Magnetic Resonance Imaging after Nasopharyngeal Endoscopic Resection and Skull Base Reconstruction.

Background: Postoperative imaging after nasopharyngeal endoscopic resection (NER) and skull base reconstruction is quite challenging due to the complexity of the post-surgical and regional anatomy. Methods: In this retrospective observational study, we included patients treated with NER from 2009 to 2019 and submitted to Magnetic Resonance Imaging (MRI) 6 and 12 months after surgery. A radiologist with 15 years of experience analyzed all MRI scans. Results: A total of 50 patients were considered in this study, 18 of whom were excluded due to imaging unavailability, and 16 of whom were not considered due to major complications and/or persistent disease. Sixteen patients were evaluated to identify the expected findings. Inflammatory changes were observed in 16/64 subsites, and regression of these changes was observed in 8/64 at 1 year. Fibrosis was observed in 5/64 subsites and was unmodified at 1 year. The nasoseptal flap showed homogeneous enhancement at 6 months (100%) and at 1 year. The temporo-parietal fascia flap (TPFF) showed a decrease in the T2- signal intensity of the mucosal layer in 57% of the patients at 1 year and a decrease in enhancement in 43%. Conclusions: Identifying the expected findings after NER and skull base reconstruction has a pivotal role in the identification of complications and recurrence.

Malignant carotid body tumors: What we know, what we do, and what we need to achieve. A systematic review of the literature.

Malignant carotid body tumors (MCBT) are rare and diagnosed after detection of nodal or distant metastases. This systematic review (SR) focuses on MCBT initially approached by surgery. Preferred Reporting Items for SR and Meta-Analysis (MA) guided the articles search from 2000 to 2023 on PubMed, Scopus, and Web of Science. Among 3548 papers, 132 (337 patients) were considered for SR; of these, 20 (158 patients) for MA. Malignancy rate was 7.3%, succinate dehydrogenase (SDH) mutation 17%, age at diagnosis between 4th and 6th decades, with a higher prevalence of females. MCBTs were mostly Shamblin III, with nodal and distant metastasis in 79.7% and 44.7%, respectively. Malignancy should be suspected if CBT >4 cm, Shamblin III, painful or otherwise symptomatic, at the extremes of age, bilateral, with multifocal disease, and SDHx mutations. Levels II-III clearance should be performed to exclude nodal metastases and adjuvant treatments considered on a case-by-case basis.

Blood Markers Predicting Clinically Occult Lymph Node Metastasis in Head and Neck Squamous Cell Carcinoma.

INTRODUCTION: The presence of cervical lymph node metastases is an unfavorable prognostic factor in head and neck squamous cell carcinoma (HNSCC) and a potential cause of treatment failure. Occult lymph node metastasis occurs in approximately 15-20% of HNSCC patients with a clinically negative neck (cN0), greatly impacting on their prognosis. The present study aimed to investigate the role of pre-treatment peripheral blood markers in predicting clinically occult cervical lymph node metastasis. METHODS: This multicenter, retrospective study was performed in a cohort of 472 patients diagnosed with cN0 HNSCC who underwent up-front surgery. Baseline neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic inflammatory marker (SIM), and systemic immune-inflammation index (SII) were calculated from available blood parameters. RESULTS: Oro-hypopharyngeal and oral cancers, locally advanced stage, moderately (G2), and poorly (G3) differentiated grade were associated with an increased risk of pathological lymph node involvement. NLR, LMR, PLR, SIM, and SII were significantly associated at multivariable analysis. NLR >2.12 was the most reliable at predicting occult lymph node metastasis (OR = 5.22; 95% CI: 2.14-12.75). We describe a predictive score integrating cancer site, local stage, and NLR which is effective at predicting positive lymph node pathological status. CONCLUSIONS: The present study provides evidence that pre-treatment peripheral blood markers, in particular NLR, represent reliable predictors of clinically occult cervical lymph node metastasis in cN0 HNSCC. Therefore, the present study provides a novel useful predictive score for directing the elective management of the neck in patients with cN0 HNSCC.

Hemicricoidectomy with modified rotational thyro-crico-tracheal anastomosis: a newborn in the family of crico-tracheal resection and anastomosis techniques.

