pillar island flap technique of oncoplastic breast reconstruction of central defects that involve the nipple-areola complex. METHODS: The procedure was performed in patients who presented with inferior pole redundancy using a vertical mammaplasty pattern. The flap was designed utilizing the territory of the lower pole as an island flap pedicled by the internal mammary artery perforators surrounded by the soft tissue of the medial pillar. RESULTS: Eight patients underwent the procedure with a mean age of 57.6 years. Median breast cup size was D (range: from C to DDD). The mean body mass index was 37.3 kg/m2 (range: from 32.1 to 41.5). The size of the defect ranged from 64 to 150 cm3 (mean, 97.2). Concomitant opposite breast vertical reduction was performed in 6 cases. Flap survival was uneventful. Nipple reconstruction was performed 6 months after radiation treatment in 4 patients. No major complications were encountered. Two patients developed minor wound breakdown after nipple reconstruction. CONCLUSIONS: The medial pillar island flap is presented as a safe and reliable option for the reconstruction of central partial mastectomy defects in patients with macromastia or breast ptosis. Internal mammary system provides predictable and robust flap viability while complete separation from the inframammary fold allows for unrestricted mobility. The procedure is designed with vertical scar mammaplasty, which results in a smooth contour to the lower pole. The flap allows for nipple reconstruction using well-vascularized skin paddle. The technique is offered as an alternative oncoplasty option for neoareolar reconstruction.

Sternalis is muscle: An anatomic variation and its clinical implications.

This report presents a case description of sternalis muscle which is an accessory muscle of anterior thoracic wall. A 56-year-old woman underwent mastectomy for breast cancer along with free flap reconstruction, revealing the presence of aberrant sternalis muscle. It was divided transversely during partial rib resection to expose internal mammary vessels. The case proceeded with successful flap transfer. Clinical implications of this anatomic variation is discussed. The authors conclude that plastic surgeons should be aware of this muscular anomaly.

Neoadjuvant Chemotherapy and Nipple-Sparing Mastectomy: Timing and Postoperative Complications.

BACKGROUND: As the demand for nipple-sparing mastectomy (NSM) increases and surgeons expand the eligibility criteria, a subset of patients may become candidates following neoadjuvant chemotherapy (NACT). However, the impact of NACT on postoperative complications remains unclear as the current literature is discordant. METHODS: A single-institution, retrospective chart review was performed on patients undergoing NSM from 1989 to 2017. Patient demographics, surgical intervention, systemic treatment, and complication rates were collected. Primary outcomes were 30-day postoperative complications, including nipple-areolar necrosis, skin flap necrosis, infection, wound dehiscence, hematoma, and seroma. Secondary outcomes included characterization of the timing between chemotherapy and surgical intervention, and the impact on complication rates. Each breast was considered independently for analysis, and breasts undergoing either NACT or primary surgery (PS) were compared. RESULTS: Of the 832 breasts included, 88 (10.6%) received NACT and 744 (89.4%) underwent PS. Baseline complication rates were not significantly different between the NACT group and the PS group (5.7% vs. 10.6%; p = 0.119). When controlling for age, body mass index (BMI), smoking, and prior radiation, NACT was not a predictor of complications. Time from completion of NACT to PS occurred at a median of 40.5 days (interquartile range 31.3-55.3), and decreased intervals were not associated with increased complication rates. CONCLUSIONS: Postoperative complications following NSM in patients completing NACT are comparable with those receiving PS. Patients undergoing NACT do not have a significantly increased risk of necrosis, unintended reoperations, or nipple loss. NACT should not be considered a contraindication for NSM.

Papillary thyroid carcinoma with bilateral axillary lymph node involvement: a case report outlining hypothesis for locoregional spread and therapeutic implications.

