Uninvolved Nodes Research Articles

Histological scoring of immune and stromal features in breast and axillary lymph nodes is prognostic for distant metastasis in lymph node-positive breast cancers.

The prognostic importance of lymph node (LN) status and tumour‐infiltrating lymphocytes (TILs), is well established, particularly TILs in triple negative breast cancers (TNBCs). So far, few studies have interrogated changes in involved and uninvolved LNs and evaluated if their morphological patterns add valuable information for the prediction of disease progression in breast cancer. In a cohort of 309 patients enriched for TNBCs (170/309), we histologically characterised immune and stromal features in primary tumours and associated involved and uninvolved axillary LNs on routine haematoxylin and eosin stained sections. Of the 309 patients, 143 had LN‐positive disease. Twenty‐five histopathological features were assessed, including the degree of TIL presence, quantitative and qualitative assessment of germinal centres (GCs) and sinus histiocytosis. Multivariate and cross‐validated proportional hazard regression analyses were used to identify optimal covariate sets for prediction of distant metastasis‐free survival (DMFS). The degree of intratumoural and peritumoural immune infiltrate was associated with architectural changes in both uninvolved and involved LNs. By including clinicopathological characteristics as well as tumour and LN histopathological features in L2‐regularised proportional hazard models, the prediction of 5‐year DMFS was improved by 3–15% over the baseline in all cancers and in TNBCs. In LN‐positive cancers, the combination of Salgado's classification, lymphocytic lobulitis, size and number of GCs in the uninvolved LNs and location of GCs in the involved LNs carried significant prognostic information. From these features, a multivariate cross‐validation‐stable risk signature was constructed, which identified low‐risk groups within both LN‐positive breast cancers and the LN‐positive TNBCs group with a 10‐year DMFS probability of 78 and 87%, respectively. This study illustrates that, by incorporating histopathological patterns of involved and uninvolved LNs combined with primary tumour immune and stromal features, the prediction of developing distant metastasis in LN‐positive breast cancers can be estimated more accurately.

Clinical Outcomes of Conventional Low Anterior Neck Field and Intensity Modulated Radiation Therapy in Oropharyngeal Cancer Patients

Radiotherapy (RT) to the uninvolved low neck can be delivered either by whole-neck intensity-modulated radiotherapy (WN-IMRT), or by matching a photon low anterior neck (LAN) field to the IMRT field. Potential benefits of the latter approach are the ability to deliver lower radiation dose to midline structures and improved dose distribution in the superior neck. However, the uncertainty of dose delivery at the match line and inadequate cover to the posterior low neck with this technique, has raised concern regarding the possibility of neck recurrences. Dosimetric studies comparing WN-IMRT with IMRT+LAN field have been published but clinical data on safety of the LAN field technique is lacking. The purpose of this study is to report outcomes following elective radiation to the lower neck using IMRT+LAN field in patients with squamous cell carcinoma (SCC) of the oropharynx (OP) and to evaluate recurrence risk at or below the match line with this technique. This is a single-centre retrospective study of OP SCC patients treated with bilateral neck IMRT between April 2005 and November 2014. p16 immunohistochemistry was performed prospectively after 2010. Our policy suggests using a LAN field in all cases with uninvolved low neck nodes (low level 3 and levels 4a/b, 5a-c) with the matching line placed at least 2cm below the inferior end of GTV. The LAN field delivers 45.5Gy in 21 fractions over 4.5 weeks). The half-beam IMRT fields encompass the high risk CTV (macroscopic disease with an isotropic margin of 10mm and involved nodal levels) treated to 65Gy in 30 fractions over 6 weeks, and the low-risk CTV (upper neck uninvolved nodes) treated to 54Gy in 30 fractions over 6 weeks. Out of 221 OP cancer patients treated with curative RT, 148 (67%) were treated with IMRT+LAN field. Median follow up was 41 months. Median age was 58 years (range, 26-86). 36 (24%) had T1, 59 (40%) T2, 21 (14%) T3 and 32 (22%) T4 disease. 20 (14%) had N0, 19 (13%) N1, 16 (11%) N2a, 73 (49%) N2b and 20 (14%) N2c disease. Of the 81 patients for whom p16 immunohistochemistry was available, 64 (79%) were p16 positive and 17 (21%) p16 negative. 109 (74%) of patients received induction chemotherapy with cisplatin and 5-fluorouracil, 128 (87%) received concomitant chemotherapy (cisplatin 29, carboplatin 98, cetuximab 1). After a median follow up of 41 months, the 3-year recurrence-free survival (RFS), regional recurrence-free survival (RRFS) and overall survival (OS) were 81.4%, 92.6% and 88.9%. The 5-year RFS, RRFS and OS were 77.6%, 86.2% and 91.2% respectively. No recurrences were seen in the LAN field and no recurrences were seen in the match line between the IMRT fields and the matched LAN field. RT to uninvolved lower neck nodal levels in selected OP SCC patients using a LAN field leads to excellent outcomes with no recurrences seen at the field match line or the low neck.