Objective: The aim of the present study is to describe our novel surgical technique of hemicricoidectomy and reconstruction with modified rotational thyro-crico-tracheal anastomosis for the treatment of non-squamous cell subglottic tumours. The procedure has been defined as Type E crico-tracheal resection and anastomosis (CTRA) following the University of Brescia (C)TRA classification introduced elsewhere. Methods: A detailed anatomical step-by-step dissection was reproduced and illustrated on a cadaveric laryngo-tracheal specimen. Moreover, oncological and functional outcomes of the first 5 patients who underwent Type E CTRA at our Institution between October 2016 and September 2022 are described. Results: Three patients underwent Type E CTRA for cricoid chondrosarcoma (CS) and 2 patients for subglottic adenoid cystic carcinoma (ACC). No post-operative complication was reported. All patients maintained intact oral intake and an intelligible voice at discharge. All but one patient with obstructive sleep apnoea hypopnea syndrome and lung comorbidity were successfully decannulated before discharge. At the last follow-up (April 2023), one patient experienced local recurrence of CS that was still amenable to conservative treatment by transoral debulking, while the remaining patients were free of disease. Conclusions: With the proper indications, Type E CTRA is a feasible and effective conservative surgical technique for selected non-squamous cell subglottic tumours.

Treatment and outcomes of minor salivary gland cancers of the larynx and trachea: a systematic review.

Objectives: Malignant minor salivary glands carcinomas (MiSGC) of the larynx and trachea are rare tumours and published evidence is sparse. We conducted a systematic review to describe shareable treatment strategies and oncological outcomes of these neoplastic entities. Methods: Full text English manuscripts published from January 1st 2000 to December 14th 2022 were included. Data on demographics, treatments and outcomes were collected. A pooled analysis of 5-year overall survival (OS) was performed. Results: Seventeen articles and 365 patients met the inclusion criteria. The most common subsites involved were subglottic and distal trachea. Adenoid cystic carcinoma was, by far, the most frequent histotype. The first-choice treatment strategy was surgery (86.8%), while adjuvant treatments were delivered in 57.4% of patients. Only 12.9% were treated with definitive radiotherapy with/without chemotherapy. The mean follow-up was 68.3 months. One hundred nine (34.9%) deaths were recorded and 62.4% were cancer-related. Five-year OS ranged from 20% to 100% and, at pooled analysis, it was 83% (range, 78-87%). Conclusions: In case of MiSGC of the larynx and trachea, surgery remains the mainstay of treatment. Adjuvant treatments are frequently delivered. Survival estimates are good overall, but highly heterogeneous.

Adenosquamous cell carcinoma of the head and neck: a retrospective single institution series.

Objectives: Head and neck adenosquamous cell carcinoma (HN-ASCC) is a rare, aggressive neoplasm, with limited data reported in the literature. The aim of this study was to assess tumour behaviour and prognostic factors impacting overall survival (OS) in a retrospective, single institution series. Methods: A retrospective study on patients affected by HN-ASCC who were treated surgically between 2002 and 2019 at the Department of Otorhinolaryngology - Head and Neck Surgery of the University of Brescia was conducted. Demographics, clinical data, OS, and relative prognostic factors were analysed. Results: The study included 32 patients, with a median age of 66 years, mostly males (84.4%) and untreated (68.8%). Adjuvant treatments followed surgery in 28.1% of patients. Compared to conventional SCC, ASCC showed a higher proportion of cases arising in the larynx (40.6%); no difference was found in other features. Advanced (pT3-4) local stage at presentation (p = 0.023), perineural invasion (PNI, p = 0.01), and positive margins (p = 0.007) were independent negative prognostic factors for OS. Conclusions: HN-ASCC is a rare, aggressive cancer, most frequently arising in the larynx of elderly males, usually diagnosed in an advanced local stage. OS is generally poor, affected by local advanced stage, PNI, and positive resection margins.

Treatment of loco-regional recurrence of nasopharyngeal carcinoma in a non-endemic area: oncologic outcomes, morbidity, and proposal of a prognostic nomogram.

