Publications by authors named "George Plitas"

47 Publications

Reply to: Metaplastic Breast Carcinoma and Other Triple-Negative Subtype Breast Cancers: Which is the Worst?

Ann Surg Oncol 2021 Feb 10. Epub 2021 Feb 10.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

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http://dx.doi.org/10.1245/s10434-021-09679-4DOI Listing
February 2021

Pretreatment neutrophil-to-lymphocyte ratio and mutational burden as biomarkers of tumor response to immune checkpoint inhibitors.

Nat Commun 2021 02 1;12(1):729. Epub 2021 Feb 1.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Treatment with immune checkpoint inhibitors (ICI) has demonstrated clinical benefit for a wide range of cancer types. Because only a subset of patients experience clinical benefit, there is a strong need for biomarkers that are easily accessible across diverse practice settings. Here, in a retrospective cohort study of 1714 patients with 16 different cancer types treated with ICI, we show that higher neutrophil-to-lymphocyte ratio (NLR) is significantly associated with poorer overall and progression-free survival, and lower rates of response and clinical benefit, after ICI therapy across multiple cancer types. Combining NLR with tumor mutational burden (TMB), the probability of benefit from ICI is significantly higher (OR = 3.22; 95% CI, 2.26-4.58; P < 0.001) in the NLR low/TMB high group compared to the NLR high/TMB low group. NLR is a suitable candidate for a cost-effective and widely accessible biomarker, and can be combined with TMB for additional predictive capacity.
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http://dx.doi.org/10.1038/s41467-021-20935-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851155PMC
February 2021

ASO Author Reflections: Clinical Importance of Histologic Subtype for Metaplastic Breast Cancer.

Ann Surg Oncol 2021 Jan 5. Epub 2021 Jan 5.

Department of Surgery, Breast Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

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http://dx.doi.org/10.1245/s10434-020-09454-xDOI Listing
January 2021

The association between tumor mutational burden and prognosis is dependent on treatment context.

Nat Genet 2021 01 4;53(1):11-15. Epub 2021 Jan 4.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

In multiple cancer types, high tumor mutational burden (TMB) is associated with longer survival after treatment with immune checkpoint inhibitors (ICIs). The association of TMB with survival outside of the immunotherapy context is poorly understood. We analyzed 10,233 patients (80% non-ICI-treated, 20% ICI-treated) with 17 cancer types before/without ICI treatment or after ICI treatment. In non-ICI-treated patients, higher TMB (higher percentile within cancer type) was not associated with better prognosis; in fact, in many cancer types, higher TMB was associated with poorer survival, in contrast to ICI-treated patients in whom higher TMB was associated with longer survival.
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http://dx.doi.org/10.1038/s41588-020-00752-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796993PMC
January 2021

Survival Outcomes for Metaplastic Breast Cancer Differ by Histologic Subtype.

Ann Surg Oncol 2021 Jan 2. Epub 2021 Jan 2.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: Metaplastic breast carcinoma (MBC) is a rare, aggressive subtype of breast cancer associated with poorer overall survival than other triple-negative breast cancers. This study sought to compare survival outcomes among histologic subtypes of MBC with those of non-metaplastic triple-negative breast cancer.

Methods: Clinicopathologic and treatment data for all patients with non-metastatic, pure MBC undergoing surgery from 1995 to 2017 and for a large cohort of patients with other types of triple-negative breast cancer during that period were collected from an institutional database. The MBC tumors were classified as having squamous, spindle, heterologous mesenchymal, or mixed histology. Survival outcomes were compared using the Kaplan-Meier method.

Results: Of 132 MBC patients, those with heterologous mesenchymal MBC (n = 45) had the best 5-year overall and breast cancer-specific survival (BCSS, 88%; 95% confidence interval [CI], 0.78-0.99), whereas those with squamous MBC had the worst survival (BCSS, 56%; 95% CI, 0.32-0.79). Overall survival, BCSS, and recurrence-free survival were worse for the patients with MBC than for the patients who had non-MBC triple-negative breast cancer, with a clinicopathologically adjusted recurrence hazard ratio of 2.4 (95% CI, 1.6-3.3; p < 0.001). Of the 10 MBC patients who received neoadjuvant chemotherapy, 4 progressed while receiving treatment, and 3 had no response.

Conclusions: Metaplastic breast carcinoma is associated with worse survival than other triple-negative breast cancers. The heterologous mesenchymal subtype is associated with the best survival, whereas the squamous subtype is associated with the worst survival. These data call for research to identify therapies tailored to MBC's unique biology.
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http://dx.doi.org/10.1245/s10434-020-09430-5DOI Listing
January 2021

Intraoperative opioids are associated with improved recurrence-free survival in triple-negative breast cancer.

Br J Anaesth 2021 02 19;126(2):367-376. Epub 2020 Nov 19.

Department of Anesthesiology, Weill Cornell Medicine, New York, NY, USA; Department of Anesthesiology and Critical Care Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address:

Background: Opioid-induced immunomodulation may be of particular importance in triple-negative breast cancer (TNBC) where an immune response is associated with improved outcome and response to immunotherapy. We evaluated the association between intraoperative opioids and oncological outcomes and explored patterns of opioid receptor expression in TNBC.

Methods: Consecutive patients with stage I-III primary TNBC were identified from a prospectively maintained database. Opioid receptor expression patterns in the tumour microenvironment were analysed using publicly available bulk and single-cell RNA-seq data.

