Higher Rates Of Locoregional Recurrence Research Articles

Predicted Th2 Infiltrate is Associated with Outcome in HPV(-) Head and Neck Cancer.

<h3>Purpose/Objective(s)</h3> We previously showed that immune infiltrate affects treatment response in Head/Neck Cancer (HNC) treated with radiation. Here, we evaluate the effect of predicted tumor infiltrating lymphocytes (TILs) on treatment failure following radiation. <h3>Materials/Methods</h3> Nintey-four human papillomavirus negative (HPV-) HNC patients in the TCGA treated with surgery and adjuvant radiation (PORT) comprised the discovery cohort. Pre-treatment tumors were analyzed using RNA-seq. These data were then used to predict tumor cell type abundance using xCell, which quantifies 64 immune, stroma, and tumor cell abundance from tissue RNA-seq data. Predicted TILs associated with overall survival (OS), distant metastasis (DM), and locoregional recurrence (LRR) in the discovery cohort were examined in a validation cohort of 102 HPV(-) HNC patients treated with surgery and PORT. All patients in the HPV(-) TCGA cohort with available mutation and gene expression data (n=403) were analyzed as were a separate 40 patient HPV(-) HNC cohort. Significant (MutSig) tumor mutations in cancer genes (OncoKB) were examined for association with predicted Th2 infiltrate. Gene expression significantly different between CD4+ T helper 2 (Th2) high and low tumors were analyzed using ingenuity pathway analysis (IPA) to identify pathways associated with predicted Th2 infiltrate. <h3>Results</h3> Several predicted TILs were associated with outcome, but only predicted Th2 infiltrate was significantly associated with higher rates of LRR in both the discovery (p=4e-3) and validation cohorts (p=9e-3). Predicted Th2 infiltrate was significantly increased in tumors harboring mutations in: CASP8, EP300, HRAS, HLA-A, and ZNF750. IPA using genes significantly (FDR 0.01) associated with predicted Th2 infiltrate identified activation of DDR-related pathways and repression of the tumor microenvironment (TME) pathway in tumors with high predicted Th2 infiltrate. Gene expression within each pathway was used to generate a pathway activation score with positive correlation between predicted Th2 and the BRCA1 in DDR pathway (Pearson R 0.73, p<2.2e-16) and negative correlation with the TME pathway (R= -0.45, p<2.2e-16). Similar patterns were seen in a separate 40 patient cohort, with predicted Th2 infiltrate correlated positively with the BRCA1 in DDR pathway (R=0.77, p=5.6e-9) and negatively with the TME pathway (R= -0.42, p=7.2e-3). <h3>Conclusion</h3> We identified predicted Th2 infiltrate associated with LRR in two homogeneously treated, HPV(-) HNC cohorts. We found that Th2 infiltrate was associated with mutations in genes known to be associated with both poor outcome and modulation of TILs. Finally, predicted Th2 was associated with increased activation of DNA damage response pathways and local repression of immune function in the TME. Thus, Th2 infiltrate may potentially mediate resistance to radiation in HPV(-) HNC.

Development and Validation of the Optimal Circumferential Resection Margin in Pathological T3 Esophageal Cancer: A Multicenter, Retrospective Study.

The clinical significance of circumferential resection margin (CRM) in esophageal squamous cell carcinoma (ESCC) remains unclear. Optimal CRM for predicting the recurrence of pathological T3 ESCC was investigated. Seventy-three patients were retrospectively investigated in the development cohort. Patients were divided into CRM-negative and CRM-positive groups, and clinicopathological factors and survival outcomes were compared between the groups. The cutoff value was validated in another validation cohort (n = 99). Receiver operating characteristic analysis in the development cohort showed the cutoff value of CRM was 600 μm. In the validation cohort, patients in the CRM-positive group showed a significantly higher rate of locoregional recurrence (p = 0.006) and worse recurrence-free survival (RFS) (p < 0.001) than those in the CRM-negative group. Multivariate analysis identified positive CRM as an independent predictive factor for poor RFS (hazard ratio, 2.695; 95% confidence interval, 1.492-4.867; p = 0.001). The predictive value of our criteria of positive CRM for RFS was higher than that of the Royal College of Pathologists (RCP) and the College of American Pathologists (CAP) criteria. Stratified analysis in the neoadjuvant chemotherapy groups also revealed that the rate of locoregional recurrence was higher in the CRM-positive group than in the CRM-negative group both in the pathological N0 and N1-3 subgroups. CRM of 600 μm can be the optimal cutoff value rather than the RCP and CAP criteria for predicting locoregional recurrence after esophagectomy. These results may support the impact of perioperative locoregional control of locally advanced ESCC.