Introduction: The study assessed outcomes and toxicities of different treatment modalities for local and/or regional recurrent nasopharyngeal carcinoma (NPC) in a non-endemic area. Methods: Patients treated with curative intent for recurrent NPC with salvage surgery, photon-based radiotherapy, proton therapy (PT), with or without chemotherapy, at different Italian referral centers between 1998 and 2020 were included. Adverse events and complications were classified according to the Common Terminology Criteria for Adverse Events. Characteristics of the patients, tumors, treatments, and complications are presented along with uni- and multivariate analysis of prognostic factors. A survival predictive nomogram is also provided. Results: A total of 140 patients treated from 1998 to 2020 were retrospectively assessed. Cases with lower age, comorbidity rate, stage, and shorter disease-free interval (DFI) preferentially underwent endoscopic surgery. More advanced cases underwent re-irradiation, fairly distributed between photon-based radiotherapy and PT. Age and DFI were independent factors influencing overall survival. No independent prognostic effect of treatment modality was observed. No significant difference in the morbidity profile of treatments was observed, with 40% of patients experiencing at least one adverse event classified as G3 or higher. Conclusion: Recurrent NPC in a non-endemic area has dissimilar aspects compared to its endemic counterpart, suggesting the need for further studies that can guide the choice of the best treatment modality.

The prognostic-nutritional index in HPV-negative head and neck squamous cell carcinoma treated with upfront surgery: a multi-institutional series.

Objectives: To evaluate the prognostic value of pre-treatment prognostic-nutritional index (PNI) in patients with HPV-negative head and neck squamous cell carcinoma (HNSCC). Methods: A multi-institutional retrospective series of HPV-negative, Stages II-IVB, HNSCCs treated with upfront surgery was evaluated. Correlation of pre-operative blood markers and PNI with 5-year overall (OS) and relapse-free (RFS) survival was tested using linear and restricted cubic spline models, as appropriate. The independent prognostic effect of patient-related features was assessed with multivariable models. Results: The analysis was conducted on 542 patients. PNI ≥ 49.6 (HR = 0.52; 95% CI, 0.37-0.74) and Neutrophil-to-Lymphocyte Ratio (NLR) > 4.2 (HR = 1.58; 95% CI, 1.06-2.35) confirmed to be independent prognosticators of OS, whereas only PNI ≥ 49.6 (HR = 0.44; 95% CI, 0.29-0.66) was independently associated with RFS. Among pre-operative blood parameters, only higher values of albuninaemia and lymphocyte count (> 1.08 x 103/microL), and undetectable basophile count (= 0 103/microL) were independently associated with better OS and RFS. Conclusions: PNI represents a reliable prognostic tool providing an independent measure of pre-operative immuno-metabolic performance. Its validity is supported by the independent prognostic role of albuminaemia and lymphocyte count, from which it is derived.

The Risk of Meningitis After Cochlear Implantation: A Systematic Review and Meta-Analysis.

OBJECTIVE: This study aims to estimate the rate of postoperative meningitis (both immediate and long-term) in patients following cochlear implants (CIs). It aims to do so through a systematic review and meta-analysis of published studies tracking complications after CIs. DATA SOURCES: MEDLINE, Embase, and Cochrane Library. REVIEW METHODS: This review was performed in line with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies tracking complications following CIs in patients were included. Exclusion criteria included non-English language studies and case series reporting <10 patients. Bias risk was evaluated using the Newcastle-Ottawa Scale. Meta-analysis was performed through DerSimonian and Laird random-effects models. RESULTS: A total of 116/1931 studies met the inclusion criteria and were included in the meta-analysis. Overall, there were 112 cases of meningitis in 58,940 patients after CIs. Meta-analysis estimated an overall rate of postoperative meningitis of 0.07% (95% confidence interval [CIs], 0.03%-0.1%; I2 = 55%). Subgroup meta-analysis showed this rate had 95% CIs crossing 0% in implanted patients who received the pneumococcal vaccine, antibiotic prophylaxis, those with postoperative acute otitis media (AOM), and those implanted less than 5 years. CONCLUSION: Meningitis is a rare complication following CIs. Our estimated rates of meningitis after CIs appear lower than prior estimates based on epidemiological studies in the early 2000s. However, the rate still appears higher than the baseline rate in the general population. The risk was very low in implanted patients who received the pneumococcal vaccine, antibiotic prophylaxis, received unilateral or bilateral implantations, developed AOM, those implanted with a round window or cochleostomy techniques, and those under 5 years.