Axillary lymph node involvement (ALNI) in well differentiated papillary thyroid carcinoma (WDPTC) is a rare sequela of disease presentation. We report a case of PTC with extensive cervical lymph node involvement, local extension to the skin of the neck and bilateral ALNI without evidence of distant disease. We posit that ALNI represents local extension of disease rather than distant metastasis. Therefore, in the absence of distant spread, ALNI should result in surgical intervention. This optimizes removal of all bulky disease and increases effectiveness of radioactive iodine (RAI) therapy. Future research centered on genomics should focus on ascertaining the behavior and prognosis of such cases, especially when anatomic spread is discordant with biologic behavior.

Mapping the distribution of nodal metastases in papillary thyroid carcinoma: Where exactly are the nodes?

OBJECTIVE: To characterize nodal disease of patients presenting with papillary thyroid carcinoma (PTC) STUDY DESIGN: Retrospective chart review. METHODS: PTC patients who underwent thyroidectomy and/or neck dissection (revision/primary) from 2004 to 2009 at a tertiary-care hospital were reviewed. Preoperative computed tomography (CT) scan and ultrasonography were utilized to identify macroscopic, clinically apparent nodal metastasis (cN+). Demographic data, type of surgery, nodal disease, and primary tumor information were recorded. RESULTS: Of 416 patients reviewed, 35% had cN+ on initial presentation (IP); of these, 88% and 50% had central (CND) and lateral nodal disease (LND), respectively. The presence of ectopic nodal (END) metastases (nodal disease outside typical CND or LND locations) was absent on IP but occurred in 9% of patients with nodal recurrence. END was typically found in the retropharyngeal area but also was noted in the sublingual region, subcutaneous location, axilla, and chest wall. Extrathyroidal extension (ETE) was found in 8.9% without nodal disease, 33.1% with nodal disease, and 57.1% with END (P < 0.0001). Primary tumor size greater than 4 cm (P = 0.05) was associated with nodal disease. CONCLUSION: This report represents a large series describing characteristics of the primary PTC tumor and associated nodal disease not only in the central and lateral neck but also in the ectopic locations. Our results suggest that a significant proportion of patients will have nodal disease in the central compartment on IP, especially younger patients. ETE and tumor size are associated with macroscopic nodal disease (including END). Nine percent of the patients with nodal recurrence had ectopic nodes occurring in various locations, most commonly in the retropharynx. CT scan can assist with identification and surgical planning of recurrent nodal disease. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:1959-1964, 2017.

Feasibility of Intraoperative Breast MRI and the Role of Prone Versus Supine Positioning in Surgical Planning for Breast-Conserving Surgery.

We assessed the feasibility of supine intraoperative MRI (iMRI) during breast-conserving surgery (BCS), enrolling 15 patients in our phase I trial between 2012 and 2014. Patients received diagnostic prone MRI, BCS, pre-excisional supine iMRI, and postexcisional supine iMRI. Feasibility was assessed based on safety, sterility, duration, and image-quality. Twelve patients completed the study; mean duration = 114 minutes; all images were adequate; no complications, safety, or sterility issues were encountered. Substantial tumor-associated changes occurred (mean displacement = 67.7 mm, prone-supine metric, n = 7). We have demonstrated iMRI feasibility for BCS and have identified potential limitations of prone breast MRI that may impact surgical planning.

Immediate breast reconstruction following mastectomy in pregnant women with breast cancer.