Abstract P3-21-01: A higher locoregional recurrence rate of nipple areolar complex sparing mastectomy with immediate implant reconstruction

Abstract Background The rate of Nipple Areolar Complex (NAC) sparing mastectomy with implant reconstruction is rapidly increasing as the Korean National Health Insurance reimbursed reconstructive surgery for breast cancer patients from 2015. However, only a few reports about oncologic safety have been reported in the absence of large-scale data. We have analyzed the oncologic outcomes of all consecutive breast cancer patients who had NAC sparing mastectomy with immediate implant reconstruction. Methods We used the data from prospectively collected clinical data of patients who underwent immediate implant reconstruction after NAC sparing mastectomy at the National Cancer Center between January 2012 and December 2017. Demographics, clinicopathological characteristics and the follow-up results were analyzed. The statistical analysis was done to infer relations between risk factors and oncologic outcomes such as death, distant metastasis or locoregional recurrence. Results: A total of 538 breasts was analyzed in 486 patients. The mean age of the patients was 44.6 years. The mean BMI was 22.48 kg/m2. The number of bilateral cases was 52 (10.7%) and 135 patients (27.8%) had multiple tumors. Median follow-up was 4.5 years. Molecular subtypes were 373 HR(+)/HER2(-) (69.3%), 31 HR(+)/HER2(+) (5.8%), 76 HR(-)/HER2(+) (14.1%) and 35 HR(-)/HER2(-) (6.5%). Chemotherapy was performed in a total of 212 (43.6%) patients, of which 68 (32.1%) were neoadjuvant and 144 (67.9%) were adjuvant purposes. Trastuzumab was administered to 53 (10.9%) of patients whose tumor size are larger than 1cm under guideline of reimbursement. Postoperative radiotherapy was performed in 131 patients (26.9%). Distant metastasis occurred in 20 patients (3.7%), and seven (1.4%) died. Locoregional recurrence occurred in 43 cases (8.0%) of 538 breasts, including 14 nipples (2.6%) and 12 subareolar lesions (2.2%). Analyzing risk factors related to locoregional recurrence, HR(-)/HER2(+) type showed the highest incidence of 11/76 (14.7%) among four subtypes. The incidence was statistically significantly lower in the group that received postmastectomy radiotherapy than in the group that did not. (6/131 (4.6%) vs 37/355 (10.4%), p=0.001). The node negative group who did not have postmastectomy radiotherapy (31/377 (8.2%)) showed a numerically higher incidence than the node positive group (8/121 (6.6%)). Conclusion Our results showed that NAC sparing mastectomy with immediate implant reconstruction had similar oncologic outcome in terms of overall survival or distant metastasis, however the locoregional recurrence was rather high. Even this is remediable problems we would admit that NAC sparing mastectomy is a bit different from traditional mastectomy. In case that we inevitably apply this operation to relatively young women with multifocal breast cancer, careful consideration would be needed. In addition, identifying risk factors of locoregional recurrence and tailored post-operative radiation therapy are expected to improve the disease-free survival of breast cancer. Citation Format: Ji Young You, Eun-Gyeong Lee, Soo Jin Park, Byeong Nam Kim, Seeyoun Lee, Eun Sook Lee, So-Youn Jung, Youngmi Kwon, Yun Ju Kim, Chan Wha Lee, Tae Hyun Kim. A higher locoregional recurrence rate of nipple areolar complex sparing mastectomy with immediate implant reconstruction [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-21-01.

Abstract P1-13-03: Radiotherapy vs. endocrine therapy for hormone receptor positive early stage breast cancer accounting for endocrine therapy adherence

Abstract Purpose/Objective(s):. Several trials have compared endocrine therapy (ET) alone vs. ET and radiotherapy (RT) in low risk early stage estrogen receptor (ER)-positive breast cancer and have shown that the addition of RT to ET modestly reduces the rate of loco-regional recurrence (LRR) without altering survival. ET may also yield modest reductions in contralateral breast events. ET alone has thus become a standard strategy in select patients. Data evaluating the efficacy of RT alone are scarce. However, the toxicity of ET is not trivial and its effectiveness is dependent upon treatment adherence. As RT courses become ever shorter and safer, a re-evaluation of the strategy of RT alone is warranted. This analysis reports on the treatment outcomes of ER-positive early stage breast cancer treated with adjuvant RT or ET alone at a multi-hospital health system. We hypothesized that adjuvant RT alone would yield loco-regional control comparable to that of ET alone and that ET adherence would influence outcomes. Materials/Methods:. The shared electronic health record of multiple facilities within a university health system was queried to identify women with pathologic T1-2 N0 breast cancer treated with breast-conserving surgery between 2007 and 2016. Data collection included demographic features, tumor characteristics, treatment type, and evidence of LRR. Analysis was restricted to those patients with ER positive disease who underwent either RT alone or ET alone. Five-year LRR were compared across groups using the Kaplan-Meier method. Results:. 240 patients met inclusion criteria. Of these, 86 were treated with RT alone and 154 with ET alone. Patient, tumor and ET variables are listed in the table below. ET adherence and duration information were available for 135 out of 154 patients who received ET alone. Patients who completed 5 years of ET or whose ET was discontinued due to the disease recurrence or death were categorized as ET-adherence (ET-A). Patients who discontinued ET before reaching 5 years due to other reasons were categorized as ET-non adherence (ET-NA). Median ET duration in ET-A was 60 months (range, 15-101 months) and in ET-NA was 13 months (range, 1-54 months). The 5-year rates of LRR for RT alone vs. ET alone were 4.1 % (95% CI 0-8.8) vs. 5.0 % (95% CI 1.1-8.9). The 5-year rates of LRR for ET-A vs. ET-NA were 2.0 % (95% CI 0-4.7) vs. 16.4 % (95% CI 1.1-31.7). While the difference in the LRR rates between RT alone vs. ET-A was not statistically significant (p= .481), ET-NA was associated with significantly higher LRR rate compared to RT alone or ET-A (p&amp;lt;.05). The rate of ET non-adherent rate was 21.4%. Conclusion:. RT yielded LRR equivalent to overall ET and superior to ET non-adherence. For patients with early stage ER+ breast cancer, a prospective randomized trial comparing RT to ET and evaluating quality of life (QoL) is needed. In light of emerging data, a five-day course of RT can be considered as an alternative to five years of ET, and RT should be strongly considered if ET adherence is in doubt. Table 1.Patient, tumor and treatment characteristicsRT alone (n=86)ET alone (n=154)Median follow-up (months)50.6 (1-135)48 (3-114)Age (median)63 (39-91)74 (50-87)StageT176 (88.4%)142 (92.2%)T210 (11.6%)12 (7.8%)HistologyGrade 38 (9.3%)9 (5.8%)+LVI5 (5.8%)3 (2.0%)Endocrine Therapy (ET)ET duration (median, months)-57 (1-101)ET-Adherent-102 (66.2%)ET-Non adherent-33 (21.4%)ET duration not available-19 (12.3%) Citation Format: Seung Won Seol, Travis Pflederer, Lauren Weller, Chelain Goodman, Eric D Donnelly, John P Hayes, Jonathan B Strauss. Radiotherapy vs. endocrine therapy for hormone receptor positive early stage breast cancer accounting for endocrine therapy adherence [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-13-03.

