The potential roles of antibody-drug conjugates in head and neck squamous cell carcinoma.

PURPOSE OF REVIEW: To summarize the actual antibody-drug conjugates (ADCs) tested for patients with advanced head and neck squamous cell carcinoma (HNSCC), outlining the results of safety and efficacy through published clinical trials. RECENT FINDINGS: ADCs combine the specificity of mAbs with the cytotoxic drug (known as payload) via a chemical linker and it is designed to selectively deliver the ultratoxic payload directly to the target cancer cells. To date, various ADCs have been investigated in multiple solid malignancies and others are in clinical development. In this study, we provide an overview of the structure and biology of ADC and we review recent clinical experience with the ADC in patients with advanced HNSCC, followed by a brief discussion of the evolvement of ADC conception, drug resistance and future perspectives. SUMMARY: ADC strategy is emerging as a potential active treatment in previously treated patients with advanced HNSCC. However, the recent improvement in the bioengineering of ADC and a better comprehension of sequencing and association strategies could provide more benefit to HNSCC patients in need of innovative therapy.

Calcitonin-secreting neuroendocrine tumor of the larynx, a diagnostic challenge of a rare neoplasm: a case report and literature review.

Background: Laryngeal neuroendocrine tumors (NETs) represent less than 1% of all malignancies originating from the larynx and available data are limited on case reports. Calcitonin secreting laryngeal NETs are extremely rare and serial dosing of calcitonin in these patients might reveal early relapse or persistence. Case Description: We report the case of a 71-year-old woman with persistent pharyngodynia who underwent surgery for an initial diagnosis of small cell undifferentiated neuroendocrine carcinoma (SCUNC) of the larynx (on the epiglottis extended to the left glosso-epiglottic vallecula). The immunohistochemical profile showed the presence of synaptophysin, neuron-specific enolase (NSE), chromogranin A, pan-cytokeratin, including cytokeratin AE1-AE2, and focally calcitonin. The circulating NSE was 13.4 microg/L (normal level <12.5 microg/L) and the basal serum level of calcitonin was 237 pg/mL (normal level <11.5 pg/mL). The patient was started on first-line carboplatin-etoposide chemotherapy because of early relapse to an axillary lymph node. After 4 cycles of treatment, a radiological stability and metabolic response were demonstrated together with a drastic decrease of circulating serum level of calcitonin (from 237 to 57.9 pg/mL). During the follow up, locoregional relapse of disease occurred, associated with an increase of serum calcitonin (89.3 pg/mL). Disease further progressed on and rechallenge with platinum-etoposide chemotherapy was administered, during which clinical progression was confirmed. Due to the lack of response, a revision of the histology was performed and concluded for a definitive diagnosis of moderately differentiated G2 NET, with a Ki-67 index of 22.6%. Conclusions: This is the eighth case report of laryngeal NET, highlighting the challenge in pathological differential diagnosis and therapeutic strategies. The association with elevated serum calcitonin and the trend of this parameter during clinical progression suggest a role of this marker in the diagnosis and early identification of recurrent laryngeal NETs.

HER2-targeted therapies for salivary gland cancers.

Salivary gland cancers (SGCs) are a heterogeneous group of rare tumors including various histological subtypes with different molecular profiling. Human epidermal growth factor receptor 2 (HER2) is one of the most intriguing and studied molecular alterations with prognostic and predictive roles. Indeed, HER2 overexpression is commonly correlated with aggressive histological subtypes and poorer prognosis. However, HER2 may represent the target of personalized treatment. We performed a literature review of use of anti-HER2 targeted agents for treatment of recurrent or metastatic SGCs. The efficacy and safety of anti-HER2 were firstly evaluated in patients affected with other solid tumors, mostly breast and gastric cancers. For SGCs the literature is mainly comprised of case reports or case series and small clinical trials. The most common used drug is trastuzumab in combination with chemotherapy (i.e. taxanes, capecitabine, carboplatin, eribulin) or with another anti-HER2 targeted agent (i.e. pertuzumab). The use of anti-HER2 therapies induces improvement in clinical responses, which are mostly durable. Besides, new anti-HER2 drugs such as antibody-drug conjugates (ADC) (i.e. trastuzumab emtansine, trastuzumab deruxtecan) have been introduced in this setting inducing further therapeutic advances. Anti-HER2 treatment strategy is emerging as potentially effective in selected HER2 overexpressing SGCs. However, prospective and multicentric clinical trials are needed to evaluate the efficacy of these therapeutic regimens within larger cohorts and to assess the most appropriate treatment sequence strategy.