Results: A total of 1143 TNBC cases were retrospectively analysed. In multivariable analysis, higher intraoperative opioid dose was associated with favourable recurrence-free survival, hazard ratio 0.93 (95% confidence interval 0.88-0.99) per 10 oral morphine milligram equivalents increase (P=0.028), but was not significantly associated with overall survival, hazard ratio 0.96 (95% confidence interval 0.89-1.02) per 10 morphine milligram equivalents increase (P=0.2). Bulk RNA-seq analysis of opioid receptors showed that OPRM1 was nearly non-expressed. Compared with normal breast tissue OGFR, OPRK1, and OPRD1 were upregulated, while TLR4 was downregulated. At a single-cell level, OPRM1 and OPRD1 were not detectable; OPRK1 was expressed mainly on tumour cells, whereas OGFR and TLR4 were more highly expressed on immune cells.

Conclusions: We found a protective effect of intraoperative opioids on recurrence-free survival in TNBC. Opioid receptor expression was consistent with a net protective effect of opioid agonism, with protumour receptors either not expressed or downregulated, and antitumour receptors upregulated. In this era of personalised medicine, efforts to differentiate the effects of opioids across breast cancer subtypes (and ultimately individual patients) should continue.
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http://dx.doi.org/10.1016/j.bja.2020.10.021DOI Listing
February 2021

Immunotherapeutic strategies in breast cancer: A clinical update.

J Surg Oncol 2021 Mar 6;123(3):710-717. Epub 2020 Nov 6.

Department of Surgery, Breast Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Immunotherapy has been incorporated into the standard of care for a wide range of malignancies. The study of tumor-infiltrating lymphocytes has emphasized the importance of the host antitumor immune response in the natural history of breast cancer. Recent clinical trials have used immunotherapeutic approaches to augment this response and improve outcomes for patients with breast cancer. Here, we review several current clinical trial data that indicate checkpoint blockade may mediate clinically significant responses.
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http://dx.doi.org/10.1002/jso.26287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889634PMC
March 2021

Regional Lymph Node Involvement Among Patients With De Novo Metastatic Breast Cancer.

JAMA Netw Open 2020 10 1;3(10):e2018790. Epub 2020 Oct 1.

Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.

Importance: Regional nodal irradiation (RNI) for node-positive breast cancer reduces distant metastases and improves survival, albeit with limited reduction in regional nodal recurrences. The mechanism by which RNI robustly reduces distant metastases while modestly influencing nodal recurrences (ie, the presumed target of RNI) remains unclear.

Objective: To determine whether some distant metastases putatively arise from occult regional nodal disease and whether regional recurrences otherwise remain largely undetected until an advanced cancer presentation.

Design, Setting, And Participants: This cohort study examined patients presenting with de novo stage IV breast cancer to the Memorial Sloan Kettering Cancer Center in New York, New York, from 2006 to 2018. Medical records were reviewed to ascertain clinicopathological parameters, including estrogen receptor status and survival. Pretreatment positron emission tomography-computed tomography (PET-CT) imaging was reviewed to ascertain the extent of regional nodal involvement at metastatic diagnosis using standard nodal assessment criteria. A subset underwent regional lymph node biopsy for diagnostic confirmation and served to validate the radiographic nodal assessment. Data analysis was performed from October 2019 to February 2020.

Exposures: Untreated metastatic breast cancer.

Main Outcome And Measures: The primary outcome was the likelihood of regional nodal involvement at the time of metastatic breast cancer presentation and was determined by reviewing pretreatment PET-CT imaging and lymph node biopsy findings.

Results: Among 597 women (median [interquartile range] age, 53 [44-65] years) with untreated metastatic breast cancer, 512 (85.8%) exhibited regional lymph node involvement by PET-CT or nodal biopsy, 509 (85%) had involvement of axillary level I, 328 (55%) had involvement in axillary level II, 136 (23%) had involvement in axillary level III, 101 (17%) had involvement in the supraclavicular fossa, and 96 (16%) had involvement in the internal mammary chain. Lymph node involvement was more prevalent among estrogen receptor-negative tumors (92.4%) than estrogen receptor-positive tumors (83.6%). Nodal involvement at the time of metastatic diagnosis was not associated with overall survival.

Conclusions And Relevance: These findings suggest that a majority of patients with de novo metastatic breast cancer harbor regional lymph node disease at presentation, consistent with the hypothesis that regional involvement may precede metastatic dissemination. This is in alignment with the findings of landmark trials suggesting that RNI reduces distant recurrences. It is possible that this distant effect of RNI may act via eradication of occult regional disease prior to systemic seeding. The challenges inherent in detecting isolated nodal disease (which is typically asymptomatic) may account for the more modest observed benefit of RNI on regional recurrences. Alternative explanations of nodal involvement that arises concurrently or after metastatic dissemination remain possible, but do not otherwise explain the association of RNI with distant recurrence.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.18790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547365PMC
October 2020

Enhancing mucosal immunity by transient microbiota depletion.

Nat Commun 2020 09 8;11(1):4475. Epub 2020 Sep 8.

Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.