Local Tumor Infiltration and Locoregional Recurrence in Desmoplastic Cutaneous Squamous Cell Carcinoma.

Perusal of the literature of cutaneous squamous cell carcinoma (SCC) reveals that the role of the desmoplastic subtype is indistinct. Data on local infiltration and recurrence are inconsistent dependent on surgical technique, histological method, and investigated collective. The aim of the study was to analyze local infiltration and locoregional recurrence of the desmoplastic subtype under a uniform procedure. Between 2005 and 2015, 320 SCCs were analyzed and histological sections of all tumors were examined. Data collection included locoregional recurrence, metastasis rate, and tumor-specific death. The median follow-up was 36.5 months. The desmoplastic subtype required significant more re-excisions (70.0% vs 23.9%, p < .001), more interventions until tumor-free margins were achieved (maximal 6 vs 2; p < .001), showed more widespread tumor infiltration with larger excisional margins (median 9 mm, 2-51 mm vs median 4 mm, 1-10 mm; p < .001), and a 5-fold higher local recurrence rate (26.7% vs 5.0%, p < .001). The metastasis rate (16.6% vs 2.3%, p < .001) was increased. The desmoplastic subtype is characterized by a widespread local infiltration associated with perineural infiltration. It seems to be a marker for decreased histological detectability with a high rate of locoregional recurrence and metastasis.

Patterns and timing of recurrence in esophageal squamous cell carcinoma patients treated with neoadjuvant chemoradiotherapy plus esophagectomy

BackgroundTumor regression grade (TRG) after neoadjuvant therapy is reportedly predictive of prognosis in esophageal cancer patients, as lack of a response to neoadjuvant therapy is associated with a poor prognosis. However, there is little information available on the timing and pattern of recurrence after esophagectomy for thoracic esophageal squamous cell carcinoma (TESCC) that takes into consideration TRG after neoadjuvant chemoradiotherapy (NACRT). Here, in an effort to gain insight into a treatment strategy that improves the prognosis of NACRT non-responders, we evaluated the patterns and timing of recurrence in TESCC patients, taking into consideration TRG after NACRT.MethodsA total of 127 TESCC patients treated with NACRT and esophagectomy between 2009 and 2017 were enrolled in this observational cohort study. TRGs were assigned based on the proportion of residual tumor cells in the area (TRG1, ≥1/3 viable cancer cells; 2, < 1/3 viable cancer cells; 3, no viable cancer cells). We retrospectively investigated the timing and patterns of recurrence and the prognoses in TESCC patients, taking into consideration TRG after NACRT.ResultsThe 127 participating TESCC patients were categorized as TRG1 (42 patients, 33%), TRG2 (56 patients, 44%) or TRG3 (29 patients, 23%). The locoregional recurrence rate was higher in TRG1 (36.4%) patients than combined TRG2–3 (7.4%) patients. Patients with TRG3 had better prognoses, though a few TRG3 patients experienced distant recurrence. There were no significant differences in median time to first recurrence or OS among patients with locoregional or distant recurrence. There was a trend toward better OS in TRG2–3 patients with recurrence than TRG1 patients with recurrence, but the difference was not significant.ConclusionsNACRT non-responders (TRG1 patients) experienced higher locoregional recurrence rates and earlier recurrence with distant or locoregional metastasis. TRG appears to be useful for establishing a strategy for perioperative treatments to improve TESCC patient survival, especially among TRG1 patients. (303 words).