Lymph node metastasis from olfactory neuroblastoma at presentation and as disease relapse: A systematic review and proportion meta-analysis of prevalence data and variables influencing regional control.

BACKGROUND: Aim of this study is to investigate the prevalence of cervical nodal metastasis at presentation and as disease relapse in primary, treatment-naive olfactory neuroblastoma (ONB), and to review treatment modalities, risk factors for regional failure and survival outcomes according to nodal status. METHODS: A systematic review and proportion meta-analysis were conducted following PRISMA guidelines based on PubMed, Web of Science, and Scopus. RESULTS: Eighteen articles were examined. The pooled proportion of patients with nodal metastasis at presentation (11.5%) was comparable to that of cN0 patients not receiving elective neck treatment developing nodal metastasis during follow-up (12.3%). Of the latter, most were Kadish stage C tumors (85.5%). CONCLUSIONS: Cervical involvement is common both at presentation and during follow-up of cN0 ONB. The highest risk of developing late nodal metastasis is seen in cN0 patients with Kadish stage C tumors not receiving elective neck treatment. Elective cN0 neck treatment should be encouraged in selected patients to increase regional control.

Functional profiles of curatively treated adenoid cystic carcinoma unveil prognostic features and potentially targetable pathways.

Adenoid cystic carcinoma (ACC) of salivary gland is a slowly growing tumor showing a propensity for delayed recurrence, with decreased survival rates. The identification of poor prognosis patients may help in defining molecular-based targeted strategies in this rare disease orphan of new treatments. Through a gene expression microarray-based approach followed by GSE functional analysis the expression profile of 46 primary untreated ACC samples and of ACC (h-TERT) tumor cells was analyzed. Patients who experienced early relapse showed enrichment in proliferation-related gene sets, including the G2-M checkpoint, E2F and myc targets, and in gene sets related to IFN signaling and aberrant proteostasis (FDR < 0.1), indicating increased mitotic and transcriptional activity in aggressive ACC. Similar functions were enriched in ACC samples classified by immunohistochemical staining as p63-negative, which exhibited increased protein burden and activation of pro-survival stress response pathways compared to p63-positive tumors. Compared to ACC tissues, ACC (h-TERT) cells share transcriptional features of aggressive p63-negative tumors. These data suggest association of specific pathway alterations with histopathological features of ACC, as recapitulated by p63 testing in patient prognostic stratification, anticipating new avenues for therapeutic intervention.

General anaesthetic vs local anaesthetic myringoplasties: a systematic review and meta-analysis.

AIMS: To assess all available data and determine the success rates and tolerability of local anaesthetic myringoplasty in comparison with those undertaken under general anaesthetic myringoplasty. MATERIALS AND METHODS: The study was designed following a PRISMA-P protocol and registered with the PROSPERO database. MEDLINE, Cochrane Library (CDSR/Central), EMBASE and CINHAL-were directly searched for studies, which met the inclusion criteria. OBJECTIVES: Primary objective was to compare perforation closure rates between patients undergoing myringoplasty under local anaesthetic and those under general anaesthetic from all available published data. Secondary outcomes include complications, such as 'any minor complications', infection rates in the first 6 month post-op, facial nerve weakness, dysgeusia and patient satisfaction. RESULTS: 27 studies were included in the final analysis and found that myringoplasty had an overall perforation closure rate of 89%. The pooled proportion of closures after myringoplasty under local anesthesia was 87% and for myringoplasties under general anesthesia was 91%. Analysis of myringoplasty under local anaesthesia focusing on 'in-office' performed procedures only, found a closure rate of 88%. CONCLUSIONS: There is no significant difference in the success rate of myringoplasty surgery when performed under local or general anaesthetic as measured by perforation closure rates. However, there are other factors, which can drive choosing local anaesthetic surgery, such as minimising anaesthetic risks, reducing costs and reducing environmental impact.

Presentation, Management, and Hearing Outcomes of Labyrinthine Fistula Secondary to Cholesteatoma: A Systematic Review and Meta-analysis.