BACKGROUND: Surgical management of breast cancer in pregnancy (BCP) requires balancing benefits of therapy with potential risks to the developing fetus. Minimal data describe outcomes after mastectomy with immediate breast reconstruction (IR) in pregnant patients. METHODS: Retrospective review was performed of patients who underwent IR after mastectomy within a BCP cohort. Parameters included intra- and post-operative complications, short-term maternal/fetal outcomes, surgery duration, and delayed reconstruction in non-IR cohort. RESULTS: Of 82 patients with BCP, 29 (35%) had mastectomy during pregnancy: 10 (34%) had IR, 19(66%) did not. All IR utilized tissue expander (TE) placement. Mean gestational age (GA) at IR was 16.2 weeks. Mean surgery duration was 198 min with IR versus 157 min without IR. Those with IR delivered at, or close to, term infants of normal birthweight. No fetal or major obstetrical complications were seen. Post-mastectomy radiation (PMRT) was provided after pregnancy in 2 (20%) patients in the IR cohort and 12 (63%) in the non-IR cohort. All patients in the IR cohort successfully transitioned to permanent implant. CONCLUSIONS: This report represents one of the largest series describing IR during BCP. IR after mastectomy increased surgery duration, but was not associated with adverse obstetrical or fetal outcomes. IR with TE may preserve reconstructive options when PMRT is indicated. J. Surg. Oncol. 2016;114:140-143. © 2016 Wiley Periodicals, Inc.

Intraoperative Supine Breast MR Imaging to Quantify Tumor Deformation and Detection of Residual Breast Cancer: Preliminary Results.

Purpose To use intraoperative supine magnetic resonance (MR) imaging to quantify breast tumor deformation and displacement secondary to the change in patient positioning from imaging (prone) to surgery (supine) and to evaluate residual tumor immediately after breast-conserving surgery (BCS). Materials and Methods Fifteen women gave informed written consent to participate in this prospective HIPAA-compliant, institutional review board-approved study between April 2012 and November 2014. Twelve patients underwent lumpectomy and postsurgical intraoperative supine MR imaging. Six of 12 patients underwent both pre- and postsurgical supine MR imaging. Geometric, structural, and heterogeneity metrics of the cancer and distances of the tumor from the nipple, chest wall, and skin were computed. Mean and standard deviations of the changes in volume, surface area, compactness, spherical disproportion, sphericity, and distances from key landmarks were computed from tumor models. Imaging duration was recorded. Results The mean differences in tumor deformation metrics between prone and supine imaging were as follows: volume, 23.8% (range, -30% to 103.95%); surface area, 6.5% (range, -13.24% to 63%); compactness, 16.2% (range, -23% to 47.3%); sphericity, 6.8% (range, -9.10% to 20.78%); and decrease in spherical disproportion, -11.3% (range, -60.81% to 76.95%). All tumors were closer to the chest wall on supine images than on prone images. No evidence of residual tumor was seen on MR images obtained after the procedures. Mean duration of pre- and postoperative supine MR imaging was 25 minutes (range, 18.4-31.6 minutes) and 19 minutes (range, 15.1-22.9 minutes), respectively. Conclusion Intraoperative supine breast MR imaging, when performed in conjunction with standard prone breast MR imaging, enables quantification of breast tumor deformation and displacement secondary to changes in patient positioning from standard imaging (prone) to surgery (supine) and may help clinicians evaluate for residual tumor immediately after BCS. © RSNA, 2016 Online supplemental material is available for this article.

Young women with breast cancer in the United States and South Korea: comparison of demographics, pathology and management.

BACKGROUND: Breast cancer diagnosed in young women may be more aggressive, with higher rates of local and distant recurrence compared to the disease in older women. Epidemiologic evidence suggests that Korean women have a lower incidence of breast cancer than women in the United States, but that they present at a younger age than their American counterparts. We sought to compare risk factors and management of young women with breast cancer in Boston, Massachusetts (US) with those in Seoul, South Korea (KR). MATERIALS AND METHODS: A retrospective review was performed of consecutive patients less than 35 years old with a diagnosis of breast cancer at academic cancer centers in the US and KR from 2000-2005. Patient data were obtained by chart review. Demographic, tumor and treatment characteristics were compared utilizing Pearson's chi- square or Wilcoxon rank-sum tests where appropriate. All differences were assessed as significant at the 0.05 level. RESULTS: 205 patients from the US and 309 from KR were analyzed. Patients in US were more likely to have hormone receptor positive breast cancer, while patients in KR had a higher rate of triple negative lesions. Patients in US had a higher mean body mass index and more often reported use of birth control pills, while those in the KR were less likely to have a sentinel node procedure performed or to receive post mastectomy radiation. CONCLUSIONS: Patients under 35 diagnosed with breast cancer in the US and KR differ with respect to demographics, tumor characteristics and management. Although rates of breast conservation and mastectomy were similar, US patients were more likely to receive post mastectomy radiation. The lower use of sentinel node biopsy is explained by the later adoption of the technique in KR. Further evaluation is necessary to evaluate recurrence rates and survival in the setting of differing disease subtypes in these patients.

