Higher Rates Of Locoregional Recurrence Research Articles

Dynamic changes in the immune infiltrate within hepatocellular carcinoma tumor correlate with response to PD-1 blockade.

e15644 Background: Hepatocellular carcinoma (HCC) is the second leading cause of cancer deaths in men worldwide, and is the most rapidly rising cause of cancer mortality in the US. Patients with resectable disease experience high rates of locoregional recurrence, and there are few effective systemic treatment options available. PD-1 blockade was recently approved for 2nd line therapy, and there are promising response rates seen in the 1st-line setting. However, only 20% of patients achieve significant response, thus we must investigate further the tumor-immune microenvironment to understand how to better modulate the immune system in this highly immunosuppressive organ. Methods: We used mass cytometry (CyTOF) and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) to study protein and transcriptomics of untreated tumor and tumor adjacent tissue, on a single-cell level. Results: Paired CyTOF analysis of 10 tumor lesions/adjacent tissues identified a significant increase in frequency of CD4+ T cells and T regulatory cells, a significant decrease in NK cells and neutrophils, and no difference in CD8+ T cells, macrophages, or dendritic cells (DCs) in the tumor microenvironment compared to the adjacent liver tissue. We also analyzed four patients who received nivolumab and subsequently went on to have their liver tumors resected; two out of the four patients treated had near-complete necrosis of their tumors (radiographically and histologically). Of note, the tumors of the two patients with significant pathologic response contained a significantly higher number of CD103+ tissue resident CD8+ and CD4+ T cells, compared to adjacent tissue. Moreover, activated CD8+ T cells (TIGIT+, PD-1+, TIM3+, and/or CD38+) were significantly higher in the tumor of nivolumab responders, indicating a tumor-specific response. We will also present single cell transcriptomic analyses of T cell and myeloid populations in responders and non-responders. Interestingly, high levels of nivolumab were detected on PD-1+ T cells in the tumor in all 4 patients; we will discuss transcriptional differences between nivolumab-targeted T cells in responders and non-responder patients. Conclusions: Based on this preliminary data we will be opening a clinical trial of neoadjuvant PD-1 blockade in HCC (NCT# pending) in March 2019.

Does every classical type of well-differentiated thyroid cancer have excellent prognosis? A case series and literature review.

Introduction: The classical type of well-differentiated thyroid cancer (WDTC) is the most common endocrine tumor with generally excellent prognosis. WDTC of the WHO stage 1 classification metastasizing to the vertebral column is not often seen for this neoplasm. Here, I present a case series of 14 individuals with aggressive classical type of WDTC.Methods: To identify the most aggressive cases of classical type WDTC, I reviewed the medical records of 4,327 patients consecutively admitted and surgically treated in a single institution for thyroid pathology in the years 2008–2016. Demographic, pathological and outcome data were collected and reviewed.Results: During the study period, 14 (4.02%) patients with aggressive forms of the classical type of WDTC were reviewed: 10 (2.87%) cases with papillary thyroid cancer (PTC) and 4 (1.14%) with follicular thyroid cancer (FTC). The median age at diagnosis was 61 years (31–84 years). Aggressive features such as extrathyroid extension 11/14 (78.57%), positive surgical margins 11/14 (78,57%), lymph node metastases 7/14 (50%), multifocality 6/14 (42.85%), regional tissue infiltration 11/14 (78.57%) and distant metastases 4/14 (28.57%) were observed. Long-term follow-up (median 40 months) demonstrated a high rate of locoregional recurrence in 12/14 (85.71%) individuals. Pulmonary and other distant metastases were observed in 4/14 (28.57%) patients, with mortality in 3/14 (21.42%) individuals.Conclusion: In patients with classical type of WDTC characterized by excellent prognosis, extremely aggressive entities might be observed, making WDTC in some cases an unpredictable tumor.

Effect of younger age on survival outcomes in T1N0M0 breast cancer: A propensity score matching analysis.

We evaluated the effect of younger age on recurrence risk in Chinese women diagnosed with T1N0M0 breast cancer (BC), using propensity score matching (PSM) analysis. We included 365 women who were diagnosed with T1N0M0 BC between 2003 and 2016, and who received surgery at our center. They were classified as younger (≤40 years) and older (>40 years). We used PSM to balance clinicopathologic characteristics between the two age groups. Survival was analyzed by the Kaplan-Meier method, before and after PSM. Over a median follow-up period of 79 months, 54 patients developed recurrences. Before PSM, younger patients had worse recurrence-free survival (RFS) than older patients. Significantly worse RFS was seen in younger patients with HER2+ BC compared with their older counterparts. Younger patients had higher rates of locoregional recurrence rather than metastasis, especially in the first 5 years after diagnosis. After PSM, the two age groups still significantly differed in 5-year RFS. Among PSM pairs with T1N0M0 BC, with equal baselines and treatment conditions, we found that patients who presented at younger ages had worse outcomes, independently of other pathological features. Younger patients with BC may require more individualized therapy to improve their prognosis.

