bims-netuvo 2021-10-31 papers

bims-netuvo

Biomed News

on Nerves in tumours of visceral organs

Issue of 2021–10–31
sixteen papers selected by
Maksym V. Kopanitsa, The Francis Crick Institute

Eukaryotic initiation factor 2 signaling behind neural invasion linked with lymphatic and vascular invasion in pancreatic cancer.
Perineural Invasion as a Risk Factor for Locoregional Recurrence of Invasive Breast Cancer.
Determinants of prognosis in patients with oral squamous cell carcinoma metastasizing to a single cervical lymph node.
Clinical Outcomes of Histologically Verified Salivary Ductal Carcinomas: Retrospective Analysis of 89 Patients Treated Over 47 Years.
Inter-Correlations Between Various High-Risk Pathological Factors in Resected Buccal Mucosal Squamous Cell Carcinoma.
Predictors of Recurrence and Survival in High-Stage Primary Cutaneous Squamous Cell Carcinoma: A Recursive Partitioning Analysis.
Comparison of Neoadjuvant Rectal Score and MRI-Based Nomogram Model as Disease-Free Survival Predictors for Locally Advanced Rectal Cancer Patients.
Comparison of Demographic and Clinicopathological Characteristics of Basal Cell Carcinoma on the Nose and Other Sites of the Face: A Cross-Sectional Study.
Comparison of Clinical and Toxicity Outcomes of Adenoid Cystic Carcinomas Treated With Intensity Modulated Radiation Therapy vs. Proton Radiotherapy.
Patterns of Perineural Skull Base Tumor Extension from Extracranial Tumors.
Resected pancreatic adenocarcinoma: An Asian institution's experience.
Neurolymphomatosis related to direct epineural invasion of the superficial peroneal nerve from subcutaneous B-cell lymphoma.
BCAR3 promotes head and neck cancer growth and is associated with poor prognosis.
Invasion of a Recurrent Laryngeal Nerve from Small, Well-Differentiated Papillary Thyroid Cancers: Patient Selection Implications for Active Surveillance.
10-Year Outcomes Following Proton Therapy for Localized Prostate Cancer.
Kallikrein 11 Down-regulation in Breast Carcinoma: Correlation With Prognostic Parameters.

Sci Rep. 2021 Oct 27. 11(1): 21197

Eukaryotic initiation factor 2 signaling behind neural invasion linked with lymphatic and vascular invasion in pancreatic cancer.

Taiichi Wakiya, Keinosuke Ishido, Norihisa Kimura, Hayato Nagase, Tadashi Yoshizawa, Satoko Morohashi, Hiroaki Fujita, Taishu Kanda, Yota Tatara, Junji Saruwatari, Hiroshi Kijima, Kenichi Hakamada.

Perineural invasion (PNI) is a typical poor prognostic factor in pancreatic ductal adenocarcinoma (PDAC). The mechanisms linking PNI to poor prognosis remain unclear. This study aimed to clarify what changes occurred alongside PNI in PDAC. A 128-patient cohort undergoing surgery for early-stage PDAC was evaluated. Subdivided into two groups, according to pathological state, a pancreatic nerve invasion (ne) score of less than three (from none to moderate invasion) was designated as the low-grade ne group. The high-grade (marked invasion) ne group (74 cases, 57.8%) showed a higher incidence of lymphatic metastasis (P = 0.002), a higher incidence of early recurrence (P = 0.004), decreased RFS (P < 0.001), and decreased DSS (P < 0.001). The severity of lymphatic (r = 0.440, P = 0.042) and venous (r = 0.610, P = 0.002) invasions was positively correlated with the ne score. Tumors having abundant stroma often displayed severe ne. Proteomics identified eukaryotic initiation factor 2 (EIF2) signaling as the most significantly enriched pathway in high-grade ne PDAC. Additionally, EIF2 signaling-related ribosome proteins decreased according to severity. Results showed that PNI is linked with lymphatic and vascular invasion in early-stage PDAC. Furthermore, the dysregulation of proteostasis and ribosome biogenesis can yield a difference in PNI severity.

DOI: https://doi.org/10.1038/s41598-021-00727-3
Int J Radiat Oncol Biol Phys. 2021 Nov 01. pii: S0360-3016(21)01580-7. [Epub ahead of print]111(3S): e197

Perineural Invasion as a Risk Factor for Locoregional Recurrence of Invasive Breast Cancer.

P Narayan, J Flynn, Z Zhang, E F Gillespie, B A Mueller, A J Xu, J J Cuaron, B McCormick, A J Khan, O Cahlon, S N Powell, H Y Wen, L Z Braunstein.