Impact of thyroid nodule size on prevalence and post-test probability of malignancy: a systematic review.

OBJECTIVES/HYPOTHESIS: Large thyroid nodules may be associated with higher risk of malignancy and less-accurate fine-needle aspiration (FNA) results, but there is currently no overarching consensus. We therefore tested two null hypotheses: 1) thyroid nodule size >3 to 4 cm is not associated with a higher baseline prevalence of malignancy (i.e., the associated pretest probability is the same, regardless of size), and 2) thyroid nodule size >3 to 4 cm is not associated with worse diagnostic accuracy (i.e., the associated sensitivity, false-negative rate, and post-test probability of malignancy is not affected by nodule diameter). STUDY DESIGN: Computerized searches of PubMed, Embase, and The Cochrane Library through July 2013 were performed, supplemented with manual searches. METHODS: A priori criteria were defined to determine inclusion and exclusion of studies. Searches and data extraction were performed by independent reviewers and focused on FNA histopathologic findings and their relationship to nodule size, study design, and potential confounders. RESULTS: Criterion-meeting studies (n = 15) included a total of 13,180 participants. The preponderance of prospective comparative studies showed a statistically significantly higher prevalence of malignancy in large nodules. Although data are mixed, evidence from the best-reported studies suggests sensitivity, false-negative rates, and frequency of true negatives among benign FNA results are worse in large nodules. CONCLUSIONS: Large nodules have a higher pretest probability of malignancy. Data from larger studies suggest reduced FNA diagnostic accuracy in nodules >3 to 4 cm in diameter. Surgery represents a reasonable clinical option for nodules >3 cm.

Application of desorption electrospray ionization mass spectrometry imaging in breast cancer margin analysis.

Distinguishing tumor from normal glandular breast tissue is an important step in breast-conserving surgery. Because this distinction can be challenging in the operative setting, up to 40% of patients require an additional operation when traditional approaches are used. Here, we present a proof-of-concept study to determine the feasibility of using desorption electrospray ionization mass spectrometry imaging (DESI-MSI) for identifying and differentiating tumor from normal breast tissue. We show that tumor margins can be identified using the spatial distributions and varying intensities of different lipids. Several fatty acids, including oleic acid, were more abundant in the cancerous tissue than in normal tissues. The cancer margins delineated by the molecular images from DESI-MSI were consistent with those margins obtained from histological staining. Our findings prove the feasibility of classifying cancerous and normal breast tissues using ambient ionization MSI. The results suggest that an MS-based method could be developed for the rapid intraoperative detection of residual cancer tissue during breast-conserving surgery.

Pilot study to evaluate feasibility of image-guided breast-conserving therapy in the advanced multimodal image-guided operating (AMIGO) suite.