Sinonasal Undifferentiated Carcinoma.

To provide a comprehensive review of the literature highlighting the recent advances in the diagnosis and management of sinonasal undifferentiated carcinoma (SNUC) RECENT FINDINGS: SNUC usually presents at advanced stage and the prognosis is usually poor with high rates of locoregional recurrence and tendency to metastasize. Special attention should be made in differentiating SNUC from other sinonasal malignancies in order to guide the appropriate treatment accordingly. Multimodality treatment is usually recommended for treating SNUC. The use of neoadjuvant chemotherapy may be associated with improved outcome and can be used to guide the subsequent treatment selection. Despite the recent advances in chemotherapeutic agents, radiation techniques, and surgical approaches, the prognosis and survival outcomes of SNUC remain poor. The addition of induction chemotherapy to the treatment approach followed by definitive local therapy needs to be further studied as it might improve the outcome.

Impact of age on pathological complete response and locoregional recurrence in locally advanced breast cancer after neoadjuvant chemotherapy

BackgroundNeoadjuvant chemotherapy (NAC) is the standard approach for downstaging of locally advanced breast cancer and can improve breast conservation rates. A pathological complete response (pCR) after NAC associated with favorable long-term outcomes has been described. There is still a high locoregional recurrence (LRR) rate after NAC and the influence of age on LRR after NAC is unclear. This study analyzed the relationship between age and LRR after NAC. MethodsTwo hundred and sixty-three patients with invasive breast cancer who received NAC followed by mastectomy or breast conserving surgery (BCS) were enrolled. Concurrent weekly epirubicin and docetaxel was the NAC regimen. ResultsTwenty-nine patients (11%) achieved a pCR after NAC. In univariate analysis, age <50 years, luminal B (HER2 positive) subtype, HER2 overexpression subtype, and triple-negative subtype were factors to predict a pCR. In multivariate analysis, age <50 years, luminal B (HER2 positive) type, HER2 overexpression, and triple-negative subtype were the independent factors to predict a pCR. No patients in the pCR group developed LRR compared with 31 patients in the non-pCR group. Eleven patients (6.9%) in the younger group (age <50 years) developed LRR compared with 20 patients (19.4%) in the older group (age ≥50 years). In multivariate analysis, younger age (<50 years) was the only independent prognostic factor for a LRR-free survival. ConclusionYounger age can predict a pCR and is an independent prognostic factor for LRR in locally advanced breast cancer patients after NAC as concurrent epirubicin and docetaxel.

What Is the Role of Elective Neck Dissection in the Management of Patients With Buccal Squamous Cell Carcinoma and Clinically Negative Neck?

Buccal squamous cell carcinoma (BSCC) is rare in the United States. Given its location, few anatomic barriers to spread exist and it has been found to have a high locoregional recurrence rate. The role of elective neck dissection (END) in patients with clinically negative neck (N0) is not clear. This study aims to answer the following research question: Among patients with N0 BSCC, does END improve locoregional control rates, distant metastasis rates, and 2- and 5-year survival rates? A retrospective cohort study was conducted. The sample included patients who received a diagnosis of BSCC. The primary predictor variable was END status (yes or no). Five institutions participated between June 2001 and June 2011: University of Washington, University of Michigan, University of Tennessee, North Memorial Oral and Maxillofacial Surgery in Minnesota, and Head and Neck Surgical Associates (Portland, OR). The primary outcome variable was locoregional recurrence. Secondary outcome variables were distant metastasis and 2- and 5-year survival rates. Other variables collected were demographic characteristics, initial operation, adjuvant therapy, clinical and pathologic data, and staging. Kaplan-Meier and Cox proportional hazards statistics were computed. The sample was composed of 98 patients with clinical N0 BSCC. The mean age was 66years (range, 30-88years), and 54% were men.Of the patients, 74 (76%) underwent END. The locoregional recurrence-free rate was 61% for END versus 38% for no END (P=.042). The distant metastasis rate was 4% for END versus 9% for no END. The 2- and 5-year disease-free survival rates were 91% and 75% (P=.042), respectively, for END and 85% and 63% (P=.019), respectively, for no END. END had a therapeutic effect, as evidenced by a lower locoregional recurrence rate, lower distant metastasis rate, and improved 2- and 5-year survival rates.