Hedgehog Inhibitors Beyond Clinical Complete Response in Basal Cell Carcinoma: Should I Stop or Should I Go?

INTRODUCTION: In advanced basal cell carcinoma (BCC), the issue of whether Hedgehog inhibitors (HHIs) should be stopped or not after clinical complete response (cCR) achievement remains an unmet clinical need. MATERIALS AND METHODS: We conducted a retrospective, multicenter study across 7 Italian dermato-oncology units including patients with BCC who continued vismodegib after cCR between 2012 and 2019. We assessed the relationship between the duration of vismodegib intake (days to cCR [DTCR], days to stop after cCR [DTS], total treatment days [TTD]), and disease-free survival (DFS). Reasons to stop vismodegib were (R1) toxicity and (R2) disease recurrence. The relationship between DTCR, DTS, TTD, and DFS in the whole population and in R1 subgroup was assessed by Pearson's correlation coefficient (P < .05) and Bayesian statistics (BF10). RESULTS: Sixty-eight BCC patients with a median (m) age of 75.5 years (39-100) were included. Most patients were male (N = 43, 63%), without Gorlin syndrome (N = 56, 82%) and with head and neck area as primary site (N = 51, 75%). After cCR, out of 68 patients, 90% (N = 61/68) discontinued vismodegib: 82% (N = 50/61) due to toxicity (R1), and 18% (N = 11/61) due to recurrence (R2). Conversely, 10% (N = 7/68) continued vismodegib until last follow-up. In the whole population (N = 68), cCR was achieved with a mDTCR of 180.50 days. DFS showed a significant correlation with DTS (P < .01, BF10 = 39.2) and TTD (P < .01, BF10 = 35566), while it was not correlated to DTCR (BF10 < 0.1). The analysis of R1 subgroup (N = 50) confirmed these results. DFS correlated with DTS in all recurrent patients (N = 38, r = 0.44, P < .01) and in the recurrent patients who stopped vismodegib for toxicity (N = 26, r = 0.665, P < .01). DFS was longer when vismodegib was maintained for >2 months after cCR (mDFS > 2 months, N = 54 vs. ≤ 2 months, N = 14: 470 vs. 175 d, P < .01). CONCLUSIONS: Our retrospective results suggest that HHIs should be continued after cCR to improve DFS in BCC.

Extracellular Vesicles and Epidermal Growth Factor Receptor Activation: Interplay of Drivers in Cancer Progression.

Extracellular vesicles (EVs) are of great interest to study the cellular mechanisms of cancer development and to diagnose and monitor cancer progression. EVs are a highly heterogeneous population of cell derived particles, which include microvesicles (MVs) and exosomes (EXOs). EVs deliver intercellular messages transferring proteins, lipids, nucleic acids, and metabolites with implications for tumour progression, invasiveness, and metastasis. Epidermal Growth Factor Receptor (EGFR) is a major driver of cancer. Tumour cells with activated EGFR could produce EVs disseminating EGFR itself or its ligands. This review provides an overview of EVs (mainly EXOs and MVs) and their cargo, with a subsequent focus on their production and effects related to EGFR activation. In particular, in vitro studies performed in EGFR-dependent solid tumours and/or cell cultures will be explored, thus shedding light on the interplay between EGFR and EVs production in promoting cancer progression, metastases, and resistance to therapies. Finally, an overview of liquid biopsy approaches involving EGFR and EVs in the blood/plasma of EGFR-dependent tumour patients will also be discussed to evaluate their possible application as candidate biomarkers.