BACKGROUND: The rate of reexcision in breast-conserving surgery remains high, leading to delay in initiation of adjuvant therapy, increased cost, increased complications, and negative psychological impact to the patient.1 (-) 3 We initiated a phase 1 clinical trial to determine the feasibility of the use of intraoperative magnetic resonance imaging (MRI) to assess margins in the advanced multimodal image-guided operating (AMIGO) suite. METHODS: All patients received contrast-enhanced three-dimensional MRI while under general anesthesia in the supine position, followed by standard BCT with or without wire guidance and sentinel node biopsy. Additional margin reexcision was performed of suspicious margins and correlated to final pathology (Fig. 1). Feasibility was assessed via two components: demonstration of safety and sterility and acceptable duration of the operation and imaging; and adequacy of intraoperative MRI imaging for interpretation and its comparison to final pathology. Fig. 1 Schema of AMIGO trial RESULTS: Eight patients (mean age 48.5 years), 4 with stage I breast cancer and 4 with stage II breast cancer, were recruited. All patients underwent successful BCT in the AMIGO suite with no AMIGO-specific complications or break in sterility during surgery. The mean operative time was 113 min (range 93-146 min). CONCLUSIONS: Our experience with AMIGO suggests that it is feasible to use intraoperative MRI imaging to evaluate margin assessment in real time. Further research is required to identify modalities that will lead to a reduction in reexcision in breast cancer therapy.

Lateral neck dissection for well-differentiated thyroid carcinoma: a systematic review.

OBJECTIVES/HYPOTHESIS: Management of the lateral neck in well-differentiated thyroid carcinoma (WDTC) remains a topic of ongoing debate. A systematic review was performed to determine if patients with WDTC who undergo lateral neck dissection (LND) have significantly different survival, recurrence, or procedure-related complication rates, as compared to those who do not. DATA SOURCES: A computerized search of MEDLINE from 1966 to October 2012 was performed, supplemented with manual searches. REVIEW METHODS: A priori criteria were used to evaluate 924 studies. Data extraction was performed by independent reviewers and focused on survival, recurrence, postoperative complications, study designs, and potential confounders. RESULTS: Forty-seven criterion-meeting studies included 24,153 participants. Stage-specific data were limited. The small volume of data specific to the N0 neck (n=3 studies, 6.3%) demonstrates no difference in disease-free survival (DFS) or recurrence with versus without LND. The data regarding the N+ neck (n=14 studies, 29.2%) were mixed with regard to the impact of LND on DFS and recurrence. The preponderance of data was reported in analyses of mixed or unreported nodal status (n=31 studies, 64.6%). Among these studies, the majority reported no difference in overall survival, DFS, disease-specific survival, or recurrence, but overall data were mixed and subject to confounding by indication and limitations in power. CONCLUSIONS: Data regarding the impact of LND on survival, recurrence, and postoperative complications are mixed. Routine prophylactic LND for WDTC does not have a clearly advantageous risk-to-benefit ratio.

Intraoperative digital specimen mammography: a significant improvement in operative efficiency.

BACKGROUND: The goal of this study was to determine the length of operative time and its effect on surgeon productivity with the use of intraoperative digital specimen mammography (IDSM) compared to standard specimen mammography (SSM). METHODS: A retrospective chart review was performed on 344 consecutive patients from a single breast surgeon from 2003 to 2010. Operative time was compared between procedures using SSM vs IDSM. Surgeon productivity was evaluated by the number of wire-localized excisions performed prior to and after implementation of IDSM. RESULTS: Two hundred thirty patients underwent SSM and 114 underwent IDSM. Average operative time in the SSM group was 78 minutes vs 68 minutes in the IDSM group (P < .0001). In the first 2 years after implementation of IDSM, the number of wire-localized excisions performed increased by 20%. CONCLUSIONS: Operative times were significantly shorter with the use of IDSM vs SSM, and this was associated with an increase in surgeon productivity.

Intraoperative monitoring: normative range associated with normal postoperative glottic function.