Adjuvant SOX chemotherapy versus concurrent chemoradiotherapy after D2 radical resection of locally advanced esophagogastric junction (EGJ) adenocarcinoma: study protocol for a randomized phase III trial (ARTEG)

BackgroundSurvival benefit of adjuvant radiotherapy for locally advanced gastric cancer following gastrectomy plus D2 lymphadenectomy has always been controversial. Esophagogastric junction (EGJ) adenocarcinoma, which is usually classified as gastric cancer in East Asia, often has a higher locoregional recurrence rate after operation because of its special anatomical characteristics. The aim of this study is to determine whether adjuvant radiotherapy can improve survival of locally advanced EGJ adenocarcinoma after D2 radical resection.MethodsIn this phase III, randomized, open label, controlled trial, we plan to recruit 378 patients with Siewert type II and III adenocarcinoma of EGJ, who had undergone transabdominal radical surgery and D2 lymphadenectomy, and were divided into pathological stage IIB to IIIC. All patients will be randomized 1:1 to receive either adjuvant chemotherapy alone (control group) or adjuvant chemotherapy plus chemoradiotherapy (experimental group). Patients allocated to control group will receive eight cycles of S-1 plus oxaliplatin (SOX), while the experimental group will receive two cycles of SOX followed by 45-Gy RT combined with S-1 and four additional cycles of SOX. The primary endpoint is 3-year disease-free survival rate (DFS). The secondary endpoints are 3-year overall survival rate (OS), 3-year locoregional recurrence-free survival rate (LRFS), 3-year distant metastasis-free survival rate (DMFS), and quality of life (QoL).DiscussionIn the past, the adjuvant treatment of EGJ adenocarcinoma needs to draw on the experience of esophageal adenocarcinoma or gastric adenocarcinoma. In this study, EGJ adenocarcinoma is considered as an independent disease, and the conclusion will provide evidence for optimal adjuvant therapy of locally advanced EGJ adenocarcinoma after D2 radical resection.Trial registrationClinicalTrials.govNCT03973008. Registered on 1 June 2019 (retrospectively registered), URL: https://clinicaltrials.gov/ct2/show/NCT03973008?term=NCT03973008&draw=2&rank=1

Prognostic factors for in-transit metastasis in patients with malignant melanoma.

Malignant melanoma represents an aggressive and unpredictable malignancy, with high locoregional recurrence rates, regardless of tumor stage and therapeutic management. This study aims to identify the main histopathological prognostic factors involved in the development of in-transit metastasis in patients with malignant melanoma. The study includes only patients that were diagnosed with malignant melanoma and with histologically confirmed in-transit metastasis who were treated in a comprehensive cancer center between 2010-2021. Histopathological parameters were investigated, univariate and multivariate analysis was performed. A total of 26 patients were included in the analysis. On univariate and multivariate analysis, only primary cutaneous melanomas located on the thorax correlated with the risk of developing in-transit metastasis, whereas clinicopathological factors such as an increased Breslow thickness and Clark level, the presence of ulceration, positive lymph nodes, a non-brisk TIL density, a high mitotic rate, a nodular subtype, and age >50 years may represent risk factors, even though we could not find any correlations. Primary cutaneous melanomas that arise on the thorax present a high risk for the occurrence of locoregional disease, whereas other clinicopathological characteristics could not be used to predict local recurrence. However, prospective and more extensive cohort studies are needed in order to validate these important prognostic factors.

Head and Neck Melanoma: What is the Goal for Margins?

Head and Neck Melanoma: What is the Goal for Margins?

Abstract 1943: Radiosensitization of PIK3CA wild type triple negative breast cancers with Bcl-family inhibition