Excellent Locoregional Control in Inflammatory Breast Cancer with a Personalized Radiation Therapy Approach

Inflammatory breast cancer (IBC) has been characterized by high locoregional recurrence (LRR) rates even after trimodality therapy. We recently reported excellent locoregional control among patients treated since formally dedicating an IBC-specific clinic and research program in 2006. Institutionally, a standard twice-daily (BID) dose escalation regimen for all IBC patients was de-escalated in select cases in 2006 after review demonstrated young age, incomplete response to neoadjuvant therapy, and positive margins identified subsets with maximal benefit from dose escalation. Here we examine local control and toxicity rates with BID versus once daily (QD) approaches. We identified 103 non-metastatic IBC patients who received trimodality therapy at our institution from 2007-2015 in a prospectively-collected database. Descriptive statistics were used to describe the study cohort and retrospectively extracted rates of radiotherapy-associated toxicity. The actuarial rate of LRR-free survival was analyzed using the Kaplan-Meier method. The median follow-up is 3.6 years. The median age is 52 years. Fifty-seven patients (55.3%) presented with stage IIIB disease, and 46 patients (44.7%) presented with stage IIIC disease. Twenty-seven patients (26.2%) achieved breast pathologic complete response (pCR) and 38 (37.6%) cN+ patients achieved axillary lymph node pCR. Three patients (3.0%) had a close/positive surgical margin (<2.0 mm). Thirty-nine patients (37.9%) received post-mastectomy radiotherapy (PMRT) to the chest wall and undissected regional lymphatics in QD fractions (median dose 50.0 Gy/25 fx, median boost dose 10.0 Gy/5 fx) and 64 patients (62.1%) received BID PMRT (median dose 51.0 Gy/34 fx, median boost dose 15.0 Gy/10 fx). Per institutional practice, patients >45 years of age, pCR after neoadjuvant chemotherapy, and negative surgical margins were dispositioned to de-escalation with QD treatment. Crude toxicity by CTCAE v4.0 grade (where appropriate) for QD and BID treatment were:Abstract TU_2_3342; Table 1ToxicityQDBIDPDermatitis G1-235 (89.7%)62 (96.9%)0.20 G34 (10.3%)2 (3.1%) G40 (0.0%)0 (0.0%)Infection1 (2.6%)2 (3.1%)1.00Rib Fracture2 (5.1%)4 (6.3%)1.00Symptomatic Lymphedema (G2+)10 (25.6%)8 (12.5%)1.00Symptomatic Fibrosis (G2+)1 (2.6%)0 (0.0%)0.38Symptomatic Pneumonitis (G2+)1 (2.6%)5 (7.8%)0.40Brachial Plexopathy0 (0.0%)2 (3.1%)0.53 Open table in a new tab Two BID patients (3.1%) and zero QD patients (0.0%) experienced LRR (P =0.53). Three- and 5-year LRR-free survival were 95.1% and 100.0% for BID and QD patients, respectively (P =0.25). Tailoring radiotherapy to clinical risk factors was associated with excellent locoregional control. De-escalation of PMRT from BID to QD was not clearly associated with reduced toxicity compared to BID, although retrospective data collection may limit this comparison.

P3.03-28 LKB1 Mutation Status is Associated with Poor Radiation Outcome in Patients with Non-Small Cell Lung Cancer

Previously, we reported that the upregulation of the NRF2/KEAP1 pathway in non-small cell lung cancers (NSCLC) bearing co-mutations in KRAS and LKB1 is critical to maintain redox homeostasis which contribute to radiation resistance in these tumors. Here, we explore the role of the LKB1 mutation as a potential predictor radiation outcome in NSCLC. We retrospectively analyzed the patients undergoing definitive treatment for newly diagnosed NSCLC who were enrolled in the prospectively collected MD Anderson Lung Cancer Moon Shot GEMINI database according to LKB1 mutation status. Cox regression analysis and log-rank tests were used to correlate with radiation outcomes according to LKB1 mutation status and/or KRAS mutation subgroup. We then investigated the mechanisms of radiation resistance in these tumors in preclinical models. Of the 173 patients with stage III NSCLC treated with definitive radiotherapy, with or without chemotherapy were analyzed according to LKB1 mutation status demonstrated that LKB1 mutation had statistically significantly higher rate of loco-regional recurrence, and shorter disease-free survival than in patients with wild type LKB1 (P = 0.013 and P = 0.037, respectively). Moreover, additional loss of either LKB1 or TP53 in KRAS-mutant tumors renders these tumors higher loco-regional recurrence after radiation (P interaction = 0.045). We identified that LKB1 loss is associated with radio-resistance in part by KEAP1/NRF2 pathway activation. Re-expression of LKB1 or NRF2 pathway suppression (via KEAP1 expression) enhanced radiotherapy sensitivity in vivo. Our results suggest that LKB1 mutation is a potential predictive impact on radiation outcome of patients with NSCLC. The upregulation of the KEAP1/NRF2 pathway in NSCLC bearing co-mutations in KRAS and LKB1 is critical to maintain redox homeostasis and determine the sensitivity for radiation.