A Systematic Review of Diagnostic and Prognostic Biomarkers for Head and Neck Cancer of Unknown Primary: An Unmet Clinical Need.

Head and neck cancer of unknown primary (HNCUP) is defined as cervical lymph node metastases without a detectable primary tumor. The management of these patients presents a challenge to clinicians since guidelines in the diagnosis and treatment of HNCUP remain controversial. An accurate diagnostic workup is fundamental for the search for the hidden primary tumor to allow the best adequate treatment strategy. The purpose of this systematic review is to present the currently available data about the diagnostic and prognostic molecular biomarkers for HNCUP. Systematic research in an electronic database was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol and identified 704 articles, of which 23 studies were selected and included in the analysis. Fourteen studies investigated HNCUP diagnostic biomarkers and focused on the human papilloma virus (HPV) and the Epstein-Barr virus (EBV) due to the strong associations with oropharyngeal cancer and nasopharyngeal cancer, respectively. HPV status was shown to possess prognostic value, correlating with longer disease-free survival and overall survival. HPV and EBV are the only available HNCUP biomarkers, and they are already used in clinical practice. A better characterization of the molecular profiling and the development of tissue-of-origin classifiers are necessary to improve the diagnosis, staging, and therapeutic management of patients with HNCUP.

Diagnostic and Prognostic Value of microRNAs in Patients with Laryngeal Cancer: A Systematic Review.

Laryngeal squamous cell cancer (LSCC) is one of the most common malignant tumors of the head and neck region, with a poor survival rate (5-year overall survival 50-80%) as a consequence of an advanced-stage diagnosis and high recurrence rate. Tobacco smoking and alcohol abuse are the main risk factors of LSCC development. An early diagnosis of LSCC, a prompt detection of recurrence and a more precise monitoring of the efficacy of different treatment modalities are currently needed to reduce the mortality. Therefore, the identification of effective diagnostic and prognostic biomarkers for LSCC is crucial to guide disease management and improve clinical outcomes. In the past years, a dysregulated expression of small non-coding RNAs, including microRNAs (miRNAs), has been reported in many human cancers, including LSCC, and many miRNAs have been explored for their diagnostic and prognostic potential and proposed as biomarkers. We searched electronic databases for original papers that were focused on miRNAs and LSCC, using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol. According to the outcome, 566 articles were initially screened, of which 177 studies were selected and included in the analysis. In this systematic review, we provide an overview of the current literature on the function and the potential diagnostic and prognostic role of tissue and circulating miRNAs in LSCC.

Exploring the role of neutrophil-to-lymphocyte ratio and blood chemistry in head and neck adenoid cystic carcinomas treated with carbon ion radiotherapy.

BACKGROUND AND PURPOSE: In recent years, there is an emerging interest in the prognostic role of chemistry blood biomarkers in oncological patients but their role in adenoid cystic carcinomas (ACCs) is still unknown. This study aims to assess the prognostic significance of baseline neutrophil-to-lymphocyte ratio (NLR) and blood chemistry in a series of head and neck ACC patients treated with carbon ion radiotherapy (CIRT). MATERIAL AND METHODS: We retrospectively retrieved the data of 49 consecutive head and neck ACC patients treated with CIRT. Univariable and multivariable Cox proportional hazard regression (Cox-ph) analyses were performed to look for a potential association of NLR, and other blood biomarker values, with disease-free survival (DFS), Local Control (LC), Metastasis Free Survival (MFS) and overall survival (OS). RESULTS: No significant association between NLR > 2,5 and DFS, LC, MFS and OS was found with univariable analysis although a trend was reported for DFS (Hazard ratio [HR]: 2,10, 95 % CI: 0,85 - 5,08, p-value = 0,11). Patients with hemoglobin (hb) ≤ 14 g/dL showed significantly better DFS, MFS and OS. Multivariable regression Cox-ph analysis for DFS, adjusted for margin status, clinical target volume and Absolute Number of Monocytes, reported the following statistically significant HRs, for both NLR > 2,5 and hb > 14 g/dL respectively: 4,850 (95 % CI = 1,408 - 16,701, p = 0,012) and 3,032 (95 % CI = 1,095 - 8,393, p = 0,033). Moreover, hb > 14 with HR = 3,69 (95 % CI: 1,23 - 11,07, p-value = 0,02), was a negative independent prognostic predictor for MFS. CONCLUSIONS: Pre-treatment NLR and hb values seem to be independent prognostic predictor for clinical outcomes in head and neck ACC patients. If their role will be validated in a larger prospective cohort, they might be worthwhile for a pre-treatment risk stratification in patients treated with CIRT.