PURPOSE/OBJECTIVE(S): Perineural invasion (PNI) is a pathologic finding observed across a spectrum of solid tumors, typically with adverse prognostic implications. Little is known about how the presence of PNI influences locoregional recurrence (LRR) among breast cancers. We evaluated the association between PNI and LRR among an unselected, broadly representative cohort of breast cancer patients, and among a propensity-score matched cohort.
MATERIALS/METHODS: We ascertained breast cancer patients seen at our institution from 2008 to 2019 for whom PNI status and salient clinicopathologic features were available. Fine-Gray regression models were constructed to evaluate the association between PNI and LRR, accounting for age, tumor size, nodal involvement, estrogen receptor (ER), progesterone receptor (PR), HER2 status, histologic tumor grade, presence of lymphovascular invasion (LVI), and receipt of chemotherapy and/or radiation. Analyses were then refined by comparing PNI-positive patients to a PNI-negative cohort defined by propensity score matching.
RESULTS: Among 8,864 invasive breast cancers, 1384 (15.6%) were noted to harbor PNI. At a median follow-up of 6.3 years, 428 locoregional recurrence events were observed yielding a 7-year LRR of 7.1% (95% CI 5.5-9.1) for those with PNI and 4.7% (95% CI 4.2-5.3; P = 0.01) for those without. On univariate analysis throughout the entire cohort, presence of PNI was significantly associated with an increased risk of LRR (HR 1.39, 95% CI 1.08 - 1.78, P < 0.01). Accounting for differences in salient clinicopathologic and treatment parameters by multivariable Fine-Gray regression modeling, the association between PNI and LRR was potentiated (HR = 1.57, 95% CI 1.2 - 2.07, P = 0.001). We further conducted propensity score matching to balance clinicopathologic parameters and treatments between the two groups (PNI vs not), again showing a similar significant association between PNI and LRR (HR = 1.46, 95% CI 1.03 - 2.08, P = 0.034).
CONCLUSION: PNI is significantly associated with LRR following the definitive treatment of invasive breast cancer. The excess risk conferred by PNI is similar in magnitude to that observed with LVI, or by ER/PR negativity. Breast cancer prognostication and therapeutic decision-making should consider the presence of PNI among other salient risk factors. Larger studies among more uniform breast cancer presentations may elucidate the extent to which these findings apply across breast cancer subtypes and stages.

DOI: https://doi.org/10.1016/j.ijrobp.2021.07.710
Oral Oncol. 2021 Oct 25. pii: S1368-8375(21)00693-X. [Epub ahead of print]123 105586

Determinants of prognosis in patients with oral squamous cell carcinoma metastasizing to a single cervical lymph node.

Pattatheyil Arun, Indu Arun, Prateek Jain, Kapila Manikantan, Rajeev Sharan.

   OBJECTIVES: Metastasis in a single lymph node without adverse tumour factors and perineural invasion has been assigned to a lower risk category by the ASCO recommendations of 2019. We analyzed patients with a single positive node with a view to identifying high risk features and their impact on prognosis within this subgroup.
MATERIALS AND METHODS: The study retrospectively analyzed 707 patients with OSCC. Descriptive statistics were used to compare distribution of clinicopathologic risk features between 323 N0 and 121 single node positive (Ns) patients. The Ns group was further analyzed for the impact of clinicopathologic factors on disease free (DFS) and overall survival (OS) using univariate and multivariate models.
RESULTS: The Ns group exhibited greater depth of invasion compared to the N0 group and significantly higher proportion of lymphovascular invasion (LVI), perineural invasion (PNI) and poorly differentiated tumors. Within the Ns group, primary tumor localised to the gingivobuccal subsite (HR 2.55, 1.18-5.52 95%CI, p = 0.02) and PNI (HR 2.55, 1.14-5.62, 95%CI p = 0.02) exhibited poor DFS. PNI also contributed to poor OS (HR 2.86, 1.27-6.47 95%CI, p = 0.01). Uninvolved margins (HR 0.46, 0.22-0.96 95%CI, p = 0.04) and chemoradiation (HR 0.18,0.05-0.68 95% CI, p = 0.01) improved OS.
CONCLUSION: Significant differences are noted in the prevalence of pathologic risk factors between the single node positive and node negative groups. Within the single node positive group, tumour factors like the gingivobuccal subsite, PNI and margin positivity impacted survival. Among nodal factors, deposit size of 12 mm or more and presence of ENE are pointers to poor prognosis. These patients would benefit from adjuvant treatment.

Keywords:  Node positive neck; Oral cancer; Pathologic risk factors; Prognostic factors; Single positive node

DOI:  https://doi.org/10.1016/j.oraloncology.2021.105586
Int J Radiat Oncol Biol Phys. 2021 Nov 01. pii: S0360-3016(21)02058-7. [Epub ahead of print]111(3S): e413-e414

Clinical Outcomes of Histologically Verified Salivary Ductal Carcinomas: Retrospective Analysis of 89 Patients Treated Over 47 Years.

S Ebrahimi, S H Patel, L A McGee, J J Garcia, D J Ma, R L Foote, Y Garces, M Neben Wittich, K Price, A Schmitt, Q Zhai, B C May, T H Nagel, M L Hinni, D M Routman, A V Chintakuntlawar, J C Rwigema.