Abstract Purpose: Compared to other breast cancer subtypes, triple negative breast cancers (TNBC) derive the least benefit from adjuvant radiation (RT) which contributes to higher rates of locoregional recurrence. Thus, there is a critical need to identify clinical strategies to increase the effectiveness of RT therapy in TNBC. Methods: Alamar blue proliferation assays were used to calculate half maximal inhibitory concentration (IC50) values for each Bcl-2 family inhibitor 72 hours after drug treatment. Clonogenic survival assays were used to evaluate radiosensitivity and to calculate the radiation enhancement ratio (rER) after combination treatment. Apoptosis was assessed through formation of cleaved PARP and annexin V/PI-based flow cytometry. Xenograft models with MDA-MB-231 cells and TNBC patient-derived xenografts (PDX4664) were used to assess radiosensitization in vivo. Results: A novel radiosensitizer screen identified Bcl-2 family inhibition as a potentially effective treatment strategy in radioresistant breast cancer models. Single-agent response to pan Bcl-2 family inhibition (ABT-263) or Bcl-xL inhibition (WEHI-539, A-1331852) was more effective in PIK3CA wild type (wt) TNBC (IC50 &amp;lt; 1µM) compared to PIK3CA mutant TNBC. Inhibition of apoptosis with ABT-263 led to radiosensitization of PIK3CA/PTEN wild-type TNBC cell lines (rER: 1.09-1.74), but had no effect on PIK3CA/PTEN mutant TNBC (rER: 0.87-1.18). Radiosensitization was observed to be Bcl-xL-dependent, with Bcl-xL inhibitor-specific radiosensitization (rER: 1.12-2.38) but a lack of Bcl-2 inhibitor (ABT-199, rER: 0.94 - 1.21) or MCL-1 inhibitor-mediated radiosensitization (S63845, rER: 0.91 - 1.06). In PIK3CA wt TNBC, combination treatment of Bcl-2 family inhibition and RT significantly increased the percent of apoptotic cells (p &amp;lt; 0.001) and led to increased formation of cleaved PARP 48 hours after RT. Sensitivity to RT was dependent on expression of MCL-1, an anti-apoptotic protein that is overexpressed in PIK3CA/PTEN mutant TNBC. Overexpression of MCL-1 in PIK3CA/PTEN wild type TNBC rescued radioresistance (rER: 0.99-1.09), whereas co-inhibition of MCL-1 and Bcl-xL in PIK3CA/PTEN mutant TNBC was sufficient to overcome radioresistance (rER: 2.32 - 2.35). In vivo, nonspecific Bcl-2 family inhibition or specific Bcl-xL inhibition in combination with RT decreased tumor growth and increased time to tumor tripling (p &amp;lt; 0.0001) in PIK3CA wt models of TNBC. Conclusions: In this study, we demonstrated that inhibition of Bcl-2 family proteins in combination with RT led to increased levels of apoptosis and cell death in PIK3CA/PTEN wt - but not PIK3CA/PTEN mutant - TNBC and we identified MCL-1 as a critical mediator of this radiosensitIvity. Together, these results indicate that Bcl-xL inhibition may be a feasible clinical strategy for the radiosensitization of PIK3CA/PTEN wild-type TNBC. Citation Format: Andrea M. Pesch, Benjamin C. Chandler, Anna R. Michmerhuizen, Nicole Hirsh, Kari Wilder-Romans, Meilan Liu, Tanner Ward, Dana Messinger, Charles Nino, Cassandra Ritter, James M. Rae, Corey W. Speers. Radiosensitization of PIK3CA wild type triple negative breast cancers with Bcl-family inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1943.

Analysis of trimodal and bimodal therapy in a selective-surgery paradigm for locally advanced oesophageal squamous cell carcinoma.

Long-term survival outcomes of trimodal therapy (TMT; chemoradiation plus surgery) and bimodal therapy (BMT; chemoradiation) have seldom been analysed. In a selective-surgery paradigm, the benefit of TMT in patients with a complete clinical response is controversial. Factors associated with survival in patients with a clinical complete response to chemoradiation were evaluated. Patients with stage II-III oesophageal squamous cell carcinoma treated with TMT or BMT from 2002 to 2017 were evaluated. The BMT group consisted of patients who were otherwise eligible for surgery but underwent chemoradiation alone followed by observation. This group included patients who later had salvage oesophagectomy. Survival was evaluated and compared between TMT and BMT groups. Elastic net regularization was performed to select co-variables for Cox multivariable survival analysis in patients with a clinical complete response. Of 143 patients, 60 (41.9 per cent) underwent TMT and 83 (58.0 per cent) BMT. Patients who underwent TMT had longer median overall survival than those who had BMT (77 versus 33 months; P = 0.019). For patients with a clinical complete response, TMT achieved longer median overall survival than BMT (123 versus 55 months; P = 0.04). BMT had a high locoregional recurrence rate (48 versus 6 per cent; P < 0.001); 26 of 29 patients with locoregional recurrence in the BMT groupunderwent salvage resection. Cox multivariable analysis demonstrated that upper-mid oesophageal tumour location (hazard ratio (HR) 2.04; P = 0.024) and tumour length (HR 1.18; P = 0.046) were associated with worse survival. Although TMT was not associated with survival, it was a predictor of reduced recurrence (HR 0.28; P = 0.028). The maximum standardized uptake value after chemoradiation also predicted recurrence (HR 1.33; P < 0.001). In patients who achieve a clinical complete response, TMT reduces locoregional recurrence but may not prolong survival. The differences in survival outcomes may be due to patient selection; therefore, a selective-surgery strategy in oesophageal squamous cell carcinoma is a reasonable approach.

Mucosal melanoma of the oral cavity

Primary mucosal melanomas of the head and neck region are uncommon but aggressive malignancies. These lesions arise from melanocytes located in mucosal membranes, predominantly in the nasal cavity, paranasal sinuses, and oral cavity. Mucosal melanomas account for less than 4% of all melanoma cases and are often missed, due to their occult initial presentations. This is in contrast to cutaneous melanomas, which constitute approximately 85% of melanoma cases and present on surfaces exposed to ultraviolet (UV) radiation. The mainstay of treatment for mucosal melanoma is surgical resection with adjuvant radiotherapy for patients with high-risk features. Despite advancements in surgical techniques, radiotherapy, and even systemic therapies, patients with mucosal melanoma face unfavourable prognoses (5-year disease-free survival &lt;25%) with high rates of locoregional recurrence and/or distant metastases. The present case addresses a 47 year-old man who presents to Otolaryngology with an apparent mucosal melanoma involving the upper lip. This patient was informed of a pigmented lesion on the mucosal surface of the upper left lip three years prior by his dentist. Although largely asymptomatic, the lesion has increased in size. The patient undergoes surgical resection with clear margins and reconstruction. He continues to follow-up to monitor for disease recurrence, having denied adjuvant radiation. This case illustrates the diagnosis and approach to mucosal melanomas and highlights some of the key distinctions between mucosal and cutaneous melanomas.