Comparing BamHI-W and CE-marked assays to detect circulating Epstein-Barr Virus (EBV) DNA of nasopharyngeal cancer patients in a non-endemic area.

OBJECTIVES: Plasma Epstein-Barr Virus (EBV)-DNA is a well-established prognostic biomarker in nasopharyngeal carcinoma (NPC). Different methods for assessment include single-copy gene targeted, European Conformity (CE)-marked assays, which are mostly employed in non-endemic settings, vs multiple-copy gene targeted, in-house BamHI-W based assays, which currently represent the most widely used method for EBV-DNA quantification. To date, evidence concerning the commutability of these different assays is still limited. MATERIALS AND METHODS: From August 2016 to March 2018, 124 plasma and 124 whole blood (WB) samples from 93 NPC patients were collected at different time-points for each patient. EBV-DNA viral load was quantified in pre- (n = 12) and post-treatment (n = 9), follow-up (n = 53), and recurrent/metastatic (R/M) (n = 50) phase. For each sample, one in-house BamHI-W vs three different CE-marked plasma assays were compared; the performance of plasma vs WB matrix was also assessed. Quantitative agreement of EBV-DNA values was evaluated by linear correlation and Bland-Altman analysis. RESULTS: A statistically significant (p = 0.0001) agreement between all CE-marked and the BamHI-W assays was found using plasma matrix, regardless of clinical phase. The results obtained in copies/ml were comparable to those expressed in IU/ml. When using WB matrix, the number of positive detections increased in the post-treatment phase. CONCLUSIONS: Our retrospective comparison supported an agreement between Plasma BamHI-W and CE-marked assays in measuring EBV-DNA for non-endemic NPC patients. There were no significant interferences from different measurement units (IU/ml vs copies/ml). Further evaluations are needed to better clarify the role of WB.

Unexpected response to fourth-line paclitaxel in a patient with metastatic oropharyngeal squamous cell carcinoma, immunotherapy-refractory: a case report.

In recent years, immune checkpoint inhibitors (ICIs), including nivolumab and pembrolizumab have revolutionized the treatment landscape in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). However, many patients do not respond to ICIs for reasons that remain largely unknown. For patients who progress on ICIs, chemotherapy and/or biologic therapies are the most widely used treatments based on the clinician's choice, with no defined sequence strategy. We report the experience of a patient with metastatic oropharyngeal squamous cell cancer p16 and human papillomavirus-DNA positive who received chemotherapy with weekly paclitaxel after progressing on nivolumab. Our patient presented a partial response to fourth line paclitaxel, which lasted more than 2 years, with an improvement of his quality of life too. These results support the hypothesis of synergism between immunotherapy and conventional chemotherapies. Even in the setting of immune-refractory disease, immunotherapy may affect tumor immune microenvironment thus leading to a synergistic effect with conventional chemotherapy and achieving unexpected results.

Monitoring patients with head and neck cancer for flu-like symptoms during the COVID-19 pandemic.