Tissue resident memory CD8 T cells (Trm) are poised for immediate reactivation at sites of pathogen entry and provide optimal protection of mucosal surfaces. The intestinal tract represents a portal of entry for many infectious agents; however, to date specific strategies to enhance Trm responses at this site are lacking. Here, we present TMDI (Transient Microbiota Depletion-boosted Immunization), an approach that leverages antibiotic treatment to temporarily restrain microbiota-mediated colonization resistance, and favor intestinal expansion to high densities of an orally-delivered Listeria monocytogenes strain carrying an antigen of choice. By augmenting the local chemotactic gradient as well as the antigenic load, this procedure generates a highly expanded pool of functional, antigen-specific intestinal Trm, ultimately enhancing protection against infectious re-challenge in mice. We propose that TMDI is a useful model to dissect the requirements for optimal Trm responses in the intestine, and also a potential platform to devise novel mucosal vaccination approaches.
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http://dx.doi.org/10.1038/s41467-020-18248-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479140PMC
September 2020

Axillary Downstaging in Occult Primary Breast Cancer After Neoadjuvant Chemotherapy.

Ann Surg Oncol 2021 Feb 19;28(2):968-974. Epub 2020 Aug 19.

Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: Neoadjuvant chemotherapy (NAC) is increasingly used for clinically node-positive (cN+) tumors with intact primary breast cancer (IPBC) to downstage the axilla, and those who convert to cN0 may be eligible for sentinel lymph node biopsy (SLNB). Rates of axillary downstaging in occult primary breast cancer (OPBC) are unknown.

Objective: The aim of this study was to determine the frequency of nodal pathologic complete response (pCR) following NAC in a cohort of patients with OPBC.

Methods: Twenty-eight patients with stage II/III OPBC treated between January 2008 and December 2019 were identified. Twenty patients had cN1-3 OPBC, pretreatment lymph node needle biopsy, and received NAC; these constituted the study population. Treatment factors and nodal pCR rates were summarized by tumor subtype.

Results: Median age at diagnosis was 54 years. Most patients presented with cN1 disease (75%) and ductal histology (80%). Nodal pCR was seen in 16/20 (80%) patients. Eight (40%) patients were triple negative, 6 (30%) were estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER +/HER2 -), and 6 (30%) were HER2 positive, with pCR rates of 88%, 50%, and 100%, respectively. Among the 15 patients who presented as cN1, 14 (93%) converted to cN0 following NAC. Of these, nine underwent SLNB and all achieved nodal pCR (100%).

Conclusion: In this small series, 80% of OPBC patients achieved nodal pCR following NAC. pCR rates varied by receptor profile, being lowest in the ER positive/HER2 negative group and highest in the HER2 positive group (50-100%); however, these rates are excellent and numerically exceed those in the literature for IPBC. Given the pCR rate, SLNB may be an option in select OPBC patients who downstage following NAC.
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http://dx.doi.org/10.1245/s10434-020-08863-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855271PMC
February 2021

Changing the Default: A Prospective Study of Reducing Discharge Opioid Prescription after Lumpectomy and Sentinel Node Biopsy.

Ann Surg Oncol 2020 Nov 30;27(12):4637-4642. Epub 2020 Jul 30.

Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: Whether routinely prescribed opioids are necessary for pain control after discharge among lumpectomy/sentinel node biopsy (Lump/SLNB) patients is unclear. We hypothesize that Lump/SLNB patients could be discharged without opioids, with a failure rate < 10%. This study prospectively examines outcomes after changing standard discharge prescription from an opioid/non-steroidal anti-inflammatory drug (NSAID) to NSAID/acetaminophen.

Patients And Methods: Standard discharge pain medication orders included opioids in the first 3-month study period and were changed to NSAID/acetaminophen in the second 3-month period. Patient-reported medication consumption and pain scores were collected by post-discharge survey. Frequency of discharge with opioid, NSAID/acetaminophen failure rate, opioid use, and pain scores were examined.

Results: From May to October 2019, 663 patients had Lump/SLNB: 371 in the opioid study period and 292 in the NSAID period. In the opioid period, 92% (342/371) of patients were prescribed an opioid at discharge; of 142 patients who documented opioid use on the survey, 86 (61%) used zero tablets. Among 56 (39%) patients who used opioids, the median number taken by POD 5 was 4. After the change to NSAID/acetaminophen, rates of opioid prescription decreased to 14% (41/292). The NSAID/acetaminophen failure rate was 2% (5/251). Among survey respondents, there was no significant difference in the maximum reported pain scores (POD 1-5) between the opioid period and the NSAID period (p = 0.7).

Conclusions: In Lump/SLNB patients, a change to default discharge with NSAID/acetaminophen resulted in a 78% absolute reduction in opioid prescription, with a failure rate of 2% and no difference in patient-reported pain scores. Most Lump/SLNB patients can be discharged with NSAID/acetaminophen.
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http://dx.doi.org/10.1245/s10434-020-08886-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554186PMC
November 2020

ASO Author Reflections: Avoiding an Axillary Lymph Node Dissection: The Benefit of Neoadjuvant Chemotherapy for Occult Primary Breast Cancer.

Ann Surg Oncol 2020 Dec 28;27(Suppl 3):865-866. Epub 2020 Jul 28.

Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

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http://dx.doi.org/10.1245/s10434-020-08939-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680299PMC
December 2020

Microscopic Extracapsular Extension in Sentinel Lymph Nodes Does Not Mandate Axillary Dissection in Z0011-Eligible Patients.

Ann Surg Oncol 2020 May 9;27(5):1617-1624. Epub 2019 Dec 9.

Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: In the ACOSOG (American College of Surgeons Oncology Group) Z0011 trial and the AMAROS (After Mapping of the Axilla: Radiotherapy or Surgery?) trial, matted nodes with gross extracapsular extension (ECE), a risk factor for locoregional recurrence, were an indication for axillary lymph node dissection (ALND), but the effect of microscopic ECE (mECE) in the sentinel lymph nodes (SLNs) on recurrence was not examined.

Methods: Between 2010 and 2017, 811 patients with cT1-2N0 breast cancer and SLN metastasis were prospectively managed according to Z0011 criteria, with ALND for those with more than two positive SLNs or gross ECE. Management of mECE was not specified. In this study, we compare outcomes of patients with one to two positive SLNs with and without mECE, treated with SLN biopsy alone (n = 685).

Results: Median patient age was 58 years, and median tumor size was 1.7 cm. mECE was identified in 210 (31%) patients. Patients with mECE were older, had larger tumors, and were more likely to be hormone receptor positive and HER2 negative, have two positive SLNs, and receive nodal radiation. At a median follow-up of 41 months, no isolated axillary failures were observed. There were 11 nodal recurrences; two supraclavicular ± axillary, four synchronous with breast, and five with distant failure. The five-year rate of any nodal recurrence was 1.6% and did not differ by mECE (2.3% vs. 1.3%; p = 0.84). No differences were observed in local (p = 0.08) or distant (p = 0.31) recurrence rates by mECE status.

Conclusions: In Z0011-eligible patients, nodal recurrence rates in patients with mECE are low after treatment with SLN biopsy alone, even in the absence of routine nodal radiation. The presence of mECE should not be considered a routine indication for ALND.
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http://dx.doi.org/10.1245/s10434-019-08104-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145724PMC
May 2020

High-intensity sequencing reveals the sources of plasma circulating cell-free DNA variants.

Nat Med 2019 12 25;25(12):1928-1937. Epub 2019 Nov 25.

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Accurate identification of tumor-derived somatic variants in plasma circulating cell-free DNA (cfDNA) requires understanding of the various biological compartments contributing to the cfDNA pool. We sought to define the technical feasibility of a high-intensity sequencing assay of cfDNA and matched white blood cell DNA covering a large genomic region (508 genes; 2 megabases; >60,000× raw depth) in a prospective study of 124 patients with metastatic cancer, with contemporaneous matched tumor tissue biopsies, and 47 controls without cancer. The assay displayed high sensitivity and specificity, allowing for de novo detection of tumor-derived mutations and inference of tumor mutational burden, microsatellite instability, mutational signatures and sources of somatic mutations identified in cfDNA. The vast majority of cfDNA mutations (81.6% in controls and 53.2% in patients with cancer) had features consistent with clonal hematopoiesis. This cfDNA sequencing approach revealed that clonal hematopoiesis constitutes a pervasive biological phenomenon, emphasizing the importance of matched cfDNA-white blood cell sequencing for accurate variant interpretation.
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http://dx.doi.org/10.1038/s41591-019-0652-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7061455PMC
December 2019

Single-Cell Map of Diverse Immune Phenotypes in the Breast Tumor Microenvironment.

Cell 2018 08 28;174(5):1293-1308.e36. Epub 2018 Jun 28.

Program for Computational and Systems Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

Knowledge of immune cell phenotypes in the tumor microenvironment is essential for understanding mechanisms of cancer progression and immunotherapy response. We profiled 45,000 immune cells from eight breast carcinomas, as well as matched normal breast tissue, blood, and lymph nodes, using single-cell RNA-seq. We developed a preprocessing pipeline, SEQC, and a Bayesian clustering and normalization method, Biscuit, to address computational challenges inherent to single-cell data. Despite significant similarity between normal and tumor tissue-resident immune cells, we observed continuous phenotypic expansions specific to the tumor microenvironment. Analysis of paired single-cell RNA and T cell receptor (TCR) sequencing data from 27,000 additional T cells revealed the combinatorial impact of TCR utilization on phenotypic diversity. Our results support a model of continuous activation in T cells and do not comport with the macrophage polarization model in cancer. Our results have important implications for characterizing tumor-infiltrating immune cells.
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http://dx.doi.org/10.1016/j.cell.2018.05.060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348010PMC
August 2018

Tumor Biology Predicts Pathologic Complete Response to Neoadjuvant Chemotherapy in Patients Presenting with Locally Advanced Breast Cancer.

Ann Surg Oncol 2017 Dec 15;24(13):3896-3902. Epub 2017 Sep 15.

Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: Neoadjuvant chemotherapy (NAC) is used to convert patients with inoperable locally advanced breast cancer (LABC) to operability, but has not traditionally been used to avoid mastectomy or axillary dissection in this subset.

Objective: The purpose of this study was to determine the rates of pathologic complete response (pCR) in LABC patients, and identify factors predictive of pCR to determine if responding patients might be suitable for limited surgery.

Methods: From 2006 to 2016, 1522 patients received NAC followed by surgery; 321 had advanced disease in the breast (cT4) and/or in the nodes (cN2/N3). pCR rates were assessed by T and N stage, and receptor subtype.