PURPOSE/OBJECTIVE(S): Salivary duct carcinomas (SDC) make up < 2% of salivary duct tumors but are very aggressive with a low 5-year survival rate of 35%. This series reports long term outcomes of patients with SDC treated at a single institution.
MATERIALS/METHODS: Patients ≥18 years with histological confirmation of SDC treated with curative intent from 1961-2018 were included in this analysis. Patients were excluded if treatment was palliative intent (N = 14), and if staging (N = 4) or locoregional control (LRC) status (N = 7) was not recorded. 89 patients (74% male) met criteria for inclusion. Median age was 66 years (range: 32 - 89). AJCC 8 staging of patients were as follows: 13% (I), 6% (II), 12% (III), 62% (IVa), and 7% (IVb). 67% of patients were lymph node positive. Kaplan Meier analyses were used to estimate LRC and OS rates. Bivariate regression analyses using disease and treatment characteristics (i.e., perineural invasion (PNI), extracapsular extension (EE), vascular invasion (VI), CN VII sacrifice, extraparenchymal involvement (EI)) for prediction of LRC and OS were performed.
RESULTS: Median follow-up was 48.5 months (0.4-343 mo). Most patients were treated with combined modality therapy; 82% (n = 73) undergoing curative surgery followed by adjuvant radiotherapy (RT) with (26%, n = 23) or without (56%, n = 50) concurrent chemo while 4.5% (n = 4) were treated with definitive RT; 2.3% (n = 2) receiving concurrent chemo. 13.5% (n = 12) were treated with surgery alone. Crude post-treatment LRC after surgery alone, surgery followed by adjuvant RT, and definitive RT alone were 66.7, 78.1 and 0% (P = 0.002), respectively. The odds of achieving LRC were diminished with incidence of VI (odds ratio (OR) = 0.07, P = 0.02), EI (OR = 0.3, P = 0.03), and T3/T4 staging (OR = 0.3, P = 0.03). Chemotherapy did not influence LRC. The occurrence of distant metastases was associated with PNI (OR = 5, P = 0.003) and EI (OR = 2.6, P = 0.03). EI status was also associated with a shorter time to recurrence (26 vs 17.3 mo, P = 0.04). Median overall survival (OS) was 55.3 months (41.7-81.7 95% CI) with 82% surviving at 2 years, 47% at 5 years, and 28% at 10 years. Failure to achieve LRC (81.7 vs 36 mo, P < 0.001), distant metastases (108.5 vs 41.7 mo, P < 0.001), VI (86.2 vs 46.8 mo, P = 0.046), T3/T4 staging (125.8 vs 48.8 mo, P = 0.02), PNI (88.1 vs 48.8 mo, P = 0.03), and EI (108.5 vs 47.3 mo, P = 0.004) were found to significantly reduce median OS.
CONCLUSION: SDC is an aggressive tumor that requires a multimodality treatment approach. Patients analyzed here had a 5-year survival greater than what is typically reported for SDC (47 vs. 35%). Definitive radiotherapy was less likely to control gross disease and should be reserved for the adjuvant setting if surgery is an option. We identified incidence of extraparenchymal involvement, perineural and vascular invasion as negative prognostic indicators of disease control and survival.

DOI: https://doi.org/10.1016/j.ijrobp.2021.07.1188
Int J Radiat Oncol Biol Phys. 2021 Nov 01. pii: S0360-3016(21)02007-1. [Epub ahead of print]111(3S): e390

Inter-Correlations Between Various High-Risk Pathological Factors in Resected Buccal Mucosal Squamous Cell Carcinoma.

P Ahlawat, T Singh, M Gairola, S Tandon, S Purohit, N Sachdeva, M Ismail Sharief, K Dobriyal, A Krishnan.

PURPOSE/OBJECTIVE(S): While exploring histopathological high-risk factors for squamous cell oral cancer most studies have included oral tongue as major subsite in their patient population. Buccal mucosal squamous cell carcinoma (BMSCC) being rare in developed countries is a less studied site in this regard. Hence most of the knowledge we have about high-risk factors of BMSCC is extrapolated from oral tongue carcinoma. The objective of this study was to explore inter-correlations between various pathological high-risk factors found in resected specimen of BMSCC.
MATERIALS/METHODS: It was a retrospective analysis in which we reviewed the final histopathology of surgical specimen of 150 patients with BMSCC who had undergone upfront surgical resection followed by adjuvant therapy. Various high-risk factors studied were pT Stage, pN Stage, depth of invasion (DOI), grade, perineural invasion (PNI), lymphovascular invasion (LVI), tumor thickness (TT), worst pattern of invasion (WPOI), and extranodal extension (ENE). Inter-correlations were performed between various pathological factors using Spearman's correlation test.
RESULTS: Inter-correlation between various factors were found and shown in Table.
CONCLUSION: pT stage showed significant positive correlation with pN stage, TT, DOI, PNI, nodal deposit size and with ENE. pN stage showed significant positive correlation with pT stage, PNI, LVI, WPOI and ENE. PNI showed significant positive correlation with pT stage, pN stage, nodal deposit size, ENE, LVI, DOI, TT, WPOI. LVI showed significant positive correlation with PNI, WPOI, pN stage, nodal deposit size and ENE. DOI showed significant positive correlation with pT stage, PNI, TT. TT showed significant positive correlation with pT stage, PNI and DOI. WPOI showed significant positive correlation with pN stage, frozen section margin, PNI, LVI and ENE. ENE showed significant positive correlation with pT stage, pN stage, PNI, LVI and WPOI. Grade, configuration and margin status of the tumor showed no significant association with any of the histopathologic variable. Many of these correlations are not shown in oral tongue cancer in most studies. Hence, it is appropriate that intercorrelation between these factors in BMSCC should be dealt differently than in oral tongue cancer. BMSCC may have different biology than oral tongue cancer.