Efficacy of Escalating the Dose to 54 Gy on Accelerated Hyperfractionated Thoracic Radiation Therapy for Limited-stage Small-cell Lung Cancer: The 6-year Outcomes at a Single Institution

The combination of accelerated hyperfractionated thoracic radiotherapy (AHF-TRT) and chemotherapy has been established as the current standard therapy for limited-stage small-cell lung cancer (LS-SCLC). Although 45 Gy in 30 fractions is commonly used for dose-fractionation, the optimal dose of AHF-RT remains unknown. In this study, we evaluated the efficacy on AHF-TRT of escalating the dose to 54 Gy. Between 2006 and 2012, 19 patients diagnosed with LS-SCLC and treated with AHF-TRT and chemotherapy were enrolled in this study. The chemotherapy regimens were cisplatin and etoposide (PE) or carboplatin and etoposide (CE). Nine patients treated between 2006 and 2010 were irradiated with 45 Gy in 30 fractions for 3 weeks. Ten patients treated between 2011 and 2012 were irradiated with 54 Gy in 36 fractions for 3 and a half weeks. AHF-RT was given in 2 phases: patients initially received 36 Gy to the gross tumor plus uninvolved mediastinal nodes, followed by a boost to the gross tumor of 9 or 18 Gy. All patients were treated with three-dimensional conformal radiation therapy with multiple fields to reduce the volume of the surrounding normal tissues, such as the esophagus, from receiving a high dose, as much as possible. Variables related to the survival were estimated by the Kaplan-Meier method, and the log rank test was used to evaluate the significance of the survival, using a p value of 0.05 to indicate significance. The CTCAE ver. 3.0 was used to grade toxicities. The median follow-up of the 45 and 54 Gy groups was 23.6 months (range: 6.3-93.7 months) and 46.1 months (range: 8.1-67.7 months), respectively. No significant differences between the two groups regarding the patient and tumor characteristics were noted. The median duration of AHF-TRT was 22 days (range: 19-27 days) in the 45 Gy group and 29 days (range: 23-30 days) in the 54 Gy group. Prophylactic cranial irradiation was administered to 4 patients (44%) in the 45 Gy group and 8 (80%) in the 54 Gy group. The median survival time (MST) was 23.6 months in the 45 Gy group and 41.5 months in the 54 Gy group. A comparison between the 45 and 54 Gy groups at 4 years showed that the overall survival rate was 22.2% vs. 50.0% (p = 0.1559), the progression-free survival (PFS) was 0% vs. 40.0% (p = 0.0191), the in-field progression-free survival (IFPFS) was 11.1% vs. 40.0% (p = 0.0318) and the distant metastasis-free survival (DMFS) was 0% vs. 50.0% (p = 0.0293), respectively. No Grade 3+ non-hematological adverse effects, such as acute esophagitis, pneumonitis or lung fibrosis, were encountered in either group. AHF-TRT at 54 Gy with concurrent PE or CE regimens significantly improved the PFS, IFPFS and DMFS without increasing the toxicity compared with 45 Gy. Although more patients with longer follow-up periods are needed to fully evaluate the usefulness and safety of this 9 Gy dose escalation, these outcomes suggest that increasing the dose to 54 Gy in AHF-TRT for LS-SCLC may be a promising modality for improving the treatment results.

A Phase 2 Dose and Volume De-escalation Trial for High- and Low-Risk HPV+ Oropharynx Cancer: Efficacy, Toxicity, and Dosimetric Analyses

In this prospective phase II de-escalation study, we used induction chemotherapy to identify favorable HPV+ oropharyngeal cancer (OPC) pts, including those with high-risk tumors, and applied significantly lower radiation or chemoradiation doses than previously reported. Pts with HPV+ OPC were classified as low-risk (≤T3, ≤N2B, ≤10 PYH) or high-risk (T4 or ≥N2C or >10 PYH). Pts received 3 cycles of carboplatin (AUC 6, D1) and nab-paclitaxel (100 mg/m2, D1/8/15). 1) Low-risk pts with ≥50% response received low-dose radiotherapy alone to 50 Gy (RT50). 2) Low-risk pts with 30-50% response OR high-risk pts with ≥50% response received low-dose chemoradiotherapy to 45 Gy (CRT45). 3) All other ( = poor response) pts received regular-dose chemoradiotherapy to 75 Gy (CRT75). All pts also received de-escalated RT volumes limited to the first echelon of uninvolved nodes. RT50 was delivered in 2 Gy/fx once daily. CRT arms consisted of paclitaxel, 5-FU, hydroxyurea, and 1.5 Gy twice daily RT every other week. Primary site biopsy and neck dissection were performed only after de-escalated treatment (RT50, CRT45) for pathologic confirmation. The primary endpoint was 2-year PFS. Secondary endpoints included pathologic complete response (pCR) rate and toxicity. Sixty-two pts were enrolled. Twenty-eight pts (45.2%) were low-risk and 34 pts (54.8%) were high-risk. A total of 71.4% of low-risk pts received RT50 and 21.4% received CRT45. 70.6% of high-risk pts received CRT45. The pCR rate was 94.4% after RT50 and 92.3% after CRT45. Median follow-up is 1 year. The 2-year PFS and OS were both 100% for low-risk pts, and 91.6% and 97.0% for high-risk pts. Mean dose to all OARs was significantly reduced as shown in the table below. Significant decrease in the rates of grade ≥3 mucositis (15.8% RT50, 46.4% CRT45, 60.0% CRT75, P = .033) and grade ≥3 dermatitis (0% RT50, 21.4% CRT45, 30.0% CRT75, P = .056) were observed. PEG-tube dependency was improved at 3 months (0% RT50, 14.8% CRT45, 70.0% CRT75, P<.001) and 6 months (0% RT50, 3.7% CRT45, 20.0% CRT75, P = .066) post-treatment. Favorable response to induction chemotherapy appears to be a powerful biomarker for dose and volume de-escalation with 50 Gy RT or 45 Gy CRT. Outstanding survival and high pCR rates suggest that completion neck dissection may not be necessary. Benefits in OAR sparing translated to significantly improved toxicity and functional outcomes.Abstract 290; Table 1OAR ─ Mean Dose (Gy)RT50CRT45CRT75ANOVA P-valueIpsilateral Parotid29.927.341.7<.001Contralateral Parotid14.715.624.3.001Ipsilateral Submandibular51.446.077.1<.001Contralateral Submandibular40.937.961.6<.001Pharyngeal Constrictor45.038.062.4<.001Larynx40.534.754.2<.001Oral Cavity26.424.543.9<.001 Open table in a new tab