Results: Of 321 LABC patients, 223 were cT4, 77 were cN2, and 82 were cN3. Forty-three percent were hormone receptor (HR) positive/human epidermal growth factor receptor 2 (HER2) negative (HR+/HER2-), 23% were triple negative, and 34% were HER2+. The overall pCR rate was 25% and differed by receptor subtype (HR+/HER2- 7%, triple negative 23%, HER2+ 48%; p < 0.001). Breast pCR occurred in 27% of patients and was similar in T4 versus non-T4 disease (29% vs. 22%; p = 0.26). Nodal pCR was achieved in 38% of cN+ patients and did not differ by nodal stage (cN1 43%, cN2 36%, cN3 32%; p = 0.23). Nodal pCR was significantly more common than breast pCR (p = 0.014) across all tumor subtypes. Receptor subtype was the only predictor of overall pCR (p < 0.001).

Conclusion: In patients with LABC, pCR after NAC was seen in 25%, and did not differ by T or N stage. Tumor biology, but not extent of disease, predicted pCR. Studies assessing the feasibility of surgical downstaging with NAC in LABC patients are warranted.
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http://dx.doi.org/10.1245/s10434-017-6085-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5697706PMC
December 2017

Axillary Dissection and Nodal Irradiation Can Be Avoided for Most Node-positive Z0011-eligible Breast Cancers: A Prospective Validation Study of 793 Patients.

Ann Surg 2017 09;266(3):457-462

*Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY †Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY ‡Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA.

Objective: To determine rates of axillary dissection (ALND) and nodal recurrence in patients eligible for ACOSOG Z0011.

Background: Z0011 demonstrated that patients with cT1-2N0 breast cancers and 1 to 2 involved sentinel lymph nodes (SLNs) having breast-conserving therapy had no difference in locoregional recurrence or survival after SLN biopsy alone or ALND. The generalizability of the results and importance of nodal radiotherapy (RT) is unclear.

Methods: Patients eligible for Z0011 had SLN biopsy alone. Prospectively defined indications for ALND were metastases in ≥3 SLNs or gross extracapsular extension. Axillary imaging was not routine. SLN and ALND groups and radiation fields were compared with chi-square and t tests. Cumulative incidence of recurrences was estimated with competing risk analysis.

Results: From August 2010 to December 2016, 793 patients met Z0011 eligibility criteria and had SLN metastases. Among them, 130 (16%) had ALND; ALND did not vary based on age, estrogen receptor, progesterone receptor, or HER2 status. Five-year event-free survival after SLN alone was 93% with no isolated axillary recurrences. Cumulative 5-year rates of breast + nodal and nodal + distant recurrence were each 0.7%. In 484 SLN-only patients with known RT fields (103 prone, 280 supine tangent, 101 breast + nodes) and follow-up ≥12 months, the 5-year cumulative nodal recurrence rate was 1% and did not differ significantly by RT fields.

Conclusions: We confirm that even without preoperative axillary imaging or routine use of nodal RT, ALND can be avoided in a large majority of Z0011-eligible patients with excellent regional control. This approach has the potential to spare substantial numbers of women the morbidity of ALND.
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http://dx.doi.org/10.1097/SLA.0000000000002354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5649371PMC
September 2017

Regulatory T Cells Exhibit Distinct Features in Human Breast Cancer.

Immunity 2016 11;45(5):1122-1134

Howard Hughes Medical Institute, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunology Program, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Ludwig Center at Memorial Sloan Kettering Cancer Center, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

Regulatory T (Treg) cells reside in lymphoid organs and barrier tissues where they control different types of inflammatory responses. Treg cells are also found in human cancers, and studies in animal models suggest that they contribute to cancer progression. However, properties of human intratumoral Treg cells and those present in corresponding normal tissue remain largely unknown. Here, we analyzed features of Treg cells in untreated human breast carcinomas, normal mammary gland, and peripheral blood. Tumor-resident Treg cells were potently suppressive and their gene-expression pattern resembled that of normal breast tissue, but not of activated peripheral blood Treg cells. Nevertheless, a number of cytokine and chemokine receptor genes, most notably CCR8, were upregulated in tumor-resident Treg cells in comparison to normal tissue-resident ones. Our studies suggest that targeting CCR8 for the depletion of tumor-resident Treg cells might represent a promising immunotherapeutic approach for the treatment of breast cancer.
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http://dx.doi.org/10.1016/j.immuni.2016.10.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5134901PMC
November 2016

Regulatory T Cells: Differentiation and Function.

Cancer Immunol Res 2016 09;4(9):721-5

Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, New York. Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York. Ludwig Center at Memorial Sloan Kettering Cancer Center, New York, New York.

The immune system of vertebrate animals has evolved to mount an effective defense against a diverse set of pathogens while minimizing transient or lasting impairment in tissue function that could result from the inflammation caused by immune responses to infectious agents. In addition, misguided immune responses to "self" and dietary antigens, as well as to commensal microorganisms, can lead to a variety of inflammatory disorders, including autoimmunity, metabolic syndrome, allergies, and cancer. Regulatory T cells expressing the X chromosome-linked transcription factor Foxp3 suppress inflammatory responses in diverse biological settings and serve as a vital mechanism of negative regulation of immune-mediated inflammation. Cancer Immunol Res; 4(9); 721-5. ©2016 AACR.
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http://dx.doi.org/10.1158/2326-6066.CIR-16-0193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5026325PMC
September 2016

How Often Does Neoadjuvant Chemotherapy Avoid Axillary Dissection in Patients With Histologically Confirmed Nodal Metastases? Results of a Prospective Study.