Abstract B05: Pathologic complete response is an independent prognostic factor for locoregional recurrence in locally advanced breast cancer patients after neoadjuvant chemotherapy

Abstract Background: Neoadjuvant chemotherapy (NAC) has been the standard approach for downstaging in locally advanced breast cancer and can improve breast conservation rates. Pathologic complete response (pCR) after NAC has been reported to have favorable long-term outcome. However, there is still high locoregional recurrence (LRR) rate after NAC. The aim of this study is to analyze the relationship of pCR and LRR. Method: A retrospective study was analyzed from 2002 to 2011, and a total of 263 invasive breast cancer patients had NAC and, following mastectomy or breast conserving surgery (BCS) at Linkou Chang Gung Memorial Hospital, were enrolled. Concurrent weekly epirubicin and docetaxel was standard NAC regimen and adjuvant therapy including hormone therapy, radiotherapy, and target therapy was started postoperatively according to the pathologic characters. Result: The median age was 48 years old (range 18-75). The mean tumor size at diagnosis was 6.0 cm (range 2.0-22.0). The median follow-up time was 54.6 months (range 9.2-126.9). After neoadjuvant chemotherapy, 200 (76%) patients underwent mastectomy and 63 (24%) patients underwent BCS. 29 (11%) patients achieved pCR in this study. In univariate analysis, age&amp;lt;50, negative ER, negative PR, positive HER2, luminal B (HER2 positive) and HER2 overexpression, triple-negative subtype were factors to predict pCR. In multivariate analysis, age &amp;lt;50, luminal B (HER2 positive), HER2 overexpression, and triple-negative subtype were factors to predict pCR. No patients in pCR group developed LRR compared with 31 (13.2%) patients with LRR in non-pCR group. In multivariate analysis, pCR and age &amp;lt;50 were independent prognostic factors for LRR. Conclusion: Our findings suggested that pCR and younger age are independent prognostic factors for LRR in breast cancer patients after NAC with concurrent eprubicin and docetaxel. Citation Format: Hsu-Huan Chou, Shin-Che Chen. Pathologic complete response is an independent prognostic factor for locoregional recurrence in locally advanced breast cancer patients after neoadjuvant chemotherapy [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B05.

Perspectives on preoperative systemic treatment and breast conservative surgery: One step forward or two steps back?

Preoperative systemic therapy (PST) has become an accepted treatment not only for locally advanced but also for early stage breast cancer patients. Clinical trials have demonstrated that the use of PST is equally to adjuvant treatments in terms of overall survival, and has the advantage of increasing rates of breast conservative surgery and rates of pathologic complete response, a surrogate endpoint for the effectiveness of systemic therapy. Initial studies have suggested higher rates of locoregional recurrence with this approach. However, the optimization of systemic and targeted therapy and the multidisciplinary care is key to achieving optimal outcomes in this setting.

Patterns of failure after resection of extrahepatic bile duct cancer: implications for adjuvant radiotherapy indication and treatment volumes

BackgroundThe role of adjuvant radiotherapy (RT) and setting proper RT target volumes have not been clearly demonstrated for extrahepatic bile duct (EHBD) cancer, due to the rarity of the disease and the lack of randomized trials. This study was conducted to evaluate the indication and treatment volume for adjuvant RT in EHBD cancer patients by identifying the prognostic factors for loco-regional (LR) failure, and analyze the patterns of LR failure.MethodsNinety-three patients with EHBD cancer, who underwent resection without adjuvant RT, at 2 medical centers, between 2001 and 2016, were analyzed retrospectively. Univariable and multivariable analyses were performed to find the prognostic factors for LR recurrence. The initial patterns of failure were recorded, especially those of LR recurrence, and categorized according to the Japanese classification.ResultsThe median follow-up duration was 30 months, and 38 (40.9%) patients experienced LR recurrence during this period. With regards to LR recurrence, close or positive resection margin (RM) status (p < 0.001) remained statistically significant in the multivariable analysis. The most common LR recurrence sites were the tumor bed (18.3%), and lymph node (LN) stations No. 8 (14.1%), No. 9 (12.7%), No. 12 (12.7%), No. 13 (5.6%), No. 14 (21.1%), No. 16 (14.1%), and No. 17 (1.4%).ConclusionsA close or positive RM status may be suggestive of high LR recurrence rates. In such cases, adjuvant RT may improve outcomes. When adjuvant RT is performed, the treatment volume should be well-designed so as to encompass the tumor bed, as well as LN stations No. 8, No. 9, No. 12, No. 14, and No. 16.