DOI: https://doi.org/10.1016/j.ijrobp.2021.07.1137
Int J Radiat Oncol Biol Phys. 2021 Nov 01. pii: S0360-3016(21)02067-8. [Epub ahead of print]111(3S): e417-e418

Predictors of Recurrence and Survival in High-Stage Primary Cutaneous Squamous Cell Carcinoma: A Recursive Partitioning Analysis.

T Smile, E Ilori, V Varra, E S Ruiz, F Murad, W Wei, D Xiong, A Vidimos, C M Poblete-Lopez, J Lucas, J G Meine, B Gastman, J L Geiger, C D Schmults, S Koyfman.

PURPOSE/OBJECTIVE(S): High stage cutaneous squamous cell carcinoma (CSCC) has an elevated risk of recurrence (5-25%). Current staging systems stratify patients rely on tumor factors only. We sought to develop an RPA incorporating patient-, tumor-, disease-, and treatment-related factors to identify prognostic subgroups for high-stage CSCC patients receiving definitive therapy.
MATERIALS/METHODS: All high-stage CSCCs, defined as Brigham & Women's Hospital (BWH) tumor (T) staging system T2B and T3, treated with curative intent were included. Recurrence-free survival (RFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared by log rank test. Recursive partitioning analysis (RPA) was performed to identify prognostic factors for RFS and OS.
RESULTS: A total of 444 patients (76% male, 95% Caucasian, median age 74 years) with 523 primary tumors were included. Median follow up was 31 months (range 1-194). 31% of patients were immunosuppressed (organ transplant 13%, chronic lymphocytic leukemia (CLL) 14%, and other reasons 3%). 432 tumors were BWH T2b and 91 were BWH T3, of whom 12% were node-positive, 32% node-negative, and 56% unknown nodal status. 33% of patients experienced recurrence. Immunosuppression, recurrent tumor, perineural invasion (PNI), and lymphovascular space invasion (LVSI) were associated with significantly worse RFS (median RFS 23 months, 95% CI, 19-28), while immunosuppression, lymph node positivity, and extranodal extension (ENE) were associated with significantly worse OS (median OS 40 months, 95% CI, 33-46). RPA identified 4 prognostic subgroups with distinct RFS patterns (P < 0.0001): class I included age < 77 years without LVSI (N = 212, 2-year RFS: 63%; 95% CI, 56-70%), class II included age ≥ 77 years without PNI (N = 132, 2-year RFS: 44%, 95% CI, 36-55%), class III included age < 77 years with LVSI (N = 36, 2-year RFS: 29%; 95% CI, 17-50%), and class IV included age ≥ 77 years with PNI (N = 60, 2-year RFS: 25%; 95% CI, 15-41%). RPA identified 4 prognostic subgroups with distinct OS patterns (P < 0.0001): class I included age < 78 years and ≤ 1 lymph node positive (N = 221, 2-year OS: 84%; 95% CI, 79-90%), class II included age ≥ 78 years and no or immunosuppression other than CLL (N = 141, 2-year OS: 64%; 95% CI, 55-73%), class III included age < 78 years and > 1 lymph node positive (N = 48, 2-year OS: 54%; 95% CI, 41-71%), and class IV included age ≥ 78 years and immunosuppression from CLL (N = 34, 2-year OS: 37%; 95% CI, 23-57%).
CONCLUSION: An RPA classification system was created for patients with high-stage primary CSCC treated with definitive intent that identifies 4 prognostic subgroups associated with recurrence-free survival and overall survival based on age, LVSI, PNI, burden of nodal metastasis, and immunosuppression status. This has implications for patient counselling, clinical trial design and post-treatment surveillance.

DOI: https://doi.org/10.1016/j.ijrobp.2021.07.1197
Int J Radiat Oncol Biol Phys. 2021 Nov 01. pii: S0360-3016(21)01219-0. [Epub ahead of print]111(3S): e34-e35

Comparison of Neoadjuvant Rectal Score and MRI-Based Nomogram Model as Disease-Free Survival Predictors for Locally Advanced Rectal Cancer Patients.

S Chen, Y Tang, N Li, J Jiang, L Jiang, B Chen, H Fang, S Qi, N Lu, Y Yang, S Wang, Y Song, Y Liu, Y Li, J Jin.