Ann Surg Oncol 2016 10 9;23(11):3467-3474. Epub 2016 May 9.

Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.

Background: In breast cancer patients with nodal metastases at presentation, false-negative rates lower than 10 % have been demonstrated for sentinel node biopsy (SLNB) after neoadjuvant chemotherapy (NAC) when three or more negative sentinel nodes (SLNs) are retrieved. However, the frequency with which axillary dissection (ALND) can be avoided is uncertain.

Methods: Among 534 prospectively identified consecutive patients with clinical stages 2 and 3 cancer receiving NAC from November 2013 to November 2015, all biopsy-proven node-positive (N+) cases were identified. Patients clinically node-negative after NAC were eligible for SLNB. The indications for ALND were failed mapping, fewer than three SLNs retrieved, and positive SLNs.

Results: Of 288 N+ patients, 195 completed surgery, with 132 (68 %) of these patients eligible for SLNB. The median age was 50 years. Of these patients, 73 (55 %) were estrogen receptor-positive (ER+), 21 (16 %) were ER- and human epidermal growth factor receptor-2-positive (HER2+), and 38 (29 %) were triple-negative. In four cases, SLNB was deferred intraoperatively. Among 128 SLNB attempts, three or more SLNs were retrieved in 110 cases (86 %), one or two SLNs were retrieved in 15 cases (12 %), and failed mapping occurred in three cases (2 %). In 66 cases, ALND was indicated: 54 (82 %) for positive SLNs, 9 (14 %) for fewer than three negative SLNs, and 3 (4 %) for failed mapping. Persistent disease was found in 17 % of the patients with fewer than three negative SLNs retrieved. Of the 128 SLNB cases, 62 (48 %) had SLNB alone with three or more SLNs retrieved. Among 195 N+ patients who completed surgery, nodal pathologic complete response (pCR) was achieved for 49 %, with rates ranging from 21 % for ER+/HER2- to 97 % for ER-/HER2+ cases, and was significantly more common than breast pCR in ER+/HER2- and triple-negative cases.

Conclusions: Nearly 70 % of the N+ patients were eligible for SLNB after NAC. For 48 %, ALND was avoided, supporting the role of NAC in reducing the need for ALND among patients presenting with nodal metastases.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070651PMC
http://dx.doi.org/10.1245/s10434-016-5246-8DOI Listing
October 2016

Genetic and epigenetic variation in the lineage specification of regulatory T cells.

Elife 2015 Oct 28;4:e07571. Epub 2015 Oct 28.

Immunology Program, Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, United States.

Regulatory T (Treg) cells, which suppress autoimmunity and other inflammatory states, are characterized by a distinct set of genetic elements controlling their gene expression. However, the extent of genetic and associated epigenetic variation in the Treg cell lineage and its possible relation to disease states in humans remain unknown. We explored evolutionary conservation of regulatory elements and natural human inter-individual epigenetic variation in Treg cells to identify the core transcriptional control program of lineage specification. Analysis of single nucleotide polymorphisms in core lineage-specific enhancers revealed disease associations, which were further corroborated by high-resolution genotyping to fine map causal polymorphisms in lineage-specific enhancers. Our findings suggest that a small set of regulatory elements specify the Treg lineage and that genetic variation in Treg cell-specific enhancers may alter Treg cell function contributing to polygenic disease.
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http://dx.doi.org/10.7554/eLife.07571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4623597PMC
October 2015

Skin Flap Necrosis After Mastectomy With Reconstruction: A Prospective Study.

Ann Surg Oncol 2016 Jan 21;23(1):257-64. Epub 2015 Jul 21.

Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: Rates of mastectomy with immediate reconstruction are rising. Skin flap necrosis after this procedure is a recognized complication that can have an impact on cosmetic outcomes and patient satisfaction, and in worst cases can potentially delay adjuvant therapies. Many retrospective studies of this complication have identified variable event rates and inconsistent associated factors.

Methods: A prospective study was designed to capture the rate of skin flap necrosis as well as pre-, intra-, and postoperative variables, with follow-up assessment to 8 weeks postoperatively. Uni- and multivariate analyses were performed for factors associated with skin flap necrosis.

Results: Of 606 consecutive procedures, 85 (14 %) had some level of skin flap necrosis: 46 mild (8 %), 6 moderate (1 %), 31 severe (5 %), and 2 uncategorized (0.3 %). Univariate analysis for any necrosis showed smoking, history of breast augmentation, nipple-sparing mastectomy, and time from incision to specimen removal to be significant. In multivariate models, nipple-sparing, time from incision to specimen removal, sharp dissection, and previous breast reduction were significant for any necrosis. Univariate analysis of only moderate or severe necrosis showed body mass index, diabetes, nipple-sparing mastectomy, specimen size, and expander size to be significant. Multivariate analysis showed nipple-sparing mastectomy and specimen size to be significant. Nipple-sparing mastectomy was associated with higher rates of necrosis at every level of severity.

Conclusions: Rates of skin flap necrosis are likely higher than reported in retrospective series. Modifiable technical variables have limited the impact on rates of necrosis. Patients with multiple risk factors should be counseled about the risks, especially if they are contemplating nipple-sparing mastectomy.
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http://dx.doi.org/10.1245/s10434-015-4709-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4697877PMC
January 2016

Reigning in regulatory T-cell function.

Nat Biotechnol 2015 Jul;33(7):718-9

Howard Hughes Medical Institute and Immunology Program, Ludwig Center.