Quantitative Shotgun Proteomics Unveils Candidate Novel Esophageal Adenocarcinoma (EAC)-specific Proteins

Esophageal cancer is the eighth most common cancer worldwide and the majority of patients have systemic disease at presentation. Esophageal adenocarcinoma (OAC), the predominant subtype in western countries, is largely resistant to current chemotherapy regimens. Selective markers are needed to enhance clinical staging and to allow targeted therapies yet there are minimal proteomic data on this cancer type. After histological review, lysates from OAC and matched normal esophageal and gastric samples from seven patients were subjected to LC MS/MS after tandem mass tag labeling and OFFGEL fractionation. Patient matched samples of OAC, normal esophagus, normal stomach, lymph node metastases and uninvolved lymph nodes were used from an additional 115 patients for verification of expression by immunohistochemistry (IHC).Over six thousand proteins were identified and quantified across samples. Quantitative reproducibility was excellent between technical replicates and a moderate correlation was seen across samples with the same histology. The quantitative accuracy was verified across the dynamic range for seven proteins by immunohistochemistry (IHC) on the originating tissues. Multiple novel tumor-specific candidates are proposed and EPCAM was verified by IHC.This shotgun proteomic study of OAC used a comparative quantitative approach to reveal proteins highly expressed in specific tissue types. Novel tumor-specific proteins are proposed and EPCAM was demonstrated to be specifically overexpressed in primary tumors and lymph node metastases compared with surrounding normal tissues. This candidate and others proposed in this study could be developed as tumor-specific targets for novel clinical staging and therapeutic approaches.

Optima: A phase II dose and volume de-escalation trial for high- and low-risk HPV+ oropharynx cancers.

6066 Background: In this prospective phase II de-escalation study, we used induction chemotherapy to identify favorable HPV+ oropharyngeal cancer (OPC) pts, including those with high-risk tumors, and applied significantly lower radiation or chemoradiation doses than previously reported. Methods: Pts with HPV+ OPC were classified as low-risk (≤T3, ≤N2B, ≤10 PYH) or high-risk (T4 or ≥N2C or &gt; 10 PYH). Pts received 3 cycles of carboplatin (AUC 6, D1) and nab-paclitaxel (100 mg/m2, D1/8/15). 1) Low-risk pts with ≥50% response received low-dose radiotherapy alone to 50Gy (RT50). 2) Low-risk pts with 30-50% response OR high-risk pts with ≥50% response received low-dose chemoradiotherapy to 45Gy (CRT45). 3) All other ( = poor response) pts received regular-dose CRT (CRT75). All pts also received de-escalated RT volumes limited to the first echelon of uninvolved nodes. CRT consisted of paclitaxel, 5-FU, hydroxyurea, and 1.5Gy twice daily RT every other week. Primary site biopsy and neck dissection were performed only after de-escalated treatment (RT50, CRT45) for pathologic confirmation. The primary endpoint was 2-year PFS. Secondary endpoints included pathologic complete response (pCR) rate and toxicity. Results: 62 pts were enrolled. 28 pts (45.2%) were low-risk and 34 pts (54.8%) were high-risk. 71.4% of low-risk pts received RT50 and 21.4% received CRT45. 70.6% of high-risk pts received CRT45. The pCR rate was 94.4% after RT50 and 92.3% after CRT45. Median follow-up is 1 year. The 2-year PFS and OS were both 100% for low-risk pts, and 91.6% and 97.0% for high-risk pts. Significant decrease in the rates of grade ≥3 mucositis (15.8% RT50, 46.4% CRT45, 60.0% CRT75, p = .033) and grade ≥3 dermatitis (0% RT50, 21.4% CRT45, 30.0% CRT75, p = .056) were observed. PEG-tube dependency was improved at 3 months (0% RT50, 14.8% CRT45, 70.0% CRT75, p &lt; .001) and 6 months (0% RT50, 3.7% CRT45, 20.0% CRT75, p = .066) post-treatment. Conclusions: Favorable response to induction chemotherapy appears to be a powerful biomarker for dose and volume de-escalation with 50Gy RT or 45Gy CRT. Outstanding survival and high pCR rates suggest that completion neck dissection may not be necessary. Toxicity and functional outcomes are significantly improved. Clinical trial information: NCT02258659.