A case report of unilateral conductive hearing loss as a consequence of malignant sinonasal melanoma: the importance of completing a full clinical history and examination

BackgroundSinonasal melanoma is a rare head and neck tumour. It is associated with a poor prognosis, high rates of loco-regional recurrence and distant metastasis. Treatment of the disease is therefore complicated, and because of limited data regarding the cancer, management is frequently tailored to the individual patient. We describe an unusual presentation of sinonasal melanoma with relevant histology, radiology and clinical photography.Case presentationThe case report describes the presentation of a 64-year-old man to the Ear, Nose and Throat department with progressive right-sided hearing loss. A thorough history highlighted other clinical symptoms including unilateral nasal obstruction and epistaxis. Clinical examination showed a right middle ear effusion with a polypoidal lesion in the right nasal cavity. Relevant imaging demonstrated a destructive process that required further assessment. An endoscopic sinus procedure was performed to obtain histological diagnosis as well as providing symptomatic relief. Histology confirmed malignant mucosal melanoma. The patient underwent maxillectomy and orbital exenteration (due to further progression of disease) at a tertiary centre with a plan for subsequent immunotherapy. This however has been delayed due to further surgery to excise a metastatic lesion to the right femur.ConclusionsThis case report highlights the importance of a thorough clinical history and examination. An unusual presentation of a sinonasal tumour can easily be missed leading to a significant delay in treatment. The case report also describes the use of functional endoscopic sinus surgery in order to obtain histological diagnosis and to debulk the tumour, providing symptomatic relief. The current literature regarding management will be discussed as well as current developments guiding future treatment.

Brachytherapy for Elderly Women with Gynecologic Cancer; Single Institutional Experience

To describe toxicity and disease outcomes in women ≥70 years old with gynecologic cancers treated with brachytherapy. We conducted an IRB approved, single-institution retrospective review of women ≥70 years old with gynecological cancers consecutively treated with intracavitary and/or interstitial brachytherapy (BT) from 2000-2019. Cancer, treatment characteristics, time to locoregional recurrence (LRR), distant metastasis (DM), and overall survival (OS) from date of biopsy, Charleston comorbidity score (CCI), and toxicity were collected. Descriptive statistics were calculated and survival was analyzed by Kaplan-Meier (KM) method with log-rank testing to determine significance for univariate analysis. Of the 39 women identified, 21 (54%) were 70-79 years old and 18 (46%) were ≥80 years old. The majority had stage I-II cancers (n = 23, 59%) and 16 (41%) had stage III-IV cancers, with cervical cancer the most common primary (n = 31, 79%), followed by endometrial (n = 4, 10%) and vaginal/vulvar (n = 4, 10%) cancers. BT technique was intracavitary in 19 (49%) and interstitial in 20 (51%). Thirty-four (87%) received BT for primary treatment with or without external beam radiotherapy, and 5 (13%) at time of progression/recurrence. Fifteen (38%) women were treated using 2D planning, while the remainder used CT-based planning. Median follow-up was 30 months for all patients (3-177 months) At the time of analysis, 31 patients (79%) had died, 6 (15%) were alive, and 2 (5%) were lost to follow-up. Median OS by KM was 40 months. Median OS was 22 months for women ³80 and 59 months for women 70-79 (p<0.001). Median OS was 52 months for CCI <5 and 22 months for CCI ≥5 (p = 0.005). Median OS was 50 months in patients without documented recurrence and 29 months for patients who recurred (p = 0.022). Overall local control (LC) was 87% with 2 (5%) LRR, 7 (18%) DM, and 3 (8%) with both LRR and DM. Of the 5 LRR, 3 were vaginal/vulvar, and 2 were cervical primary disease sites. Patients with LRR had a lower average CCI 4.2 vs. 4.9 than those without LRR. Time to DM was shorter for vaginal/vulvar cancers (p = 0.013) and OTT >56 days (p = 0.006). Patients with DM had a lower average CCI 4.3 vs. 5.0 than those without DM. Thirteen patients (33%) experienced grade 3 toxicities including 8 (24%) acute and 7 (18%) late toxicities, there were no grade ≥4 toxicities. Elderly women with gynecological cancers treated with brachytherapy tolerated treatment well with no grade ≥4 toxicities recorded and excellent LC. While CCI ≥5 was a significant predictor for shorter OS, it was not associated with higher rates of LRR nor DM.

The Evaluation of Magee Equation 2 in Predicting Response and Outcome in Hormone Receptor-Positive and HER2-Negative Breast Cancer Patients Receiving Neoadjuvant Chemotherapy.