Primary surgery with or without postoperative radiotherapy in early stage squamous cell carcinoma in the anal canal and anal margin

Background Standard treatment of localized squamous cell carcinoma of the anus (SCCA) is radiotherapy (RT) combined with chemotherapy, that is, chemoradiation (CRT). Primary surgery has a limited role, but is a recommended treatment for small well differentiated SCCA localized in the anal margin, with re-excision or postoperative RT/CRT in case of involved surgical margins. The evidence supporting these strategies is limited. Aim To study the recurrence patterns and survival outcomes in patients treated with surgery alone compared with surgery followed by postoperative RT/CRT. Material and methods From a large Nordic database we identified 93 patients with stage TxT1–2N0M0 SCCA treated with surgery alone (n = 59) or surgery followed by RT/CRT (n = 34). Surgery consisted of local excision in 86 patients and abdominoperineal resection in seven patients, all of them in the surgery alone group. In 38 (41%) of the patients, the tumor was localized merely in the anal margin and in all remaining cases the anal canal was involved. Median RT dose to the tumor bed was 54 (range 46–66) Gy. Adjuvant RT to lymph nodes was given in 75% of the patients. Half of the patients received concomitant chemotherapy, usually 5-fluorouracil and mitomycin C. Results The locoregional recurrence (LRR) rate was significantly higher after surgery alone compared to surgery followed by adjuvant RT/CRT (36% vs. 9%, p = .006). The 3-year recurrence free survival (RFS) and overall survival (OS) were significantly better in patients who received postoperative RT/CRT than in patients who did not (3-year RFS 84.2% vs. 52.7%, p < .001 and 3-year OS 87.2% vs. 70%, p = .026). Conclusions Surgery alone of SCCA was associated with a high LRR rate and poor survival. The addition of postoperative RT/CRT lead to significantly improved locoregional control and survival.

Abstract P1-09-05: Radiosensitization of androgen receptor (AR)-positive triple-negative breast cancer (TNBC) cells using seviteronel (INO-464), a selective CYP17 lyase and AR inhibitor

Abstract Background: Increased rates of locoregional recurrence (LR) have been observed in TNBC despite chemotherapy and radiation (RT). A novel radiosensitizer screen nominated the AR as a promising target for treatment of radioresistant breast cancer, including TNBC. We assessed the activity of seviteronel (Sevi), a selective CYP17 lyase and AR inhibitor in Phase 2 clinical development for advanced breast and prostate cancer, as a potential radiosensitizer in AR+ TNBC model. Methods: Clonogenic survival assays were used to determine the intrinsic RT sensitivity of 21 breast cancer cell (BCC) lines. IC50 values were determined for 130 clinically available compounds and correlation coefficients were calculated using IC50 values and SF-2Gy. Gene expression was measured using RNA Seq or qRT-PCR and protein expression was measured using RPPA arrays. AR function was assessed using functional inhibition with Sevi in MDA-MB-453, ACC-422, ACC-460, SUM-185 (all four AR+ TNBC), MDA-MB-231 (AR- TNBC), and T47D (AR- ER+) BCC lines. Double-stranded DNA (dsDNA) break repair was assessed with γH2AX foci counting. In vivo tumor growth was measured with varying control and treatment groups (16-20 tumors/group). Kaplan-Meier analysis was performed to estimate local control. A Cox proportional hazards model and multi-variate analysis (MVA) were used to determine variables associated with LRF survival. Results: Our novel radiosensitizer screen identified the activity of anti-androgen therapy as a potentially effective strategy for radiosensitization in RT-resistant BCC lines (R2 =0.46, p-value &amp;lt; 0.01) (Speers et al, J Clin Oncol 35, 2017 (suppl; abstr e12102). Heterogeneity in AR expression was identified in human BCC lines and TNBC samples from patients (N=2098). There was a strong correlation between AR RNA expression and protein expression across all BC intrinsic subtypes. AR inhibition using Sevi induced radiation sensitivity in vitro with an enhancement ratio (ER) of 1.24-1.69 in four different AR+ TNBC lines. No such radiosensitization was seen in AR(-) TNBC or ER+, AR(-) BCC lines. Radiosensitization was at least partially dependent on impaired dsDNA break repair with significant delays in dsDNA break repair at 16 and 24 hours in all AR+ TNBC lines examined (p-value &amp;lt; 0.01). AR inhibition with Sevi significantly radiosensitized AR+ TNBC xenografts in mouse models and markedly delayed tumor-volume tripling time (TTT) and tumor growth (MDA-MB-453: median TTT 16.1 days for RT alone vs. not reached after 45 days for Sevi+RT, p-value &amp;lt;0.001). Similar delays were seen in tumor growth, weight, and tumor doubling. Clinically, TNBC patients whose tumors had higher than median expression of AR had higher rates of LR after RT (HR for LR ˜3, p-value &amp;lt;0.01, 2 independent datasets). In MVA, high AR expression was the variable most significantly associated with worse LR survival after RT in TNBC patients, outperforming all other variables (HR of 3.42; p-value &amp;lt; 0.01). Conclusions: Our results implicate the AR as a mediator of radioresistance in breast cancer and support the rationale for developing Sevi as a novel radiosensitizing agent in AR+ TNBC. Citation Format: Speers CW, Chandler B, Olsen E, Wilder-Romans K, Moubadder L, Nyati S, Rae J, Hayes DF, Spratt DE, Wahl DR, Eisner J, Feng FY, Pierce LJ. Radiosensitization of androgen receptor (AR)-positive triple-negative breast cancer (TNBC) cells using seviteronel (INO-464), a selective CYP17 lyase and AR inhibitor [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-09-05.