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http://dx.doi.org/10.1038/nbt.3285DOI Listing
July 2015

Extent of microinvasion in ductal carcinoma in situ is not associated with sentinel lymph node metastases.

Ann Surg Oncol 2014 Oct 5;21(10):3330-5. Epub 2014 Aug 5.

Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: Ductal carcinoma in situ with microinvasion (DCISM) is a rare diagnosis with a good prognosis. Although nodal metastases are uncommon, sentinel lymph node biopsy (SLNB) remains standard care. Volume of disease in invasive breast cancer is associated with SLNB positivity, and, thus we hypothesized that in a large cohort of patients with DCISM, multiple foci of microinvasion might be associated with a higher risk of positive SLNB.

Methods: Records from a prospective institutional database were reviewed to identify patients with DCISM who underwent SLNB between June 1997 and December 2010. Pathology reports were reviewed for number of microinvasive foci and categorized as 1 focus or ≥2 foci. Demographic, pathologic, treatment, and outcome data were obtained and analyzed.

Results: Of 414 patients, 235 (57 %) had 1 focus of microinvasion and 179 (43 %) had ≥2 foci. SLNB macrometastases were found in 1.4 %, and micrometastases were found in 6.3 %; neither were significantly different between patients with 1 focus versus ≥2 foci (p = 1.0). Patients with positive SLNB or ≥2 foci of microinvasion were more likely to receive chemotherapy. At median 4.9 years (range 0-16.2 years) follow-up, 18 patients, all in the SLNB negative group, had recurred for an overall 5-year recurrence-free proportion of 95.9 %.

Conclusions: Even with large numbers, there was no higher risk of nodal involvement with ≥2 foci of microinvasion compared with 1 focus. Number of microinvasive foci and results of SLNB appear to be used in decision making for systemic therapy. Prognosis is excellent.
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http://dx.doi.org/10.1245/s10434-014-3920-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4389284PMC
October 2014

Transient regulatory T cell ablation deters oncogene-driven breast cancer and enhances radiotherapy.

J Exp Med 2013 Oct 14;210(11):2435-66. Epub 2013 Oct 14.

Memorial Sloan-Kettering Cancer Center; and Breast Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.

Rational combinatorial therapeutic strategies have proven beneficial for the management of cancer. Recent success of checkpoint blockade in highly immunogenic tumors has renewed interest in immunotherapy. Regulatory T (T reg) cells densely populate solid tumors, which may promote progression through suppressing anti-tumor immune responses. We investigated the role of T reg cells in murine mammary carcinogenesis using an orthotopic, polyoma middle-T antigen-driven model in Foxp3(DTR) knockin mice. T reg cell ablation resulted in significant determent of primary and metastatic tumor progression. Importantly, short-term ablation of T reg cells in advanced spontaneous tumors led to extensive apoptotic tumor cell death. This anti-tumor activity was dependent on IFN-γ and CD4(+) T cells but not on NK or CD8(+) T cells. Combination of T reg cell ablation with CTLA-4 or PD-1/PD-L1 blockade did not affect tumor growth or improve the therapeutic effect attained by T reg cell ablation alone. However, T reg cell targeting jointly with tumor irradiation significantly reduced tumor burden and improved overall survival. Together, our results demonstrate a major tumor-promoting role of T reg cells in an autochthonous model of tumorigenesis, and they reveal the potential therapeutic value of combining transient T reg cell ablation with radiotherapy for the management of poorly immunogenic, aggressive malignancies.
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http://dx.doi.org/10.1084/jem.20130762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3804934PMC
October 2013

Axillary dissection can be avoided in the majority of clinically node-negative patients undergoing breast-conserving therapy.

Ann Surg Oncol 2014 Jan 22;21(1):22-7. Epub 2013 Aug 22.

Breast Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, USA.

Background: The extent to which ACOSOG Z0011 findings are applicable to patients undergoing breast-conserving therapy (BCT) is uncertain. We prospectively assessed how often axillary dissection (ALND) was avoided in an unselected, consecutive patient cohort meeting Z0011 eligibility criteria and whether subgroups requiring ALND could be identified preoperatively.

Methods: Patients with cT1,2cN0 breast cancer undergoing BCT were managed without ALND for metastases in <3 sentinel nodes (SNs) and no gross extracapsular extension (ECE). Patients with and without indications for ALND were compared using Fisher's exact and Wilcoxon rank sum tests.

Results: From August 2010 to November 2012, 2,157 invasive cancer patients had BCT. A total of 380 had histologic nodal metastasis; 93 did not meet Z0011 criteria. Of 287 with ≥1 H&E-positive SN (209 macrometastases), 242 (84 %) had indications for SN only. ALND was indicated in 45 for ≥3 positive SNs (n = 29) or ECE (n = 16). The median number of SNs removed in the SN group was 3 versus 5 in the ALND group (p < 0.0001). Age, hormone receptor and HER2 status, and grade did not differ between groups; tumors were larger in the ALND group (p < 0.0001). Of ALND patients, 72 % had additional positive nodes (median = 1; range 1-19). No axillary recurrences have occurred (median follow-up, 13 months).