Uniform FDG-PET guided GRAdient Dose prEscription to reduce late Radiation Toxicity (UPGRADE-RT): study protocol for a randomized clinical trial with dose reduction to the elective neck in head and neck squamous cell carcinoma

BackgroundIn definitive radiation therapy for head and neck cancer, clinically uninvolved cervical lymph nodes are irradiated with a so-called ‘elective dose’ in order to achieve control of clinically occult metastases. As a consequence of high-resolution diagnostic imaging, occult tumor volume has significantly decreased in the last decades. Since the elective dose is dependent on occult tumor volume, the currently used elective dose may be higher than necessary.Because bilateral irradiation of the neck contributes to dysphagia, xerostomia and hypothyroidism in a dose dependent way, dose de-escalation to these regions can open a window of opportunity to reduce toxicity and improve quality of life after treatment.MethodsUPGRADE-RT is a multicenter, phase III, single-blinded, randomized controlled trial.Patients to be treated with definitive radiation therapy for a newly diagnosed stage T2-4 N0-2 M0 squamous cell carcinoma of the oropharynx, hypopharynx or larynx are eligible. Exclusion criteria are recurrent disease, oncologic surgery to the head and neck area, concomitant chemotherapy or epidermal growth factor receptor inhibitors.In total, 300 patients will be randomized in a 2:1 ratio to a treatment arm with or without de-escalation of the elective radiation dose and introduction of an intermediate dose-level for selected lymph nodes. Radiation therapy planning FDG-PET/CT-scans will be acquired to guide risk assessment of borderline-sized cervical nodes that can be treated with the intermediate dose level.Treatment will be given with intensity-modulated radiation therapy or volumetric arc therapy with simultaneous-integrated boost using an accelerated fractionation schedule, 33 fractions in 5 weeks. The primary endpoint is ‘normalcy of diet’ at 1 year after treatment (toxicity). The secondary endpoint is the actuarial rate of recurrence in electively irradiated lymph nodes at 2 years after treatment (safety).DiscussionThe objective of the UPGRADE-RT trial is to investigate whether de-escalation of elective radiation dose and the introduction of an intermediate dose-level for borderline sized lymph nodes in the treatment of head and neck cancer will result in less radiation sequelae and improved quality of life after treatment without compromising the recurrence rate in the electively treated neck.Trial registrationClinicalTrials.gov Identifier: NCT02442375.

Lymph node dissection for melanoma: where do we stand?

The extent and timing of regional lymphadenectomy and its role in patients with clinically localized primary melanoma has been the subject of considerable debate. While therapeutic lymphadenectomy for clinically positive nodes is uniformly accepted, the benefit of regional lymphadenectomy in patients with clinically uninvolved lymph nodes potentially harboring micrometastatic disease is less clear. Efforts to better select patients for complete regional lymphadenectomy after sentinel lymph node biopsy are underway. The future holds the promise of more stringent selection criteria and perhaps the identification of subgroups of patients for which a therapeutic benefit may be realized. Moreover, novel sensitive radiological techniques for detecting in vivo micrometastatic nodal disease may improve surgical precision, further decreasing potential morbidities of lymphadenectomy.

The Impact of Pathologically Positive Lymph Nodes in the Clinically Negative Neck: An Analysis of 39,301 Patients with Papillary Thyroid Cancer.

Management of patients with low-risk papillary thyroid cancer (PTC) with clinically uninvolved lymph nodes (cN0 LNs), but who harbor metastatic central LNs (pN1a), remains unclear. The number of central LNs examined, radioactive iodine (RAI) utilization, and survival were compared across cN0 patients based on pN stage: pN0 (negative) versus pNx (unknown) versus pN1a (pathologically positive). Adults with a PTC≥1cm who were cN0 preoperatively were compared based on surgical pathology using the National Cancer Data Base (NCDB; 2003-2011), after univariate and multivariate adjustment. Overall survival (OS) was examined using Kaplan-Meier curves, the log-rank test, and Cox proportional hazards modeling. Overall, 39,301 patients were included; median tumor size was 1.9cm. More LNs were examined for pN1a versus pN0 diagnosis (pN1a median=5 LNs vs. pN0 median=2 LNs; p<0.0001), with a median of two central LNs found to be positive on surgical resection. Compared with pN0, pN1a patients were 78% more likely to receive RAI (odds ratio 1.78, 95% confidence interval [CI] 1.65-1.91; p<0.0001). After adjusting for receipt of RAI, no difference in OS was observed for pN1a versus pN0 or pNx patients (p=0.72). Treatment with RAI was associated with improved OS (hazard ratio 0.78, 95% CI 0.62-0.98, p=0.03), but the effect of RAI did not differ based on pN stage (interaction p=0.67). More LNs were examined for positive versus negative pN diagnosis in patients with cN0 PTC. Unsuspected central neck nodal metastases in cN0 PTC patients are associated with increased RAI utilization, but no survival difference.