OBJECTIVES/HYPOTHESIS: Despite increasing use of intraoperative nerve monitoring (IONM), there is limited information on normative electrophysiologic electromyographic (EMG) parameters. The objective of this study was to define normative parameters of recurrent laryngeal nerve (RLN) intraoperative neuromonitoring during thyroid surgery associated with normal postoperative vocal cord function. STUDY DESIGN: Prospective data collection in a tertiary care center. METHODS: Quantitative analysis of evoked waveform amplitude and threshold was performed on 125 patients with 167 nerves at risk. Values were displayed as a mean with 5th percentile and 95th percentiles (5th-95th). Postoperative vocal cord function in all patients was documented. RESULTS: All patients had normal postoperative laryngeal function (group I-normal) except for two patients who had postoperative transient vocal cord paralysis (group II-abnormal/outlier). The final amplitude between 247 and 3607 µV at the end of dissection/end of surgery was associated in all group I patients with a normal postoperative neural function. Final intraoperative amplitude measures for group II averaged just 97.5 µV, significantly different than our normative ranges obtained for group I, and fell outside of the group I 5% to 95% percentile range (P = .016). Final amplitude adequately predicted postoperative RLN impaired function immediately after surgery. CONCLUSIONS: We propose IONM EMG data criteria that predict normal postoperative vocal cord function monitoring and provide information about nerve functioning at the end of the operation, thereby allowing adaptation of the surgical strategy when a bilateral procedure is indicated to avoid bilateral nerve paralysis.

Does failure to perform prophylactic level VI node dissection leave persistent disease detectable by ultrasonography in patients with low-risk papillary carcinoma of the thyroid?

BACKGROUND: There is controversy regarding the need for prophylactic level VI central node dissection in patients with low-risk papillary thyroid carcinoma (PTC). This study focuses on the incidence of persistent level VI nodal disease in low-risk PTC without prophylactic central node dissection. METHODS: PTC was known at the time of thyroidectomy in 304 of the 761 patients who had initial thyroid surgery from 2001 to 2007. Therapeutic level VI node dissection was performed for suspicious or positive nodes. A prophylactic central node dissection was not done if suspicious nodes were not identified. All patients had a high-resolution ultrasonography, and almost all patients had a suppressed serum thyroglobulin level 4-6 months after thyroidectomy. RESULTS: A total of 112 of 304 patients (37%) had a therapeutic level VI node dissection. A prophylactic central node dissection was not performed in the remaining 192 patients. One hundred and sixty-one of the 192 patients (84%) were low risk. Biopsy-proven persistent disease was identified at the 4-6-month postoperative ultrasonography in only 3 of the 161 low-risk patients (1.8%). The suppressed serum thyroglobulin level was increased in these 3 patients and 2 additional patients. CONCLUSION: Failure to perform a prophylactic central node dissection in low-risk PTC resulted in both a very low incidence of persistent level VI nodal disease and elevated suppressed thyroglobulin 4-6 months after thyroidectomy.

Tobacco smoke induces polycomb-mediated repression of Dickkopf-1 in lung cancer cells.

Limited information is available about epigenetic mechanisms by which cigarette smoke enhances the initiation and progression of lung cancer. To examine this issue, A549 and Calu-6 lung cancer cells were cultured in normal media with or without tobacco smoke condensate (TSC) under clinically relevant exposure conditions. Ten-day TSC exposure dramatically increased the tumorigenicity of lung cancer cells in nude mice. Microarray and quantitative reverse transcription-PCR (RT-PCR) experiments revealed that this phenomenon coincided with diminished expression of Dickkopf-1 (Dkk-1). Western blot, chromatin immunoprecipitation, methylation-specific PCR, and pyrosequencing experiments showed that repression of Dkk-1 coincided with decreased H4K16Ac, increased H3K27me3, and recruitment of SirT1, EZH2, SUZ12, and Bmi1 without DNA hypermethylation within the Dkk-1 promoter despite prolonged TSC exposures. Removal of TSC from culture media resulted in loss of promoter-associated polycomb repressor complexes and reexpression of Dkk-1. siRNA-mediated knockdown of EZH2 and SirT1 partially abrogated TSC-mediated inhibition of Dkk-1 expression. Western blot and quantitative RT-PCR array experiments showed that TSC exposure as well as knockdown of Dkk-1 activated Wnt signaling and significantly up-regulated Wnt5a in lung cancer cells. Knockdown of Dkk-1 recapitulated the dramatic protumorigenic effects of TSC exposure in Calu-6 cells. Despite the transient nature of Dkk-1 repression following TSC exposure in vitro, Dkk-1 remained silenced in tumor xenografts derived from TSC-treated Calu-6 cells. Collectively, these data provide evidence that cigarette smoke directly engages polycomb machinery to activate a signaling network implicated in maintenance of cancer stem cells.