OBJECTIVE: The current study systematically reviewed the literature to compare auditory outcomes of patients treated for labyrinthine fistula (LF) based on characteristics of disease and surgical management. DATABASES REVIEWED: PubMed, Scopus, Web of Science. METHODS: Original series (at least five cases) published from 2000 reporting management and hearing results of LF secondary to cholesteatoma were included. Proportion and odds-ratio (OR) meta-analyses were conducted through inverse variance random-effects models based on logit transformation. RESULTS: The prevalence of LF is estimated to be 7% (95% confidence interval [CI], 5-9%). Fistulae involving the lateral semicircular canal (90%; 95% CI, 87-93%) and larger than 2 mm (53%; 95% CI, 43-64%) were common, whereas membranous involvement was less frequent (20%; 95% CI, 12-30%). Complete removal of the cholesteatoma matrix overlying the LF was mostly applied. Bone conduction (BC) preservation was frequently achieved (81%; 95% CI, 76-85%); new-onset postoperative anacusis was rarely reported (5%; 95% CI, 4-8%). A higher chance of BC preservation was associated with sparing the perilymphatic space (OR, 4.67; 95% CI, 1.26-17.37) or membranous labyrinth (OR, 4.56; 95% CI, 2.33-8.93), exclusive lateral semicircular canal involvement (OR, 3.52; 95% CI, 1.32-9.38), smaller size (<2 mm; OR, 3.03; 95% CI, 1.24-7.40), and intravenous steroid infusion (OR, 7.87; 95% CI, 2.34-26.42). CONCLUSION: LF occurs in a significant proportion of patients with cholesteatoma. In the past two decades, complete removal of the cholesteatoma matrix followed by immediate sealing has been favored, supported by the high proportion of BC preservation. Hearing preservation depends primarily on characteristics of the LF, and specific surgical strategies should be pursued. Intraoperative and postoperative intravenous steroid infusion is recommended.

The Enhanced Recovery After Surgery (ERAS) protocol in head and neck cancer: a matched-pair analysis.

Objective: In this study, we aimed to describe the prospective implementation of the Enhanced Recovery after Surgery (ERAS) protocol in an Italian tertiary academic centre. Methods: Adult patients receiving surgery for primary or recurrent clinical stage III/IV squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx were enrolled. The primary objective was to evaluate the impact of the ERAS protocol on length of hospital stay (LOS). The secondary objective was to assess its impact on complications. To evaluate the results of the ERAS protocol, a matched-pair analysis was conducted, comparing ERAS patients with comparable cases treated before 2018. Results: Forty ERAS and 40 non-ERAS patients were analysed. There were no significant differences between the cohorts regarding age, gender, stage of disease, comorbidity, ASA score, and duration of surgery. A significantly shorter LOS for the ERAS group (median, 14 days; range, 10-19) than for non-ERAS patients (median, 17.5 days; range, 13-21) was observed (p = 0.0128). The incidence of complications was not significantly different (p = 0.140). Conclusions: Our study demonstrates that the introduction of an ERAS protocol in the daily practice is feasible, and can result in significant reduction in LOS.

Patterns of recurrences in sinonasal cancers undergoing an endoscopic surgery-based treatment: Results of the MUSES* on 940 patients: *MUlti-institutional collaborative Study on Endoscopically treated Sinonasal cancers.

OBJECTIVES: The improvements in survival with expansion of the survivors' population, along with evolution of endoscopically-based treatment modalities, have contributed to emphasize the clinical relevance of recurrences in sinonasal cancers. However, at present, literature is scant regarding the pattern of recurrences and the therapeutic strategies available to manage long survivors who experienced single or multiple failures. The aim of the present study was to analyze sinonasal cancers recurrences to provide data regarding rates and patterns of relapse, predictors of failure and prognostic impact of the recurrence. MATERIALS AND METHODS: All patients receiving multimodal treatments including endoscopic surgery between 1995 and 2021 in three European referral centers were included. Statistical analysis of survival was performed through univariable, multivariable and unidirectional multistate models. Survival after recurrence analysis was implemented for patients experiencing at least one recurrence. RESULTS: The 5- and 10-year recurrence free survival rates were 34.1% and 38.4% for the whole population. With a mean follow-up time of 60 months, a global recurrence rate of 32.9% was observed. The 5- and 10-year survival after recurrence rates were 27.2% and 21.7%, respectively. Incidence and rates of recurrences were significantly associated with histology subtypes. CONCLUSION: This study provides valuable oncologic outcomes regarding a large homogenous cohort of patients affected by sinonasal malignances treated within a multimodal framework, emphasizing the strong correlation of histologic type with prognosis, as well as with pattern of recurrences.