What Is a False Negative Sentinel Node Biopsy: Definition, Reasons and Ways to Minimize It?

Sentinel node biopsy helps in assessing the involvement of axillary lymph node without the morbidity of full axillary lymph node dissection, namely arm and shoulder pain, paraesthesia and lymphoedema. The various methods described in the literature identify the sentinel lymph nodes in approximately 96% of cases and associated with a false negativity rate of 5 to 10%. A false negative sentinel node is defined as the proportion of cases in whom sentinel node biopsy is reported as negative, but the rest of axillary lymph node(s) harbours cancer cells. The possible causes of a false negative sentinel lymph node may be because of blocked lymphatics either by cancer cells or following fibrosis of previous surgery/radiotherapy, and an alternative pathway opens draining the blue dye or isotope to another uninvolved node. The other reasons may be two lymphatic pathways for a tumour area, the one opening to a superficial node and the other in deep nodes. Sometimes, lymphatics do not relay into a node but traverse it going to a higher node. In some patients, the microscopic focus of metastasis inside a lymph node is so small-micrometastasis (i.e. between 0.2 and 2mm) or isolated tumour cells (i.e. less than 0.2mm) that is missed by the pathologist. The purpose of this review is to clear some fears lurking in the mind of most surgeons about the false negative sentinel lymph node (FNSLN).

Abstract 2032: Germline genetic variants in GATA3 and breast cancer treatment outcomes in SWOG 8897 trial

Abstract Purpose: GATA3 is involved in estrogen signaling and mammary cell differentiation, and is frequently mutated in breast cancer. Germline variations of GATA3 are prognostic in childhood acute lymphoblastic leukemia (ALL). Thus, we sought to examine their prognostic and predictive role in breast cancer. Methods: SWOG S8897 comprised two groups of breast cancer patients. In the first high-risk group, women were randomly assigned to CAF vs. CMF, and secondarily randomized to tamoxifen or not. In the second low risk group, women did not receive any adjuvant therapy after surgery. Germline DNA was extracted from uninvolved axillary lymph nodes and 12 candidate GATA3 SNPs were genotyped. Associations of genotypes with treatment outcomes were evaluated in 441 women in the treated and 799 in the untreated groups separately. Hazard ratio (HR) for disease free (DFS) and overall survival (OS) for each SNP was estimated using multivariate Cox hazard regression. Further stratified analyses by tamoxifen were performed in the treated group. Results: After correcting for multiple testing, we identified significant associations of two variants (rs3802604 and rs568727) with DFS and OS for patients who received adjuvant chemotherapy. Women carrying the variant GG genotype at rs3802604 had significantly poorer DFS (HR = 1.95, 95% CI: 1.27-2.99, p = 0.002) and OS (HR = 2.45, 95% CI: 1.48-4.05, p = 0.0005), compared to women carrying the common AA genotype. Associations of similar magnitude were found for rs568727. In contrast, no association with either SNP was found in the untreated group. Subgroup analysis suggested that these two SNPs more strongly influenced treatment outcomes in the patients who also received tamoxifen. Seven additional variants were also associated with OS and DFS in the tamoxifen treated group. Only 3 of the 12 SNPs analyzed in GATA3 were not associated with survival in this subgroup; however, these three SNPs (rs3781093, rs3824662, and rs3802600) associated with OS in the group not treated with tamoxifen. Functional annotation revealed that several GATA3 SNPs, e.g., rs3802604, rs369421, and rs3824662, are likely to function by affecting transcription factor binding and/or altering regulatory chromatin states at this locus. Conclusions: GATA3 harbors common germline genetic variants that are related to survival following adjuvant chemotherapy and endocrine therapy in breast cancer patients. Citation Format: Victoria L. Larsen, William E. Barlow, Jun J. Yang, Qianqian Zhu, Laura F. Hutchins, Susan A. Kadlubar, Kathy S. Albain, Robert B. Livingston, James M. Rae, I-Tien Yeh, Peter M. Ravdin, Silvana Martino, Alan P. Lyss, C. Kent Osborne, Gabriel N. Hortobagyi, Daniel F. Hayes, Christine B. Ambrosone, Song Yao. Germline genetic variants in GATA3 and breast cancer treatment outcomes in SWOG 8897 trial. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2032.

Details of out-field regional recurrence after involved-field irradiation with concurrent chemotherapy for locally advanced esophageal squamous cell carcinoma.