Background and PurposeMagee Equations have been developed as accurate tools for predicting response and clinical outcomes in breast cancer patients treated with adjuvant systemic therapy using basic clinicopathological parameters. This study aims to evaluate the alternative application of Magee Equation 2 score in predicting pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) in hormone receptor (HR)-positive, HER2-negative breast cancer.Patients and MethodsPatients with HR-positive, HER2-negative breast cancer who received NAC from January 2010 to May 2018 at Siriraj Hospital, Mahidol University, Thailand, were recruited. Pre-treatment status of HR and HER2 was used to calculate the Magee Equation 2 scores. The pCR rates among different clinicopathological parameters were analyzed. Survival analysis was performed by Log-rank test. Kaplan–Meier survival curves were analyzed.ResultsA total of 215 patients were eligible. The pCR rates for low, intermediate, and high scores were 4.8%, 3.6%, and 23.8%, respectively. Patients with high scores had significantly higher size reduction and pCR rates compared to those with intermediate or low scores (p<0.001). Those with high scores had higher rates of locoregional recurrence and death. The patients with high score had significantly lower overall survival (p=0.034).ConclusionAmong patients with HR-positive and HER2-negative breast cancer treated with NAC, Magee Equation 2 might be used as a tool for predicting the pCR and clinical outcome.

Tumor Spread Through Air Spaces Is a Predictor of Occult Lymph Node Metastasis in Clinical Stage IA Lung Adenocarcinoma.

In patients with stage IA lung adenocarcinoma (ADC), sublobar resection and tumor spread through air spaces (STAS) are associated with high rates of locoregional recurrence, half of which occur within the regional lymph nodes (LNs). Our objectives were to investigate the association between occult LN metastasis (ONM) and STAS and to assess their prognostic value in patients with clinical stage IA lung ADC. The association between STAS and ONM was analyzed in patients who underwent lobectomy and LN dissection for clinical stage IA lung ADC (n= 809). Multivariable logistic regression analysis was carried out to identify predictors of ONM. Site-specific recurrence by surgical procedure was investigated in patients with pathologic node-negative disease (n= 1055) using a competing risk approach. ONM was identified in 129 patients (16%)-one-third of ONMs were located only in intrapulmonary nodes. STAS was more common in patients with ONM than in those without ONM (67% versus 39%; p < 0.001) and in patients with multiple ONMs than in those with a single ONM (86%-89% versus 60%-67%). STAS was a significant predictor of ONM (p = 0.004) on multivariable analysis, independent of tumor size, maximum standardized uptake value, and lymphovascular invasion. In patients with STAS-positive ADC (high ONM risk), the risk of recurrence in the treated lobe and regional LNs increased as the extent of resection decreased (recurrence risk: lobectomy < segmentectomy < wedge resection). In patients with STAS-negative ADC, the risk of locoregional recurrence did not differ by procedure type. Presence of STAS predicts ONM in patients with clinical stage IA lung ADC and can help stratify risk of recurrence by extent and type of resection.

Intrinsic radiosensitivity, genomic-based radiation dose and patterns of failure of penile cancer in response to adjuvant radiation therapy.

Optimal postoperative radiation therapy (PORT) dose is unclear in penile squamous cell carcinoma (PeSCC). Herein, we characterized the radiosensitivity index (RSI) and genomic-adjusted radiation dose (GARD) profiles in a cohort of patients with PeSCC, and assessed the application of GARD to personalize PORT. A total of 25 PeSCC samples were identified for transcriptomic profiling. The RSI score and GARD were derived for each sample. A cohort of 34 patients was reviewed for clinical correlation. The median RSI for PeSCC was 0.482 (range 0.215-0.682). The majority (n=21; 84%) of cases were classified as radioresistant. PeSCC GARD ranged from 9.56 to 38.39 (median 18.25), suggesting variable therapeutic effects from PORT. We further determined the optimal GARD-based RT doses to improve locoregional control. We found that therapeutic benefit was only achieved in 52% of PeSCC lesions with PORT of 50Gy, in contrast to 84% benefit from GARD-modeled PORT of 66Gy. In the clinical cohort, the majority of patients presented with pathological N2 or N3 disease (n=31; 91%) and was treated with adjuvant concurrent platinum-based chemoradiotherapy (CRT, n=30; 88%). Fourteen of the 34 patients (41%) had locoregional recurrence (LRR), of which half had LRR within six months of completion of PORT. The majority of PeSCC are intrinsically radioresistant with a low GARD-based therapeutic effect from PORT dose of 50Gy, consistent with the observed high rate of LRR in the clinical cohort. A GARD-based strategy will allow personalizing PORT dose prescription to individual tumor biology and improve outcomes.

Prediction of a positive circumferential resection margin at surgery following neoadjuvant chemotherapy for adenocarcinoma of the oesophagus.