PURPOSE/OBJECTIVE(S): To compare the prognostic value of neoadjuvant rectal (NAR) score and MRI-based nomogram model for locally advanced rectal cancer (LARC) treated with neoadjuvant therapy.
MATERIALS/METHODS: Retrospective analysis was performed for 233 patients with LARC (T3-4 and/or N1-2, M0), who were initially treated in our institution from Mar.2015 to Mar.2018. All patients had baseline MRI assessments and received neoadjuvant therapy and TME surgery. The neoadjuvant rectal (NAR) score was calculated according to the baseline MRI factor (cT) and pathological stage (pT, pN). NAR = [5pN-3(cT-pT)+12]2/9.61. The patients were sequentially allocated to two cohorts (training cohort and validation cohort) in a ratio of 4:3 based on the date of image examination. The nomogram model was constructed based on the results of univariate logistic regression analysis and multivariable cox regression analysis of the training cohort for disease-free survival (DFS). The nomogram and NAR score were evaluated by Harrell's concordance index (C-index), calibration plots, receiver operating characteristic curve (ROC) analysis, and decision curve analysis (DCA) in both training and validation cohort.
RESULTS: With a median follow-up of 43.2 months (13.3-61.3months) in the training cohort and 32.0 months (12.3-39.5 months) in the validation cohort. Multivariate cox regression analysis identified the MRI-detected extramural vascular invasion (mrEMV), pathological T stage (ypT) and perineural invasion (PNI) as independent predictors. According to previous studies, lymph vascular invasion (LVI) (which was founded to be significant after univariate regression analysis) and three other independent predictors are included in the nomogram model. The univariate survival analysis showed that the nomogram model and NAR score were correlated with 3-year DFS (P < 0.05). For comparison, the nomogram performed better over the NAR score (C-index 0.76 (95% CI 0.70-0.84) versus 0.66 (95% CI 0.60-0.71) for the training cohort, and 0.77 (95% CI 0.70-0.85) versus 0.69(0.60-0.78) for the validation cohort).The nomogram model achieved a better 3-year DFS predictive capacity (AUC = 0.84 in the training cohort; AUC = 0.77 in the validation cohort) than NAR score (AUC = 0.70 in the training cohort; AUC = 0.73 in the validation cohort). DCA revealed that the use of the nomogram model was associated with better benefit gains relative to the prediction of 3-year DFS compared to NAR score in training cohort (threshold probability range between 0.06 and 0.54) and validation cohort (threshold probability range between 0.08 and 0.50).
CONCLUSION: We developed and validated a novel nomogram model based on MRI factor and pathological factors for predicting DFS in LARC treated with neoadjuvant therapy. Compared with NAR score, nomogram model shows the better potential predictive value of prognosis, which could improve the risk stratification and individual treatment for LARC patients.

DOI: https://doi.org/10.1016/j.ijrobp.2021.07.349
Iran J Otorhinolaryngol. 2021 Sep;33(118): 257-262

Comparison of Demographic and Clinicopathological Characteristics of Basal Cell Carcinoma on the Nose and Other Sites of the Face: A Cross-Sectional Study.

Hossein Kavoussi, Ali Ebrahimi, Mansour Rezaei, Fariba Najafi, Mahsa Zarpoosh, Reza Kavoussi.

   Introduction: The clinicopathological characteristics of basal cell carcinoma (BCC) in different areas of the face, including the nose, are important and may be different. Accurate recognition of these characteristics may be necessary for the planning and selection of appropriate treatment.
Materials and Methods: This cross-sectional study was conducted on 328 patients (131 females and 197 males) with 371 documented facial BCC in the West of Iran within 2013-2018. The demographic and clinicopathological data of the patients in the nose area were compared with other sites of the face by appropriate statistical methods.
Results: Out of 371 lesions, 38.8% of the cases were on the nose, 75.8% were primary lesions, 97.8% had no perineural invasion, 89.2% were nodular, and 65.8% were of nodular clinical and pathologic type, which were the most common variables of patients. It was revealed that early-onset (P<0.001), smaller size (P<0.001), high-risk pathologic type (P=0.01), and recurrent lesions (P=0.013) were significantly higher in the nasal BCC. However, there was no significant difference between BCC in the nose and other sites of the face in terms of gender (P=0.654), high-risk clinical type (P=0.06), and perineural invasion (P=0.275).
Conclusion: Considering the nasal site as an important cosmetic unit, more limitation of the nose in performing any procedure, and presence of the more risk factors in the nose than in other areas of the face, the definite treatment of nasal BCC requires special attention, expertise, and experience.

Keywords:  Basal cell carcinoma; Face; Nose; Perineural invasion

DOI:  https://doi.org/10.22038/ijorl.2021.47720.2575
Int J Radiat Oncol Biol Phys. 2021 Nov 01. pii: S0360-3016(21)02057-5. [Epub ahead of print]111(3S): e413

Comparison of Clinical and Toxicity Outcomes of Adenoid Cystic Carcinomas Treated With Intensity Modulated Radiation Therapy vs. Proton Radiotherapy.

S Ebrahimi, S H Patel, D J Ma, J C Rwigema, R L Foote, S C Lester, T H Nagel, M J Eric, T A DeWees, M A Golafshar, D M Routman, M Y Halyard, M A Neben-Wittich, L A McGee.