BackgroundThe purpose of this study was to describe the patterns of out-field regional recurrence after involved-field irradiation (IFI) in definitive concurrent chemoradiotherapy (CCRT) for locally advanced esophageal squamous cell carcinoma (LA-ESCC) and identify the possible risk factors.Patients and methodsEighty patients with LA-ESCC who received CCRT with IFI between January 2003 and January 2009 at the Shandong Cancer Hospital were recruited and analyzed. Imaging scans demonstrating first sites of failure were compared with original computed tomography-based radiation treatment plans, and failure patterns were defined as in-field, outfield regional (failures in initially uninvolved regional nodes), and distant failures.ResultsAfter a median follow-up time of 52.6 months, 24 patients had evidence of out-field regional failure, 43 patients had evidence of in-field failure, and 33 patients had the evidence of distant failure. Multivariate analysis revealed that out-field regional failure was associated with clinical tumor status (T4 vs T1–3, odds ratio [OR] =6.547, P=0.002), tumor length (>8 cm vs ≤8 cm, OR =4.130, P=0.036), response to CCRT (complete response vs no complete response, OR =2.646, P=0.035), and in-field failure (no in-field failure vs in-field failure, OR =1.32, P=0.016). Survival analyses indicated that, compared to in-field failure or distant failure alone group, out-field regional failure alone group tended to have longer overall (P=0.006) and progression-free survival (P=0.164).ConclusionOur data suggested that the predominant failure pattern after IFI was not out-field regional failure, which also did not influence survival significantly, and that out-field regional failure did not shorten the time to disease recurrence, which also did not influence survival significantly. In addition, out-field regional failure was likely to appear later than in-field and distant failures. The relatively advanced local disease followed by poor local control and distant metastases contributed more to the poor outcome of LA-ESCC. Further prospective studies are needed to verify the findings of this study.

Breast Carcinoma–associated Fibroblasts Share Similar Biomarker Profiles in Matched Lymph Node Metastasis

This study sought to understand the role of breast carcinoma-associated fibroblasts in the progression of cancer cells into lymph nodes. We compared fibroblasts of primary tumors and matched the involved lymph nodes to select fibroblast activation markers, namely α-smooth muscle actin (α-SMA), S100A4, and vimentin, as well as to determine the frequency of transforming growth factor β1, a pleiotropic cytokine that induces the differentiation of fibroblasts to myofibroblasts, and its downstream effectors: CXCR4 and p-AKT. We disposed samples of 80 primary invasive ductal carcinomas and matched the involved lymph nodes from 43 cases into 3 tissue microarrays, and analyzed stromal and tumor epithelial cells separately by immunohistochemistry. Control uninvolved lymph nodes were analyzed by whole-tissue sections. Cancer-associated fibroblast in lymph nodes with macrometastasis expressed similar profiles of vimentin, α-SMA, and S100A4 as those found in primary tumors. Cancer-associated fibroblast were uniformly estrogen receptor, progesterone receptor, HER-2, Ki-67, and p53 negative, but expressions of transforming growth factor β1 (TGFβ1), CXCR4, and p-AKT staining (62.3%, 52.4%, 65%, respectively) were equivalent between primary and lymph node metastasis (LNM) fibroblasts. A significant coexpression of TGFβ1 with p-AKT and CXCR4 in LNMs suggested the involvement of these proteins with TGFβ1 signaling. These biomarkers, including α-SMA and S100A4, were negative in fibroblasts of cancer-free lymph nodes, with the exception of vimentin. Our finding that expressions of biological markers were similar in fibroblasts of the primary tumors and in matched LNMs, but were absent in cancer-free lymph nodes, supports the assumption that the lymph node stroma mimics the microenvironment observed in primary tumors.

Involved-field radiotherapy for esophageal squamous cell carcinoma: theory and practice.

Esophageal carcinoma (EC) is characterized by a high rate of lymph node metastasis and its spread pattern is not always predictable. Chemoradiotherapy has an important role in the treatment of EC in both the inoperable and the pre-operative settings. However, regarding the target volume for radiation, different clinical practices exist. Theoretically, in addition to the clinical target volume administered to the gross lesion, it might seem logical to deliver a certain dose to the uninvolved regional lymph node area at risk for microscopic disease. However, in practice, it is difficult because of the intolerance of normal tissue to radiotherapy (RT), particularly if all regions containing the cervical, mediastinal, and upper abdominal nodes are covered. To date, the use of elective nodal irradiation (ENI) is still controversial in the field of radiotherapy. Some investigators use involved-field radiotherapy (IFRT) in order to reduce treatment-related toxicities. It is thought that micrometastases can be controlled, to some extent, by chemotherapy and the abscopal effects of radiation. It is the presence of overtly involved lymph nodes rather than the micrometastatic nodes negatively affects survival in patients with EC. In another hand, lymph nodes stationed near primary tumors also receive considerable incidental irradiation doses that may contribute to the elimination of subclinical lesions. These data indicate that an irradiation volume covering only the gross tumor is appropriate. When using ENI or IFRT, very few patients experience solitary regional node failure and out-of-field lymph node failure is not common. Primary tumor recurrence and distant metastases, rather than regional lymph node failure, affect the overall survival in patients with EC. The available evidence indicates that the use of ENI seems to prevent or delay regional nodal relapse rather than improve survival. In a word, these data suggest that IFRT is feasible in EC patients.

Management of locally advanced HPV-related oropharyngeal squamous cell carcinoma: where are we?

HPV-related (HPV+) oropharyngeal cancer (OPC) has a better prognosis compared to HPV unrelated (HPV-) OPC. This review summarizes and discusses several of the controversies regarding the management of HPV+ OPC, including the mechanism of its treatment sensitivity, modern surgical techniques, chemotherapy regimens, and treatment de-intensification protocols. We also discuss and reconsider potential adverse prognostic factors such as tumor EGFR expression, tumor hypoxia, and patient smoking history, as well as the significance of retropharyngeal adenopathy. Finally, we discuss elective nodal treatment of uninvolved lymph node stations. While this review does not exhaust all controversies related to the management of HPV+ OPC, it aims to highlight some of the most clinically relevant ones.