OBJECTIVE: To capture and monitor flu-like symptoms in relation to the clinical characteristics and the oncologic treatment of a large head and neck cancer (HNC) patient cohort during the Coronavirus disease 2019 (COVID-19) pandemic. METHODS: Patients were monitored through by 2 rounds of interviews. Clinical characteristics of patients with no symptoms (group 0) and of those reporting ⩾1 (group A), ⩾3 (group B), or ⩾5 symptoms (group C) were analyzed. Patients with ⩾1 symptom at both interviews were defined as group A2. RESULTS: Five hundred patients with HNC were analyzed. A higher frequency of patients with the following characteristics was observed in group A vs group 0: active treatment (40% vs 24%, p = 0.0002), gastrostomy (6% vs 2%, p = 0.027), recent active treatment (48% vs 29%, p < 0.0001), and higher number of concomitant medications (p = 0.01). A lower median age was observed in group B vs group no-B (patients with fewer than three symptoms) (59 vs 63.55 years, p = 0.016) and in group A2 vs group no-A2 (patients without at least one symptom at both interviews) (56 vs 63 years, p = 0.021); patients in group B received more recent active treatment than those in group no-B and in group A2 vs those in group no-A2 (p = 0.024 and 0.043, respectively); patients in group B had a lower body mass index than those in group no-B (22.4 vs 23.93 kg/m2, p = 0.0066). CONCLUSIONS: This work is based on patient-reported symptoms and signs independently of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing. In the future, these results might serve as a a benchmark for clinicians triaging and managing patients with HNC during infectious outbreaks involving flu-like symptoms.

IL-1 and senescence: Friends and foe of EGFR neutralization and immunotherapy.

Historically, senescence has been considered a safe program in response to multiple stresses in which cells undergo irreversible growth arrest. This process is characterized by morphological and metabolic changes, heterochromatin formation, and secretion of inflammatory components, known as senescence-associated secretory phenotype (SASP). However, recent reports demonstrated that anti-cancer therapy itself can stimulate a senescence response in tumor cells, the so-called therapy-induced senescence (TIS), which may represent a temporary bypass pathway that promotes drug resistance. In this context, several studies have shown that EGFR blockage, by TKIs or moAbs, promotes TIS by increasing IL-1 cytokine production, thus pushing cells into a "pseudo-senescent" state. Today, senotherapeutic agents are emerging as a potential strategy in cancer treatment thanks to their dual role in annihilating senescent cells and simultaneously preventing their awakening into a resistant and aggressive form. Here, we summarize classic and recent findings about the cellular processes driving senescence and SASP, and we provide a state-of-the-art of the anti-cancer strategies available so far that exploits the activation and/or blockade of senescence-based mechanisms.

Critical diagnostic delay associated with unusual presentation of hepatocellular carcinoma (HCC) with orbital metastases: a case report.

Orbital metastases are an extremely rare finding in patients with hepatocarcinoma (HCC), especially as its first presentation. Therefore, the risk of misdiagnosis is high, as well as that of drastic delays of the therapeutic algorithm. Here we report a 71-year-old man presenting with orbital metastases as the initial sign of HCC, whose initial misdiagnosis led to the impossibility to start life-saving cancer treatment. The patient's history has begun on March 2018 with a growing tumefaction of the right orbit initially treted with antibiotics and corticosteroids without benefit. Subsequently, a facial CT scan showed a voluminous right intra-orbital mass, eroding the orbital roof. Tissue biopsy documented well differentiated malignant epithelial tumor cells. Under the suspect of primitive lachrymal gland tumor, the patient was admitted to the head and neck Unit with surgical intent. However, a subsequent 18F-FDG-PET documented the presence of liver lesions and multiple sites of metastasis. A new biopsy, this time on liver nodules, was carried out and the diagnosis of HCC was finally made. Samples from the first biopsy were then reviewed and judged consistent with HCC metastasis. Unfortunately, the initial misdiagnosis resulted in a six-month delay of the start of a therapeutic approach. During that time, patient's general conditions got extremely worse, making him unable to afford an antiblastic treatment. The patient died three months after the definitive diagnosis. This case suggests that the presence of intraorbital lesion requires a multimodal approach starting from the initial presentation. Performing a complete staging since tumor's clinical onset is mandatory, preferably before carrying out a tissue biopsy. Even though HCC represents a rare cause of intraocular metastasis, it needs to be ruled out when an orbital mass is documented, as the short median survival and the frequently poor conditions of HCC patients make a timely diagnosis crucial.