The effect of dose escalation for large squamous cell carcinomas of the anal canal: A National Cancer Database study.

791 Background: Chemoradiation allows for organ preservation in patients with anal cancer, but patients with large tumors (T3/T4) continue to have high rates of locoregional recurrence. With conformal radiation techniques, there is interest in dose escalation to improve local control for large tumors. Methods: The National Cancer Database (NCDB) was used to identify patients with anal cancer from 2004-2013 with tumors &gt; 5 cm in size. Adult patients with T3 or T4 squamous cell carcinoma who received definitive chemoradiation were included. Patients with prior resection were excluded. Higher dose was defined as &gt; than or equal to 5940 Gy. Statistical analyses were performed using logistic regression, Kaplan-Meier, and Cox proportional hazards for overall survival (OS). Results: In total, 1349 patients were analyzed with 412 (30.5%) receiving higher dose radiation therapy (RT). Dose in the higher group ranged from 5940 – 7000 Gy. 5-year OS was 58% and 60% for higher and lower dose RT, respectively. On univariate analysis, higher dose RT (HR 0.998, CI 0.805 - 1.239, p = 0.9887) was not associated with a change in OS but older age (HR 1.484, CI 1.193 - 1.844, p = 0.0004), male sex (HR 1.660, CI 1.355 - 2.033, p &lt; 0.0001), comorbidities (HR 1.496, CI 1.183 - 1.893, p = 0.0008), and long RT (HR 1.248, CI 1.016 - 1.533, p = 0.0347) were significantly associated with decreased OS. The results of multivariate analysis are shown in the Table. Conclusions: There was no observed difference in OS for dose escalation of anal cancers &gt; 5 cm in this population-based analysis, but differences in local control cannot be assessed through the NCDB. Males, elderly, and comorbid patients were particularly high-risk populations with poor chemoradiation survival outcomes. Reducing treatment breaks is important for improving outcomes. Whether dose escalation of large tumors may improve local control and colostomy-free survival remains an important question and is the subject of ongoing trials. [Table: see text]

The prognosis of invasive micropapillary carcinoma compared with invasive ductal carcinoma in the breast: a meta-analysis

BackgroundInvasive micropapillary carcinoma (IMPC) of the breast is a rare variant of invasive ductal carcinoma (IDC). The prognosis of IMPC compared with that of IDC remains controversial; we conducted a meta-analysis to evaluate the prognostic difference between IMPC and IDC.MethodsWe searched the PubMed, Cochrane Library, and EMBASE databases for relevant studies comparing overall survival (OS), disease-specific survival (DSS), relapse-free survival (RFS), local-regional recurrence-free survival (LRRFS) or distant metastasis-free survival (DMFS) rates between IMPC and IDC. Fixed-effect and random-effect models were utilized based on the heterogeneity of the eligible studies. Heterogeneity was further evaluated by subgroup and sensitivity analyses.ResultsFourteen studies with 1888 IMPC patients were included in the meta-analysis. The summarized odds ratio (OR) and 95% confidence interval (95% CI) was calculated to estimate the prognostic difference between IMPC and IDC. IMPC patients showed an unfavorable prognosis for RFS (OR; 2.04; 95% CI: 1.63–2.55) and LRRFS (OR: 2.82; 95% CI: 1.90–4.17) compared with IDC. However, no significant difference was observed in OS (OR: 0.93; 95% CI: 0.78–1.10), DSS (OR: 1.16; 95% CI: 0.95–1.40) and DMFS (OR: 0.95; 95% CI: 0.67–1.35) between IMPC and IDC. No obvious statistical heterogeneity was detected, except for DSS. Funnel plots and Egger’s tests did not reveal publication bias, except for RFS.ConclusionsThis analysis showed that IMPC patients have a higher rate of loco-regional recurrence than IDC patients. However, OS, DSS and DMFS were not significantly different between IMPC and IDC. These results could help clinicians select therapeutic and follow-up strategies for IMPC patients.