Risk Factors for Central Compartment Lymph Node Metastasis in Papillary Thyroid Microcarcinoma: A Meta-Analysis.

The surgical management of papillary thyroid microcarcinoma (PTMC), especially regarding the necessity of central lymph node dissection (CLND), remains controversial. This meta-analysis was conducted to investigate the clinicopathologic factors predictive of central compartment lymph node metastasis (CLNM) in patients diagnosed with PTMC. PubMed, EMBASE, Ovid, Web of Science, and the Cochrane Library were searched from their inception to September 2013. Published studies that explored the association between clinicopathologic factors and CLNM in PTMC patients were included. From the identified studies, we extracted the number of individuals with or without each risk factor to calculate the CLNM-positive proportions and used fixed/random-effects models for the meta-analyses of overall relative risk (RR). The pooling analysis on the association between CLNM or the different CLNDs and prognosis was also conducted. A total of 19 eligible studies that included 8345 patients were identified. Three studies did therapeutic CLND, while the other 16 studies performed prophylactic CLND in PTMC patients. Meta-analyses revealed that CLNM was associated with male gender (RR = 1.36; 95 % CI 1.22-1.52, p = 0.001), younger age (<45 years; RR = 1.15; 95 % CI 1.04-1.27, p = 0.006), larger tumor size (>5 mm; RR = 1.51 95 % CI 1.32-1.65, p = 0.001), multifocality (RR = 1.40; 95 % CI 1.27-1.54, p = 0.001), and extrathyroidal extension (RR = 1.81; 95 % CI 1.34-2.43, p = 0.001). Meta-regression analysis indicated that a disparity in the proportion of PTMC patients with CLNM in each study was the main factor resulting in heterogeneity among the 19 studies. In addition, the pooling analyses suggested that CLNM did not significantly predict neck recurrences [hazard ratio (HR) = 0.95, 95 % CI 0.67-1.22, p = 0.054], and the prophylactic CLND group did not improve local control significantly compared to the therapeutic group (RR = 0.96, 95 % CI 0.46-2.01, p = 0.544). Prophylactic CLND may be performed in PTMC patients with clinically uninvolved central lymph nodes but with high risk factors; multicenter studies with long-term follow-up are recommended to better understand the risk factors and surgical management for central nodes in PTMC.

Fluorescence imaging after intraoperative intravenous injection of indocyanine green for detection of lymph node metastases in colorectal cancer

PurposeThis short communication aims at reporting the potential role of ICG fluorescence imaging after an intraoperative IV injection in the detection of lymph nodes (LNs) of a colorectal cancer origin. Patients and methodsTwo patients who were included in a protocol study evaluating the role of ICG in the detection of peritoneal metastases of colorectal origin (Protocol NCT-01995591) also had fluorescent LNs at exploration with a dedicated near-infrared camera system (Photodynamic Eye, PDE; Hamamatsu Photonics, Hamamatsu, Japan). An IV injection of ICG was delivered intraoperatively at 0.25 mg/kg. All LNs were also explored for their fluorescence, and tumor to background ratio (TBR) was calculated with IC-Calc 2.0 program. ResultsOne patient had two retroperitoneal lymph node metastases and one mesocolic on a pre-operative work-up. The three tumoural lymph nodes at histopathology were hyperfluorescent in comparison to other uninvolved LNs. One patient had no pre-operatively known LN metastases and had one epigastric hyperfluorescent LN discovered at intraoperative exploration. This LN of 6 mm in size was malignant at histopathology. ConclusionThis is the first report about tumoural LN of colorectal cancer origin detected by fluorescence imaging with intraoperative IV free-ICG injection. ICG fluorescence imaging by intraoperative IV injection represents an easy method for detecting metastatic LNs in colorectal cancer. This proof of concept should lead to further research in this field.

Incidental radiation to uninvolved internal mammary lymph nodes in breast cancer.

Routine treatment of clinically uninvolved internal mammary nodes in breast cancer patients requiring post-mastectomy radiation therapy is controversial. The purpose of this study was to measure the incidental radiation dose to the internal mammary lymph nodes not included in the planning target volume (PTV) in women with breast cancer receiving post-mastectomy radiation therapy. This retrospective protocol utilized CT-based 3D conformal treatment plans. Fifty consecutive patients were included in the analysis: 25 left breast and 25 right breast patients. 3D conformal treatment plans chest wall tangent fields and matched supraclavicular were used. All plans were prescribed to a total dose of 50 Gy in 25 fractions to the chest wall and 46 Gy in 23 fractions to the supraclavicular field. The internal mammary node chain was intentionally not included in the target volume. For purposes of this study, internal mammary vessels were contoured following the Radiation Therapy Oncologist Group atlas with a 7-mm PTV expansion, utilizing original CT simulation images. The internal mammary nodes were contoured in between the first 3 and first 5 intercostal spaces for comparison. Percent volume of internal mammary node PTV receiving 95 % of the prescribed dose (47.5 Gy) with 7-mm expansion and first 5 intercostal spaces for all patients was 25.2 % (range 0.04-97.6 %, standard deviation (SD) 23.5). The mean internal mammary node dose for all patients was 24.98 Gy (range 3.54-55.93 Gy, SD 16). Results of this study suggest the incidental dose to the internal mammary nodes does not achieve clinically significant therapeutic levels in post-mastectomy breast cancer patients treated with standard 3D conformal radiation therapy chest wall irradiation. If risk factors for microscopic involvement are present, internal mammary nodes must be specifically included in target volumes in order to be adequately treated.