PURPOSE/OBJECTIVE(S): Adenoid cystic carcinomas (ACC) are indolent malignancies with a predilection for perineural invasion (PNI), often requiring complex multimodal care. This study compares clinical and toxicity outcomes in patients treated with either intensity modulated radiation therapy (IMRT) or proton therapy (IMPT).
MATERIALS/METHODS: 48 ACC patients treated with definitive or adjuvant RT from 2013-2020 at a single institution were included in this IRB approved analysis. Acute and chronic toxicity (CTCAE 4) was prospectively recorded weekly through treatment and at each follow-up appointment. Multivariate, bivariate, and Kaplan Meier analyses were utilized.
RESULTS: IMRT (N = 25) and IMPT (N = 23) groups were matched for gender (44 vs 52% F), age (56 vs 53 yr), primary site presentation (56 vs 57% major salivary glands), AJCC stage (8 vs 13% (I), 24 vs 22% (II), 32 vs 22% (III), and 36 vs 43% (IV)), and treatment intent (84 vs 78% adjuvant). Median follow-up was 43.7 mo (IMRT) and 23.8 mo (IMPT). IMPT use tended to favor primary site location including and superior to the palate (56% vs 24%) while IMRT use tended to favor locations below the palate (60% vs 22%). There was no difference in treatment modality selection for a lateral primary site location (22% IMPT vs 16% IMRT), most of which were parotid (N = 8/9). 44% of IMRT patients received RT to cervical lymph nodes in comparison to only 13% with IMPT (P = 0.03). Patients treated with IMPT tended to have a higher overall dose (median 6 vs 6.6 Gy; P = 0.01). Clinical outcomes at last follow-up were similar between the 2 cohorts: locoregional control (88% IMRT vs 91% PT); metastasis-free (72% IMRT vs 91% IMPT) and overall survival (96% IMRT vs 94% IMPT at 2 years). No difference was observed in acute or chronic grade 2 (G2; 88 vs 87% acute, 39 vs 33% chronic) or grade 3 (G3; 20 vs 22% acute, 17 vs 14% chronic) toxicity profiles. Acute toxicities included pain, mucositis, fatigue, and dermatitis, while chronic toxicities were xerostomia, dysphagia, pain, and dysgeusia. There were no reports of symptomatic neurological toxicities including neuropathy and encephalopathy. Reports of ≥2 acute G2 toxicity were associated with histological evidence of PNI (OR = 27, P = 0.001), while ≥2 chronic G2 toxicities were associated with clinical evidence of PNI and positive margins (OR = 10.1, P = 0.007; OR = 11, P = 0.03). Factors that were assessed and found not to be associated with toxicity profiles included stage, LN radiation, cranial nerve tracking, lymphovascular invasion, tumor volume and location.
CONCLUSION: Patients treated with both IMRT and IMPT appear to have acceptable clinical outcomes and toxicity profiles. IMPT selection in this series appeared to favor subsites near the base of skull and higher dose yet resulted in similar toxicity profiles as those patients treated with IMRT. Longer follow up is needed.

DOI: https://doi.org/10.1016/j.ijrobp.2021.07.1187
Neuroimaging Clin N Am. 2021 Nov;pii: S1052-5149(21)00041-1. [Epub ahead of print]31(4): 473-483

Patterns of Perineural Skull Base Tumor Extension from Extracranial Tumors.

Bernhard Schuknecht.

  Perineural extension is an increasingly recognized pathway of extension of cutaneous, mucosal, and salivary gland neoplasms associated with a severe adverse prognosis. Imaging identification is feasible by MR imaging 3-dimensional contrast-enhanced submillimetric sequences. The trigeminal nerve branches and facial nerve are the most commonly involved. PET with computed tomography may aid in the identification of the primary tumor location or recognition of recurrence, but only in conjunction with MR imaging does it achieve similar detection rates for perineural extension. Computed tomography scanning is an adjunct to MR imaging to increase specificity and for surgical treatment planning.

Keywords:  3D MR submillimetric sequences; Facial-trigeminal nerve anastomoses; Head and neck malignancy; Perineural invasion and extension; Skull base

DOI:  https://doi.org/10.1016/j.nic.2021.05.007
Cancer Rep (Hoboken). 2021 Oct;4(5): e1393

Resected pancreatic adenocarcinoma: An Asian institution's experience.

Kennedy Yao Yi Ng, Edwin Wei Xiang Chow, Bochao Jiang, Cindy Lim, Brian Kim Poh Goh, Ser Yee Lee, Jin Yao Teo, Damien Meng Yew Tan, Peng Chung Cheow, London Lucien Peng Jin Ooi, Pierce Kah Hoe Chow, Joycelyn Jie Xin Lee, Juinn Huar Kam, Ye Xin Koh, Prema Raj Jeyaraj, Ek Khoon Tan, Su Pin Choo, Chung Yip Chan, Alexander Yaw Fui Chung, David Tai.

   BACKGROUND: Pancreatic adenocarcinoma (PDAC) is highly lethal. Surgery offers the only chance of cure, but 5-year overall survival (OS) after surgical resection and adjuvant therapy remains dismal. Adjuvant trials were mostly conducted in the West enrolling fit patients. Applicability to a general population, especially Asia has not been described adequately.
AIM: We aimed to evaluate the clinical outcomes, prognostic factors of survival, pattern, and timing of recurrence after curative resection in an Asian institution.
METHODS AND RESULTS: The clinicopathologic and survival outcomes of 165 PDAC patients who underwent curative resection between 1998 and 2013 were reviewed retrospectively. Median age at surgery was 62.0 years. 55.2% were male, and 73.3% had tumors involving the head of pancreas. The median OS of the entire cohort was 19.7 months. Median OS of patients who received adjuvant chemotherapy was 23.8 months. Negative predictors of survival include lymph node ratio (LNR) of >0.3 (HR = 3.36, P = .001), tumor site involving the body or tail of pancreas (HR = 1.59, P = .046), presence of perineural invasion (PNI) (HR = 2.36, P = .018) and poorly differentiated/undifferentiated tumor grade (HR = 1.86, P = .058). The median time to recurrence was 8.87 months, with 66.1% and 81.2% of patients developing recurrence at 12 months and 24 months respectively. The most common site of recurrence was the liver.
CONCLUSION: The survival of Asian patients with resected PDAC who received adjuvant chemotherapy is comparable to reported randomized trials. Clinical characteristics seem similar to Western patients. Hence, geographical locations may not be a necessary stratification factor in RCTs. Conversely, lymph node ratio and status of PNI ought to be incorporated.