Recognition of NY-ESO-1+ tumor cells by engineered lymphocytes is enhanced by improved vector design and epigenetic modulation of tumor antigen expression.

The therapeutic use of T cell receptor (TCR)-transduced peripheral blood lymphocytes (PBL) targeting tumor-associated antigens is emerging as a promising investigational treatment for patients with cancer. Initial response rates to therapy were low, suggesting the need to improve the function of TCR-transduced PBL. We constructed standard bicistronic retroviral vectors using an internal promoter or internal ribosomal entry site element as well as vectors incorporating coding sequences for 2A linker peptides between coding sequences for alpha and beta chains targeting the cancer-testis (CT) antigen, NY-ESO-1. Incorporation of coding sequences for 2A linker peptides in the bicistronic TCR expression cassette resulted in up to a fourfold increase in TCR expression and a significant improvement in effector function as measured by interferon-gamma release following co-culture with peptide-pulsed targets and NY-ESO-1+ tumors. We also sought to enhance reactivity of TCR-transduced PBL against tumor targets by modulation of tumor antigen expression on target cells. Induction of NY-ESO-1 expression on tumor targets using the demethylating agent 5-aza-2'-deoxycytidine (alone or in combination with the histone deacetylase inhibitor depsipeptide) resulted in enhanced interferon-gamma secretion by the TCR-transduced PBL on culture with treated targets. Taken together, these results indicate that design of TCR-based vectors incorporating 2A linker peptides improves TCR expression and effector function of transduced PBL. Furthermore, induction of CT antigen expression through treatment of tumor targets with chromatin-remodeling agents may augment TCR-based immunotherapy targeting these antigens. These results have relevance for TCR-based gene therapies targeting common epithelial malignancies.

Combining agents that target the tumor microenvironment improves the efficacy of anticancer therapy.

PURPOSE: Over the past 60 years, cytotoxic chemotherapy has targeted the cancer cell. Despite this, there have been few cancer cures. A new approach to cancer therapy is to target the multicellular biological entity of the tumor microenvironment. EXPERIMENTAL DESIGN: Lenalidomide, an immunomodulatory drug, sunitinib, a tyrosine kinase inhibitor, and low-dose metronomic cyclophosphamide, were tested alone and in combination for their abilities to inhibit endothelial cell tube formation, rat aortic ring outgrowth, tumor growth, and metastatic development in mice. In addition, ectopic tumor lysates were evaluated for the presence of proangiogenic proteins. RESULTS: The three agents alone were shown to significantly inhibit endothelial cells' ability to form tubes and significantly inhibit the multicellular microenvironment in the rat aortic ring assay (P < 0.01 and P < 0.001). This effect was also significantly augmented when the agents were combined. Furthermore, the three-drug combination was able halt the progression of tumor growth almost completely in xenograft models of ocular melanoma, colon cancer, pancreatic cancer, and cutaneous melanoma. These agents significantly decrease the number of proliferating cells in tumors, significantly increase the number of cells undergoing active cell death in tumors, and significantly decrease the number of blood vessels in treated tumors (P < 0.05). Combination therapy shows a decrease in the compensatory up-regulation of proangiogenic proteins after treatment when compared with single-agent therapy. CONCLUSIONS: This combination of agents causes an inhospitable microenvironment for tumor cells and shows great promise for use in the clinic.