BackgroundA positive circumferential resection margin (CRM) has been associated with higher rates of locoregional recurrence and worse survival in oesophageal cancer. The aim of this study was to establish if clinicopathological and radiological variables might predict CRM positivity in patients who received neoadjuvant chemotherapy before surgery for oesophageal adenocarcinoma.MethodsMultivariable analysis of clinicopathological and CT imaging characteristics considered potentially predictive of CRM was performed at initial staging and following neoadjuvant chemotherapy. Prediction models were constructed. The area under the curve (AUC) with 95% confidence intervals (c.i.) from 1000 bootstrapping was assessed.ResultsA total of 223 patients were included in the study. Poor differentiation (odds ratio (OR) 2·84, 95 per cent c.i. 1·39 to 6·01) and advanced clinical tumour status (T3–4) (OR 2·93, 1·03 to 9·48) were independently associated with an increased CRM risk at diagnosis. CT‐assessed lack of response (stable or progressive disease) following chemotherapy independently corresponded with an increased risk of CRM positivity (OR 3·38, 1·43 to 8·50). Additional CT evidence of local invasion and higher CT tumour volume (14 cm3) improved the performance of a prediction model, including all the above parameters, with an AUC (c‐index) of 0·76 (0·67 to 0·83). Variables associated with significantly higher rates of locoregional recurrence were pN status (P = 0·020), lymphovascular invasion (P = 0·007) and poor response to chemotherapy (Mandard score 4–5) (P = 0·006). CRM positivity was associated with a higher locoregional recurrence rate, but this was not statistically significant (P = 0·092).ConclusionThe presence of advanced cT status, poor tumour differentiation, and CT‐assessed lack of response to chemotherapy, higher tumour volume and local invasion can be used to identify patients at risk of a positive CRM following neoadjuvant chemotherapy.

Oncologic Trends, Outcomes, and Risk Factors for Locoregional Recurrence: An Analysis of Tumor-to-Nipple Distance and Critical Factors in Therapeutic Nipple-Sparing Mastectomy.

Oncologic outcomes with nipple-sparing mastectomy continue to be established. The authors examine oncologic trends, outcomes, and risk factors, including tumor-to-nipple distance, in therapeutic nipple-sparing mastectomies. Demographics, outcomes, and overall trends for all nipple-sparing mastectomies performed for a therapeutic indication from 2006 to 2017 were analyzed. Oncologic outcomes were investigated with specific focus on recurrence and associated factors, including tumor-to-nipple distance. A total of 496 therapeutic nipple-sparing mastectomies were performed, with an average follow-up time of 48.25 months. The most common tumor types were invasive carcinoma (52.4 percent) and ductal carcinoma in situ (50.4 percent). Sentinel lymph node sampling was performed in 79.8 percent of nipple-sparing mastectomies; 4.1 percent had positive frozen sentinel lymph node biopsy results, whereas 15.7 percent had positive nodal status on permanent pathologic examination. The most common pathologic cancer stage was stage IA (42.5 percent) followed by stage 0 (31.3 percent). The rate of local recurrence was 1.6 percent (n = 8), and the rate of regional recurrence was 0.6 percent (n = 3). In all, 171 nipple-sparing mastectomies had magnetic resonance imaging available with which to assess tumor-to-nipple distance. Tumor-to-nipple distance of 1 cm or less (25.0 percent versus 2.4 percent; p = 0.0031/p = 0.1129) and of 2 cm or less (8.7 percent versus 2.0 percent; p = 0.0218/p = 0.1345) trended to higher rates of locoregional recurrence. In univariate analysis, tumor-to-nipple distance of 1 cm or less was the only significant risk factor for recurrence (OR, 13.5833; p = 0.0385). No factors were significant in regression analysis. In early stage and in situ breast carcinoma, therapeutic nipple-sparing mastectomy appears oncologically safe, with a locoregional recurrence rate of 2.0 percent. Tumor-to-nipple distances of 1 cm or less and 2 cm or less trended to higher recurrence rates. Risk, III.

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

PurposeInflammatory 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 formal dedication of an IBC-specific clinic and research program in 2006. Institutionally, a standard twice-daily (BID) dose escalation regimen for all patients with IBC was de-escalated in select cases in 2006 after review demonstrated that young age, incomplete response to neoadjuvant therapy, and positive margins identified subsets with maximal benefit from dose escalation. We report local control and toxicity rates specific to BID versus once-daily (QD) radiation therapy approaches. Methods and MaterialsFrom a prospectively collected database, we identified 103 patients with nonmetastatic IBC who received trimodality therapy at our institution from 2007 to 2015. Descriptive statistics were used to describe the study cohort and compare retrospectively extracted rates of radiation therapy–associated toxicity. The actuarial rate of LRR-free survival was analyzed using the Kaplan-Meier method. ResultsThe median follow-up is 3.6 years. Thirty-nine patients (37.9%) received postmastectomy radiation therapy (PMRT) to the chest wall and undissected regional lymphatics in QD fractions (median dose, 50.0 Gy in 25 fractions [fx]; median boost dose, 10.0 Gy in 5 fx) and 64 patients (62.1%) received BID PMRT (median dose, 51.0 Gy in 34 fx; median boost dose, 15.0 Gy in 10 fx). Crude rates of toxicity were not different between patients treated with QD or BID PMRT. Two BID patients (3.1%) and no QD patients (0.0%) experienced LRR (P = .53). The 3- and 5-year LRR-free survival were 95.1% and 100.0% for BID and QD patients, respectively (P = .25). ConclusionsTailoring radiation therapy 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 with BID, although retrospective data collection may limit this comparison.