Keywords:  pancreatic adenocarcinoma; prognostic factors; resected

DOI:  https://doi.org/10.1002/cnr2.1393
Clin Neurol Neurosurg. 2021 Oct 18. pii: S0303-8467(21)00521-7. [Epub ahead of print]210 106992

Neurolymphomatosis related to direct epineural invasion of the superficial peroneal nerve from subcutaneous B-cell lymphoma.

G Fargeot, T Maisonobe, C Vandendries, M Le Garff-Tavernier, V Leblond, K Viala.

  Neurolymphomatosis is a rare complication of systemic lymphomas, and is classically related to hematogenous spread or intraneural spread of tumor cells from the leptomeninges. Here we report a case of neurolymphomatosis related to direct epineural invasion of the superficial peroneal nerve from subcutaneous localization of B-cell lymphoma. Nerve biopsy revealed striking histological features suggestive of contiguous infiltration of the superficial peroneal nerve by subcutaneous lymphoma. We think this case report sheds new light on neurolymphomatosis pathophysiology with an unreported mechanism in B-cell lymphoma. It also points out that the clinical spectrum in neurolymphomatosis is really variable, pure sensory mononeuritis being a rare presentation. Finally, our case is also strongly illustrative of the contribution of early nerve ultrasonography in the patient diagnosis and in guidance of the nerve biopsy.

Keywords:  magnetic resonance neurography; nerve biopsy; nerve ultrasound; neurolymphomatosis; small cell lymphocytic lymphoma; vasculitis

DOI:  https://doi.org/10.1016/j.clineuro.2021.106992
Cell Death Discov. 2021 Oct 27. 7(1): 316

BCAR3 promotes head and neck cancer growth and is associated with poor prognosis.

Ze Zhang, Yafei Wang, Yun Wang, Chunli Wang, Yanjie Shuai, Jingtao Luo, Ruoyan Liu.

Breast cancer anti-estrogen resistance protein 3 (BCAR3) is involved in anti-estrogen resistance and other important aspects of breast cancer. However, the role of BCAR3 in other solid tumors remains unclear. The relationship between the clinicopathologic characteristics of head and neck squamous cell carcinoma (HNSCC) patients and BCAR3 was analyzed using the Wilcoxon's signed-rank test and logistic regression. The association between BCAR3 expression and clinicopathologic features and survival was analyzed using Cox regression and the Kaplan-Meier method. In vivo and in vitro assays were performed to validate the effect of BCAR3 on HNSCC growth. BCAR3-related mRNAs were determined by calculating the Pearson's correlation coefficient based on The Cancer Genome Atlas (TCGA). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, and gene set enrichment analysis (GSEA) were used to predict the potential functions of BCAR3. BCAR3 expression is overexpressed in HNSCC and was shown to be associated with perineural invasion (PNI) and poor survival. BCAR3 silencing significantly attenuated the proliferation of HNSCC cells, whereas BCAR3 depletion inhibited tumor growth in vitro. GO and KEGG functional enrichment analyses, and GSEA showed that BCAR3 expression in HNSCC was associated with biological processes, such as cell adhesion, actin binding, cadherin binding, and angiogenesis. BCAR3, which promotes HNSCC growth, is associated with perineural invasion and may be a potential molecular prognostic marker of poor survival in HNSCC.

DOI: https://doi.org/10.1038/s41420-021-00714-7
Thyroid. 2021 Oct 29.

Invasion of a Recurrent Laryngeal Nerve from Small, Well-Differentiated Papillary Thyroid Cancers: Patient Selection Implications for Active Surveillance.

Samantha K Newman, Victoria Harries, Laura Y Wang, Marlena R McGill, Ian Ganly, Jeffrey Girshman, R Michael Tuttle.

Background: The success of an active surveillance management approach to low-risk papillary thyroid cancer (PTC) is heavily dependent on proper patient selection. For example, primary tumors located in a subcapsular position immediately adjacent to the trachea or a recurrent laryngeal nerve (RLN) are considered to be inappropriate for active surveillance. Since pre-operative imaging cannot reliably rule out extrathyroidal extension or reveal the full course of the RLN relative to the thyroid gland, it is important for clinicians to understand subcapsular tumor locations and minimum tumor sizes that are most likely to be associated with gross invasion of the RLNs. Methods: We assessed the medical records of 123 patients treated at Memorial Sloan Kettering Cancer Center (MSK) between 1986 and 2015 who had a primary PTC tumor demonstrating gross extrathyroidal extension to either the right or left RLN. Thirty patients with a primary tumor ≤2 cm in diameter demonstrating extrathyroidal extension into an RLN were included in the analysis. Results: Gross invasion of an RLN by tumors ≤2 cm is a rare event that was seen in only 0.8% (35/4,334) of patients with PTC who underwent initial thyroid surgery at MSK between 1986 and 2015. Gross RLN invasion was associated with subcapsular PTC tumors located in either the right paratracheal area (60%), left paratracheal area (36.7%), or right lateral posterior lobe area not adjacent to the trachea (3.3%). Only a quarter of the patients had imaging findings suggestive of extrathyroidal extension and only 30% had clinically apparent vocal paresis/paralysis on pre-operative examination. Invasion of the RLN was not observed for primary tumors <0.9 cm in diameter, regardless of tumor location. Conclusions: Well-differentiated PTC tumors ≥0.9 cm in maximal diameter which are located in the right paratracheal, left paratracheal, and right lateral posterior lobe subcapsular positions are usually not appropriate for active surveillance even in the absence of definitive evidence for nerve invasion on pre-operative imaging or vocal cord examination. Patient selection for active surveillance management should take into account not only the size and growth rate of a tumor but also its location in relation to the expected course of RLNs.