Conclusions: ALND was avoided in 84 % of a consecutive series of patients having BCT, suggesting that most patients meeting ACOSOG Z0011 eligibility have a low axillary tumor burden. Age, ER, and HER2 status were not predictive of ALND, and the criteria used for ALND (≥3 SNs, ECE) reliably identified patients at high risk for residual axillary disease.
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http://dx.doi.org/10.1245/s10434-013-3200-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349525PMC
January 2014

Controversies in the management of regional nodes in melanoma.

J Natl Compr Canc Netw 2012 Mar;10(3):414-21

Memorial Sloan-Kettering Cancer Center, Gastric and Mixed Tumor Service, New York, New York 10021, USA.

The surgical management of the regional lymph node basin of melanoma has undergone significant changes in the past 2 decades, most of which have been guided by prospective randomized trials. Historically, routine elective lymph node dissection was recommended for the management of melanoma regardless of clinical nodal involvement. Subsequent randomized trials failed to show a clear benefit for all patients, and sentinel lymph node (SLN) biopsy emerged as an alternative. Although the prognostic value of SLN biopsy in intermediate-thickness melanoma is well accepted, its value for patients with thin and thick lesions is debated. The therapeutic advantage of removing an involved SLN, and the need for a completion lymph node dissection after the identification of a positive SLN, are areas of continued controversy. This article discusses these issues in the management of the regional lymph node basin in patients with melanoma.
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http://dx.doi.org/10.6004/jnccn.2012.0038DOI Listing
March 2012

Obstructive jaundice expands intrahepatic regulatory T cells, which impair liver T lymphocyte function but modulate liver cholestasis and fibrosis.

J Immunol 2011 Aug 22;187(3):1150-6. Epub 2011 Jun 22.

Hepatobiliary Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

Although obstructive jaundice has been associated with a predisposition toward infections, the effects of bile duct ligation (BDL) on bulk intrahepatic T cells have not been clearly defined. The aim of this study was to determine the consequences of BDL on liver T cell phenotype and function. After BDL in mice, we found that bulk liver T cells were less responsive to allogeneic or syngeneic Ag-loaded dendritic cells. Spleen T cell function was not affected, and the viability of liver T cells was preserved. BDL expanded the number of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg), which were anergic to direct CD3 stimulation and mediated T cell suppression in vitro. Adoptively transferred CD4(+)CD25(-) T cells were converted into Treg within the liver after BDL. In vivo depletion of Treg after BDL restored bulk liver T cell function but exacerbated the degrees of inflammatory cytokine production, cholestasis, and hepatic fibrosis. Thus, BDL expands liver Treg, which reduce the function of bulk intrahepatic T cells yet limit liver injury.
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http://dx.doi.org/10.4049/jimmunol.1004077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3372324PMC
August 2011

Neutrophil IL-10 suppresses peritoneal inflammatory monocytes during polymicrobial sepsis.

J Leukoc Biol 2011 Mar 24;89(3):423-32. Epub 2010 Nov 24.

Hepatopancreatobiliary Service, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

Septic peritonitis remains a major cause of death. Neutrophils and inflammatory monocytes are principal components of the innate immune system and are essential for defense against a range of microbial pathogens. Their role and interaction in polymicrobial sepsis have not been defined clearly. Using a murine model of CLP to induce moderate sepsis, we found that neutrophil depletion did not alter survival, whereas depletion of neutrophils and inflammatory monocytes markedly reduced survival. After neutrophil depletion, inflammatory monocytes had greater phagocytic capacity and oxidative burst, and increased expression of costimulatory molecules, TNF, and iNOS. Notably, peritoneal neutrophils produced IL-10 following CLP. Adoptive i.p. transfer of WT but not IL-10(-/-) neutrophils into septic mice reduced monocyte expression of TNF. In vitro experiments confirmed that monocyte suppression was mediated by neutrophil-derived IL-10. Thus, during septic peritonitis, neutrophils suppress peritoneal inflammatory monocytes through IL-10 and are dispensable for survival.
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http://dx.doi.org/10.1189/jlb.0810479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3040467PMC
March 2011

Conventional DCs reduce liver ischemia/reperfusion injury in mice via IL-10 secretion.

J Clin Invest 2010 Feb 19;120(2):559-69. Epub 2010 Jan 19.

Hepatopancreatobiliary Service, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, New York 10065, USA.

TLRs are recognized as promoters of tissue damage, even in the absence of pathogens. TLR binding to damage-associated molecular patterns (DAMPs) released by injured host cells unleashes an inflammatory cascade that amplifies tissue destruction. However, whether TLRs possess the reciprocal ability to curtail the extent of sterile inflammation is uncertain. Here, we investigated this possibility in mice by studying the role of conventional DCs (cDCs) in liver ischemia/reperfusion (I/R) injury, a model of sterile inflammation. Targeted depletion of mouse cDCs increased liver injury after I/R, as assessed by serum alanine aminotransferase and histologic analysis. In vitro, we identified hepatocyte DNA as an endogenous ligand to TLR9 that promoted cDCs to secrete IL-10. In vivo, cDC production of IL-10 required TLR9 and reduced liver injury. In addition, we found that inflammatory monocytes recruited to the liver via chemokine receptor 2 were downstream targets of cDC IL-10. IL-10 from cDCs reduced production of TNF, IL-6, and ROS by inflammatory monocytes. Our results implicate inflammatory monocytes as mediators of liver I/R injury and reveal that cDCs respond to DAMPS during sterile inflammation, providing the host with protection from progressive tissue damage.
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http://dx.doi.org/10.1172/JCI40008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2810082PMC
February 2010