Squamous differentiation in papillary thyroid carcinoma: a rare feature of aggressive disease

BackgroundPapillary thyroid carcinoma with squamous differentiation (PTC-SD) is a poorly understood pathologic finding of unknown clinical significance. Selected case reports have suggested that PTC-SD is an aggressive tumor with a poor prognosis. Here we present the largest case series of PTC-SD reported in the United States. Materials and methodsThe cancer registry at our tertiary care referral center was reviewed to identify all patients from 1995-2015 who had been diagnosed with PTC-SD on initial total thyroidectomy or lymph node dissection for recurrent disease. All cases were reviewed by an endocrine pathologist to confirm the diagnosis. Patient demographic, pathology, and outcomes data were collected and reviewed. ResultsDuring the study period, ten patients were diagnosed with PTC-SD, six in the primary tumor at the time of initial surgery, and four in lymph node metastases during surgery for recurrent disease. The median age at diagnosis was 56 y and half of the patients were male. Aggressive features such as multifocality (67%), extrathyroidal extension (67%), positive margin (89%), lymph node metastases (80%), and extranodal extension (60%) were far more prominent than is typically seen in classic PTC. Long-term follow-up (median 56.5 mo) demonstrated high rates of locoregional recurrence (60%), pulmonary metastases (30%), and mortality (10%). ConclusionsSquamous differentiation is a rare finding in PTC that is associated with aggressive pathologic features and poor long-term outcomes. This phenomenon may represent a step in progression toward dedifferentiation; thus, patients with PTC-SD should have close, life-long surveillance and should be treated according to evidence-based guidelines for high-risk thyroid cancers.

The Importance of Treatment and Timing in Metaplastic Breast Cancer

Metaplastic breast cancer (MBC) is a rare variant of breast cancer with high rates of locoregional recurrence and limited data available regarding patterns of care and treatment outcomes. We queried the National Cancer Data Base (NCDB) to examine the impact of clinical and treatment factors on overall survival (OS) in patients with metaplastic breast cancer. We identified patients in the NCDB diagnosed with MBC from 2004-2013 without metastatic disease, who received definitive management, and had complete information with regards to treatment and survival status. Univariate and multivariable Cox proportional hazard models were used to assess covariates related to OS. Actuarial analyses estimated survival rates. Chi-square tests and ANOVA were done to examine correlations between disease factors. Overall, 3,825 patients with MBC were identified. Of those with known clinical data, median age was 62 years old with a median tumor size of 3.0 cm, 83% were poorly differentiated, 63% were ER/PR/Her2 (triple) negative, and 18% were LN+. Forty-five percent underwent breast conservation therapy, and 55% underwent mastectomy. With respect to additional treatment, 49% received radiotherapy and 67% received chemotherapy, with 13% receiving neoadjuvant chemotherapy. At 5 and 10 years, the OS rates were 69.5% and 54.3%, respectively. On multivariable analysis, older age (HR=1.02, p<0.001), higher Charlson-Deyo Score (HR=1.48-2.14, p<0.001), larger tumor size (HR=2.15-3.35, p<0.001), LN+ disease (HR=1.34, p=0.029), neoadjuvant treatment (HR=1.56, p=0.001), higher pathologic stage (HR=1.87-3.37, p=0.001), positive margins (HR=1.65, p=0.017), and treatment without radiation (HR=1.63, p<0.001) or chemotherapy (HR=1.55, p<0.001) were significantly associated with worse OS. Patients receiving mastectomy were associated with significantly worse OS if they did not receive chemotherapy (HR=2.06, p<0.001). Those receiving radiation therapy had a worse OS (HR=0.83, p=0.04) however they also were significantly more likely to have a higher clinical/pathologic stage and/or LN+ disease. Those who underwent lumpectomy alone without radiotherapy (HR=2.53, p<0.001) or chemotherapy (HR=1.90, p<0.001) had significantly worse OS. Metaplastic breast cancer is a heterogeneous disease which is often triple negative. Receipt of radiation improves survival in patients undergoing lumpectomy while systemic therapy improves survival regardless of local therapy. Optimizing systemic therapy and radiotherapy may be associated with improved OS.