Bone fracture as a novel immune-related adverse event with immune checkpoint inhibitors: Case series and large-scale pharmacovigilance analysis.

Although immune checkpoint inhibitors (ICIs) are associated with different immune-related adverse events (irAEs), the potential effect on the skeleton is poorly defined albeit biologically plausible and assessable through pharmacovigilance. We described a case series of patients experiencing skeletal fractures while on ICIs at the National Cancer Institute of Milan. To better characterize the clinical features of skeletal irAEs reported with ICIs, we queried the FDA Adverse Event Reporting System (FAERS) and performed disproportionality analysis by means of reporting odds ratios (RORs), deemed significant by a lower limit of the 95% confidence interval (LL95% CI) > 1. Bone AEs emerging as significant were scrutinized in terms of demographic and clinical data, including concomitant irAEs or drugs affecting bone resorption or causing bone damage. Four patients with skeletal events while on ICIs were included in our case series, of which three exhibited vertebral fractures. In FAERS, 650 patients with bone and joint injuries and treated with ICIs were retrieved, accounting for 822 drug-event pairs. Statistically significant ROR was found for eight, two and one bone AEs respectively with PD-1, PD-L1 and CTLA-4 inhibitors, being pathological fracture (N = 46; ROR = 3.17; LL95%CI = 2.37), spinal compression fracture (42; 2.51; 1.91), and femoral neck fracture (26; 2.38; 1.62) the most common. Concomitant irAEs or drugs affecting bone metabolism were poorly reported. The increased reporting of serious vertebral fractures in patients without concomitant irAEs and no apparent preexisting risk factors could suggest a possible cause-effect relationship and calls for close clinical monitoring and implementation of dedicated guidelines.

Immunotherapy in head and neck squamous cell carcinoma and rare head and neck malignancies.

The dismal prognosis of recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) prompted recent advances in the field of therapeutic approaches beyond cytotoxic cancer therapy. In recent years, the deeper and increasing knowledge on the genomic landscape and the upcoming new data on immunotherapy enacted by HNSCCs have led to successful therapeutic targeting of the immune system. Immune checkpoint inhibitors (ICIs) have changed state of the art in R/M patients and could have a potential role even in early disease. The purpose of this work is to summarize the role of immunotherapy for R/M HNSCC in clinical practice, with insights about future perspectives. Updated immunotherapy results in other R/M head and neck cancers such as thyroid, salivary glands, nasopharynx, sinonasal cancers, and nuclear protein in testis (NUT) are presented.

Pancreatic mucinous cystadenocarcinoma in a patient harbouring BRCA1 germline mutation effectively treated with olaparib: A case report.

BACKGROUND: Pancreatic mucinous cystadenocarcinoma (MCAC) is a rare malignancy with a poor prognosis when it presents metastases at diagnosis. Due to its very low incidence, there are no clear recommendations for the treatment of advanced disease. Olaparib (an oral PARP inhibitor) has been approved for the maintenance treatment of patients with metastatic pancreatic adenocarcinoma harbouring germline BRCA1/2 mutations. Herein, we report the first case of a germline BRCA1 mutated unresectable MCAC which was effectively treated with olaparib. CASE SUMMARY: A 41-year-old woman, without personal or family history of cancer, was diagnosed with ovarian and peritoneal metastases of MCAC. She underwent 12 cycles of gemcitabine plus oxaliplatin (GEMOX) obtaining a partial response and allowing radical surgery. One year later, local recurrence was documented, and other 12 cycles of GEMOX were administered obtaining a complete response. Seven years later, another local recurrence, not amenable to surgical resection, was diagnosed. She started FOLFIRINOX (oxaliplatin, irinotecan, leucovorin and fluorouracil), obtaining a partial response after 8 cycles. Given the excellent response to platinum-based chemotherapy, BRCA testing was performed, and a BRCA1 germline mutation was detected. She was switched to maintenance olaparib due to chemotherapy-related toxicities and achieved an almost complete metabolic response, with a reduction in the diameter of the lesion, after three months of therapy. CONCLUSION: The current case suggests the beneficial effect of olaparib in BRCA mutated MCAC. However, further studies are required.