Abstract P4-04-24: Metastatic lymph node fibroblasts maintain similar profile of stromal biomarkers registered in primary breast carcinomas

Abstract Background: Lymph node metastasis is the predominant dissemination route of breast carcinoma (BC) and remains as an important prognostic indicator of this disease. Several studies demonstrated a similar gene profiling or gene/biological markers assessed by immunohistochemistry in neoplastic epithelial cells at both sites. Recent evidence pointed that cancer associated fibroblasts (CAFs) play a critical role in breast cancer progression and migration. The evidence of CAFs in close association to epithelial tumor cells within lymph node metastasis raised the possibility of a common source of CAFs in these two lesions. However, little is known about the differentially expressed genes or proteins between fibroblasts of the primary tumor and its nodal metastasis. The contribution of CAFs in lymph node colonization is still unknown. Objective: Our aim was to compare the profile of biomarkers between fibroblasts in lymph nodes and those found in the primaries. We compared differences in frequency of activated CAFs through the expression of α-SMA and S100A4 in 43 matched pairs of invasive breast carcinomas and respective macro-metastatic lymph nodes arrayed in TMAs. We also investigated a panel of immunohistochemical biomarkers associated to TGFβ1 (that induces α-SMA and myofibroblast differentiation in CAFs) including CXCR4, pAKT, pm-TOR and c-myc. In addition the frequency of all these markers were assessed in samples of matched disease free lymph nodes obtained from the same patients (which contain fibroblastic reticular cells, limited to the exterior capsule). Results: CAFs characterization confirmed the positive expression of α-SMA (approximately 50%) and S100A4 (100%) on fibroblasts of both sites in contrast to uninvolved lymph nodes, which were uniformly negative. As expected, CAFs were ER, PR, Her-2, CD9 and p53 negative at both sites. As KI67 labeling rate was always lower than 10% in fibroblasts they were considered negative. Comparison between fibroblasts from the stromal component of the primaries and respective lymph nodes indicated that the frequency of TGFβ1, CXCR4 and pAKT positivity was similar whereas a significant lower rate of c-myc and pm-TOR frequency was observed in the metastatic lymph nodal fibroblasts. All biological markers were negative in normal lymph nodes highlighting their association with activated fibroblasts. None of the markers showed association with presence/absence of lymph node metastasis or with other clinic-pathological parameters. Primary carcinomas lacked any potential associations among the evaluated biological markers in fibroblast cells, however, in the stromal tissue of lymph nodes, significant relationships between TGFβ1 and CXCR4, pAKT and c-myc, were observed. Conclusion: Our results indicated the presence of activated fibroblasts expressing α-SMA and S100A4 in fibroblasts of breast cancer primaries as well in their matched metastatic lymph nodes. High concordance for the expression of the analyzed biomarkers in matched pairs of breast cancer primaries and metastatic lymph nodes suggested the maintenance of a similar supportive microenvironment in metastatic sites. Financial Support: FAPESP and CNPq. Citation Format: Fiorita GL Mundim, Fatima S Pasini, Suely Nonogaki, Fernando A Soares, M Mitzi Brentani, Angela F Logullo. Metastatic lymph node fibroblasts maintain similar profile of stromal biomarkers registered in primary breast carcinomas [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-04-24.

Analysis of reticulin fiber pattern in lymph nodes with metastasis from oral squamous cell carcinoma

Introduction: The aim of the study was to determine the susceptibility of lymph nodes to metastasis in oral squamous cell carcinoma (OSCC) by analyzing the alterations in reticulin fiber pattern. Materials and Methods: This retrospective study on 30 cases of OSCC had 15 cases that presented with lymph node metastasis (test group) and 15 cases without metastatic episodes (control group). Four micron thick sections of the tumor proper and the resected lymph nodes of the cases were stained with hematoxylin and eosin, and Gordon and Sweet’s stain for reticulin. Statistical analysis of the variations in the staining patterns of reticulin at the invasive tumor front (ITF), involved and uninvolved lymph nodes were done with Statistical Package for Social Sciences (SPSS) 15 version using chi-square test. Results: The assessment of reticulin fiber patterns at the ITF, cortical and medullary areas of lymph nodes in test cases showed thin, long individual fibers, as compared to thick, shorter interlacing fibers that were seen in control cases. The peritumoral and uninvolved areas in metastatic lymph nodes of almost all test cases showed very scant fibers. Conclusion: Reticulin pattern alteration by aggressive tumors may be appreciated as a part of the wide spectrum of “proneoplastic” stromal alterations. The histopathologist can discern these changes and thereby aid the clinician in predicting tumor behavior, the clinical course of the disease, and weighing the prognostic implications.