Salvage surgery in recurrent sinonasal cancers: Proposal for a prognostic model based on clinicopathologic and treatment-related parameters.

BACKGROUND: Evidence on survival and major prognosticators after salvage surgery in recurrent sinonasal cancers (SNC) is limited. METHODS: A retrospective, single-center study of recurrent SNC treated with salvage surgery between 1997 and 2019 was conducted. Univariate and multivariable analyses were performed to define a prognostic score for overall survival (OS). RESULTS: One hundred and eighteen patients were included. Recurrent SNC originated mostly in the naso-ethmoidal box (67.8%) and were mainly epithelial (76.2%), high-grade (49.2%), and locally advanced (rpT4, 60.1%) malignancies. Negative margins were achieved in 56.6% of cases. Two- and 5-year OS were 71.7% and 56%, respectively. The prognostic model included treatment modality for primary tumor, histology, rpT class, margin status, perineural invasion, and adjuvant radiotherapy and stratified patients into three prognostic groups (5-year OS: 84.4%, 44.9%, and 0%, respectively). CONCLUSIONS: Treatment of recurrent SNC can result in good long-term survival estimates with limited morbidity. Our score can provide excellent prognostic stratification.

Does Reorganization of Clinicopathological Information Improve Prognostic Stratification and Prediction of Chemoradiosensitivity in Sinonasal Carcinomas? A Retrospective Study on 145 Patients.

Background: The classification of sinonasal carcinomas (SNCs) is a conundrum. Consequently, prognosis and prediction of response to non-surgical treatment are often unreliable. The availability of prognostic and predictive measures is an unmet need, and the first logical source of information to be investigated is represented by the clinicopathological features of the disease. The hypothesis of the study was that clinicopathological information on SNC could be exploited to better predict prognosis and chemoradiosensitivity. Methods: All patients affected by SNC who received curative treatment, including surgery, at the Unit of Otorhinolaryngology-Head and Neck Surgery of the University of Brescia between October 1998 and February 2019 were included in the analysis. The institutional series was reviewed and a survival analysis was performed. Machine learning and multivariable statistical methods were employed to develop, analyze, and test 3 experimental classifications (classification #1, based on cytomorphological, histomorphological, and differentiation information; classification #2, based on differentiation information; and classification #3, based on locoregional extension) of SNC, based on the inherent clinicopathological information. The association of experimental classifications with prognosis and chemoradiosensitivity was tested. Results: The study included 145 patients. From a prognostic standpoint, the machine learning-generated classification of SNC provided better prediction than the current World Health Organization classification. However, the prediction of the chemoradiosensitivity of SNC was not achievable. Conclusions: Reorganization of clinicopathological information, with special reference to those related to tumor differentiation, can improve the reliability of prognosis of SNC. Prediction of chemoradiosensitivity remains an unmet need and further research is required.

Cytotoxic effects of targeted agent alone or with chemotherapy in the treatment of adenoid cystic carcinoma: a preclinical study.

Adenoid cystic carcinoma (ACC) is a rare malignancy characterized by high incidence of relapse. When relapsing, ACC has an indolent but relentless behaviour, thus leading to a poor long-term prognosis. The treatment of choice of relapsing ACC remains surgery followed by radiotherapy, whenever feasible. Therapeutic weapons are limited to systemic drugs. The most widely used chemotherapy regimen is the combination of cisplatin and doxorubicin, however with low response rate and not long lasting; there is also a lack of alternatives for second line therapies in case of disease progression. Therefore, a more comprehensive strategy aimed at identifying at preclinical level the most promising drugs or combination is clearly needed. In this study, the cytotoxic effects of two standard chemotherapy drugs, cisplatin and doxorubicin, and of five targeted therapy-drugs was tested in vitro, on an h-TERT immortalized ACC cell line, and in vivo, on zebrafish embryos with ACC tumoral cell xenograft. Then, combinations of one standard chemotherapy drug plus one targeted therapy drug were also evaluated, in order to find the best treatment strategy for ACC. Data obtained demonstrated that both vorinostat and olaparib significantly increased the standard chemotherapy cytotoxic effects, suggesting new interesting therapeutic options for ACC.