Molecular Subtypes and Pathogenic Germline Mutations Vary by Ethnicity in Young Women Treated With Breast-Conserving Surgery and Radiation Therapy

Historically, young age has been associated with higher rates of locoregional recurrence following breast-conserving surgery and radiation therapy. A greater proportion of Hispanic, African American (AA), and Asian women are diagnosed at a young age compared with Caucasian women. The primary objective of this study was to characterize the distributions of molecular subtypes and pathogenic germline variants in different ethnicities of young women treated with breast-conserving surgery and radiation therapy (BCT). From January 1, 2000 through December 31, 2015, 253 women aged 50 or younger at diagnosis were treated with BCT at our institution. Radiation consisted of tangential fields to the whole breast in all patients. A boost to the tumor bed and radiation to the regional lymph nodes was delivered at the discretion of the treating physician. Systemic therapy consisted of hormone therapy with or without ovarian suppression, chemotherapy, and/or targeted biologic therapies such as Trastuzumab. Molecular subtype was approximated by immunohistochemistry (IHC) receptor status. 180(71%) of these patients underwent genetic testing and 62 (25%) had expanded gene panel testing of 6-70 cancer susceptibility genes beyond BRCA 1 and 2. Fisher’s exact test was used for molecular subtype comparisons between ethnicities. Locoregional control (LRC), disease-free survival (DFS), and overall survival (OS) were estimated using the Kaplan-Meier method. This cohort was comprised of 61% Caucasian, 25% Asian, 10% Hispanic, and 4% AA women. Distributions of molecular subtype by ethnicity were as follows: Caucasians (63% luminal A, 16% luminal B, 2% Her2(+), 19% basal); Asians (65% luminal A, 21% luminal B, 5% Her2(+), 10% basal); Hispanics (31% luminal A, 15% luminal B, 54% basal); AA (44% luminal A, 33% luminal B, 22% basal). There were significant differences in molecular subtype distributions between Hispanic women with Caucasian (p=0.002) and Asian women (p<0.001). In a subset of 142 patients treated from 2000-2011 with a median follow-up of 6.5 years, 5-year LRC, DFS, and OS were 97%, 93%, and 97%, respectively. Univariate analyses found no statistically significant associations between molecular subtype with LRC, DFS, and OS. Pathogenic mutations were detected in 15 (8%) patients and were distributed by ethnicity as follows: Caucasians (11: APC(2), BARD1, BRCA1(3), BRCA2, CHEK2(2), MUTYH, PALB2); Hispanics (2: BRCA1, PALB2); Asians (1: MUTYH); AA (1: PALB2). Expanded panel testing was not routinely performed at our institution until 2013 and its utility in risk stratification is the subject of future investigation. A heterogeneous distribution of molecular subtypes and germline variants appeared to vary by ethnicity in young women treated with BCT.

External radiotherapy and brachytherapy in the management of extrahepatic and intrahepatic cholangiocarcinoma: available evidence.

This review aims to summarize the currently available evidence for the role of external radiotherapy and brachytherapy in the management of cholangiocarcinoma. High locoregional disease recurrence rates after surgical resection alone for both the extrahepatic cholangiocarcinoma (EHCC) and intrahepatic cholangiocarcinoma (IHCC) provide a rationale for using adjuvant radiotherapy with chemotherapy. We performed a literature search related to radiotherapy in cholangiocarcinoma published between 2000 and 2016. The role of radiation is discussed in the adjuvant, neoadjuvant, definitive and the palliative setting. Evidence from Phase II trials have demonstrated efficacy of adjuvant chemoradiation in combination with chemotherapy in EHCC. Locally advanced cholangiocarcinoma may be treated with neoadjuvant chemoradiotherapy. In the case of downsizing, assessment for resection may be considered. Brachytherapy offers dose escalation after external radiotherapy. Selected unresectable cases of cholangiocarcinoma may be considered for stereotactic body radiation therapy with neoadjuvant and/or concurrent chemotherapy. Liver transplantation is a treatment option in selected patients with EHCC and IHCC after neoadjuvant chemoradiation. Stenting in combination with palliative external radiotherapy and/or brachytherapy provides improved stent patency and survival. Newer advanced radiation techniques provide a scope for achieving better disease control with reduced morbidity. Effective multimodality treatment incorporating radiotherapy is the way forward for improving survival in patients with cholangiocarcinoma.

Improving the diagnosis and treatment of acral melanocytic lesions.

Melanocytic lesions of acral sites are common, with an estimated prevalence of 28-36% in the USA. While the majority of these lesions are benign, differentiation from acral melanoma (AM) is often challenging. AM is a unique subtype of melanoma, with distinct molecular characteristics that are thought to contribute to its high rate of locoregional recurrence and worse prognosis. The advent of dermoscopy has since improved the diagnostic accuracy of AM, resulting in earlier detection and arguably improved survival. Additionally, the identification of unique genomic amplifications in AM invites the potential for future AM-specific targeted therapies. Herein, we discuss the importance of dermoscopy in the diagnosis of acral melanocytic lesions and review the treatment strategies for AM.