Comparison of Sequential Testing and Next Generation Sequencing in advanced Lung Adenocarcinoma patients - A single centre experience.

OBJECTIVES: Molecular diagnosis determines therapeutic strategies for patients with non-small-cell lung cancer - adenocarcinoma (NSCLC-A) but depends on resources availability. We compared a sequential single-gene testing algorithm to next generation sequencing in NSCLC-A to assess differences in terms of effectiveness, costs, tissue consumption and time. MATERIALS AND METHODS: We analyzed a retrospective cohort of advanced NSCLC-A patients treated at the Sant'Orsola-Malpighi University Hospital. The sequential testing includes a first analysis of EGFR and KRAS status with further molecular testing physician driven. The available NGS panel detects 35 hotspot mutations,19 amplifications and 23 rearrangements. RESULTS: We included 1758 patients; 1221 characterized with the sequential algorithm between January 2014 to February 2019 and 537 with Next Generation Sequencing (NGS) until January 2020. The prevalence of EGFR, ALK and KRAS alterations was similar between the stepwise and NGS group (16.5% vs 14.3%, 6.3% vs 6.3% and 36% vs 33.5%, respectively). Differently, ROS-1 rearrangements prevalence was higher in stepwise respect to NGS group (4.7% vs 0.7%). Similarly, the stepwise group presented higher prevalence than NGS for MET amplification (11.2% vs 2.2%), MET mutations (9.0% vs 2.4%), HER2 amplification (3.3% vs 1.9%) and mutations (9.8% vs 3.0%), and BRAF mutations (4.5% vs 5.6%). Among the NGS group other mutations were found in 141 patients (26.3%) and the presence of concurrent mutations in 131 (24.4%). The stepwise algorithm presented a relevant dropout rate that increased at each step, with 11.4%, 16.4% and 49.3% respectively for ALK, ROS1 and other analysis. Sequential testing's expenditure was 1375 € per patient, vs 770 € for NGS. Moreover, NGS testing can be performed with just a 25 µm slide respect to an estimated 33.3 µm slide for sequential strategy. CONCLUSION: NGS offered a less expensive and more reliable model of diagnosis respect to sequential one for patients affected by NSCLC-A.

Long-term survival of two patients with recurrent pancreatic acinar cell carcinoma treated with radiofrequency ablation: A case report.

BACKGROUND: Pancreatic acinar cell carcinoma (PACC) is a rare type of malignant pancreatic cancer that represents approximately 1% of all pancreatic neoplasms. Due to its very low incidence, only a few retrospective studies are available. Although surgery is the first choice for treatment, most patients experience recurrence (mainly in the liver) and there are no clear recommendations for patients with advanced disease. CASE SUMMARY: We report two patients with PACC treated with surgery who experienced tumour recurrence in the liver. Patient 1 carried a germline mutation in the APC gene. Both patients were treated with gemcitabine plus oxaliplatin and gemcitabine plus capecitabine as first- and second-line therapies, respectively. After a favourable response to chemotherapy, the patients underwent radiofrequency ablation of the remaining liver metastases. For patient 1, we documented a relapse in the liver after a disease-free period of 9 mo, and treatment with gemcitabine plus capecitabine was restarted. The patient achieved a complete response, and he remains alive without evidence of disease recurrence after six years. After radiofrequency ablation, patient 2 experienced disease-free survival for 21 mo, when peritoneal relapse was diagnosed and treated with chemotherapy. The patient achieved a stable disease state for nearly two years; nevertheless, further progressive disease was documented, and he died seven years after the first relapse. CONCLUSION: PACC presents different biological behaviours than pancreatic adenocarcinoma. Multidisciplinary treatment involving local ablative therapies may be considered for PACC.