DOI: https://doi.org/10.1089/thy.2021.0310
Int J Radiat Oncol Biol Phys. 2021 Nov 01. pii: S0360-3016(21)01741-7. [Epub ahead of print]111(3S): e266-e267

10-Year Outcomes Following Proton Therapy for Localized Prostate Cancer.

C M Bryant, R H Henderson, W M Mendenhall, R C Nichols, X Liang, Z Su, M Bandyk, K C Balaji, J Costa, N P Mendenhall.

PURPOSE/OBJECTIVE(S): To report 10-year outcomes for patients treated with proton therapy for localized prostate cancer.
MATERIALS/METHODS: The 10-year outcomes from a prospective outcome tracking protocol were assessed and reported for 1272 men with localized prostate cancer. Risk groups were classified per NCCN guidelines. Median proton therapy dose was 78 GyRBE (72 to 82 GyRBE) delivered at 1.8 to 2 GyRBE per fraction. Androgen deprivation therapy (ADT) was received by 193 men for a median 6 months (range 1 to 36 months). Biochemical control was defined using the Phoenix definition. Common Terminology Criteria for Adverse Events, version 5.0, was used for toxicity scoring. The International Prostate Symptom Score (IPSS) and Expanded Prostate Index Composite (EPIC) was used for patient-reported outcomes. Freedom from biochemical failure (FFBF) and toxicity rates were calculated using the Kaplan Meier method. EPIC domain score changes considered clinically significant were 5 (bowel), 6 (urinary irritative /obstructive), 7 (urinary incontinence), and 11 (sexual).
RESULTS: The median follow-up time was 10.2 years. The 10-year FFBF rates for patients with very low-risk, low-risk, favorable intermediate-risk, unfavorable intermediate-risk, high-risk, and very high-risk prostate cancer were 97%, 96%, 88%, 82%, 68%, 49%, respectively. Median PSA nadir was 0.2 ng/mL. On multivariate analysis, risk category, PSA, and the presence of perineural invasion predicted 10-year biochemical control. The 7- and 10-year grade 3+ gastrointestinal and urologic toxicity rates were 1.0% and 1.3% and 4.1% and 6.2%, respectively. On multivariate analysis (MVA), the use of prescription blood thinners significantly increased the 10-year risk for grade 3+ gastrointestinal toxicity. The use of prescription blood thinners, the presence of diabetes mellitus, a prostate volume 40+ grams, the use of pretreatment alpha blockers, an IPSS score of 15+, and the use of ADT were associated with late grade 3+ genitourinary (GU) toxicity on MVA. The dose-volume histogram parameter V70 (GyRBE) of bladder volume (< 33 cc vs. 33+ cc) also predicted for late grade 3+ GU toxicity on MVA. A clinically significant decline in EPIC sexual summary scores occurred at 10 years (67 to 41). No other clinically significant change was seen in EPIC summary scores.
CONCLUSION: These long-term results show that proton therapy can provide favorable biochemical control outcomes for patients with localized prostate cancer. Additional strategies are needed to improve disease control for patients with very high-risk disease. Late grade 3+ GI toxicity rates are low and, as noted with other radiation modalities, the rate of late grade 3+ GU toxicity increases with time even after 5 years. There was an expected decline in overall sexual function as the patient cohort aged following proton therapy. These long-term results establish benchmarks for future comparative trials.

DOI: https://doi.org/10.1016/j.ijrobp.2021.07.871
In Vivo. 2021 Nov-Dec;35(6):35(6): 3233-3243

Kallikrein 11 Down-regulation in Breast Carcinoma: Correlation With Prognostic Parameters.

Tulin Ozturk, Ecem Zeynep Kain, Mete Bora Tuzuner, Ayca Diren, Sebnem Batur, Hulya Yilmaz-Aydogan, Oguz Ozturk, Turgay Isbir.

   BACKGROUND: Expression of kallikrein-11 (KLK11) has been found to be related to the prognosis of various human cancer types but its physiological functions in the steps of breast cancer (BC) progression are still unknown.
MATERIALS AND METHODS: BC and adjacent normal breast tissue samples were collected from 28 patients. KLK11 expression levels were determined by real-time polymerase chain reaction for each sample and associations with known prognostic features were statistically analyzed.
RESULTS: Although there was slight up-regulation in tumor tissues overall, significant down-regulation of KLK11 expression in tumor tissue was observed in the elderly and in patients with perineural invasion. Furthermore, tumor size, grade, mitotic score, necrosis, calcification, lymphatic invasion, hormone receptor status and Ki67 expression were associated with altered KLK11 level.
CONCLUSION: Changes in expression levels of KLK11, associated with patient characteristics, might be used as complementary data in order to predict clinical outcome and prognosis in BC.

Keywords:  KLK11; Kallikrein 11; breast cancer; hK11

DOI:  https://doi.org/10.21873/invivo.12618