Plasma ctDNA Monitoring of a PTCH1-Mutant Metastatic Adult Medulloblastoma Showing a Durable Benefit With Vismodegib.

Adult medulloblastoma (MB) is a rare disease affecting 0.6 persons per million adults over 19 years of age. The SHH-activated/TP53-wild type is the most common subtype, accounting for 60% of adult MBs, being characterized by mutations in PTCH1, SMO, or the TERT promoter. Several small studies demonstrate objective but short-lived responses to SMO inhibitors such as vismodegib or sonidegib. Like other oncogene-addicted solid tumors, detection of the corresponding drivers through liquid biopsy could aid in the molecular diagnosis and monitoring of the disease through less invasive procedures. However, most studies have only evaluated cerebrospinal fluid as the ctDNA reservoir, and very limited evidence exists on the role of liquid biopsy in plasma in patients with primary central nervous system tumors, including MB. We present the case of a 26-year-old patient with a recurrent MB, in which next-generation sequencing (FoundationOne CDx) revealed a mutation in PTCH1, allowing the patient to be treated with vismodegib in second line, resulting in a durable benefit lasting for 1 year. Using an in-house digital PCR probe, the PTCH1 mutation could be tracked in ctDNA during treatment with first-line chemotherapy and while on treatment with vismodegib, demonstrating a precise correlation with the radiological and clinical behavior of the disease.

Feasibility study of a SiPM-fiber detector for non-invasive measurement of arterial input function for preclinical and clinical positron emission tomography.

Pharmacokinetic positron emission tomography (PET) studies rely on the measurement of the arterial input function (AIF), which represents the time-activity curve of the radiotracer concentration in the blood plasma. Traditionally, obtaining the AIF requires invasive procedures, such as arterial catheterization, which can be challenging, time-consuming, and associated with potential risks. Therefore, the development of non-invasive techniques for AIF measurement is highly desirable. This study presents a detector for the non-invasive measurement of the AIF in PET studies. The detector is based on the combination of scintillation fibers and silicon photomultipliers (SiPMs) which leads to a very compact and rugged device. The feasibility of the detector was assessed through Monte Carlo simulations conducted on mouse tail and human wrist anatomies studying relevant parameters such as energy spectrum, detector efficiency and minimum detectable activity (MDA). The simulations involved the use of 18F and 68Ga isotopes, which exhibit significantly different positron ranges. In addition, several prototypes were built in order to study the different components of the detector including the scintillation fiber, the coating of the fiber, the SiPMs, and the operating configuration. Finally, the simulations were compared with experimental measurements conducted using a tube filled with both 18F and 68Ga to validate the obtained results. The MDA achieved for both anatomies (approximately 1000 kBq/mL for mice and 1 kBq/mL for humans) falls below the peak radiotracer concentrations typically found in PET studies, affirming the feasibility of conducting non-invasive AIF measurements with the fiber detector. The sensitivity for measurements with a tube filled with 18F (68Ga) was 1.2 (2.07) cps/(kBq/mL), while for simulations, it was 2.81 (6.23) cps/(kBq/mL). Further studies are needed to validate these results in pharmacokinetic PET studies.

FDG-PET-based neural correlates of Addenbrooke's cognitive examination III scores in Alzheimer's disease and frontotemporal degeneration.

Introduction: The Addenbrooke's Cognitive Examination III (ACE-III) is a brief test useful for neuropsychological assessment. Several studies have validated the test for the diagnosis of Alzheimer's disease (AD) and frontotemporal dementia (FTD). In this study, we aimed to examine the metabolic correlates associated with the performance of ACE-III in AD and behavioral variant FTD. Methods: We enrolled 300 participants in a cross-sectional study, including 180 patients with AD, 60 with behavioral FTD (bvFTD), and 60 controls. An 18F-Fluorodeoxyglucose positron emission tomography study was performed in all cases. Correlation between the ACE-III and its domains (attention, memory, fluency, language, and visuospatial) with the brain metabolism was estimated. Results: The ACE-III showed distinct neural correlates in bvFTD and AD, effectively capturing the most relevant regions involved in these disorders. Neural correlates differed for each domain, especially in the case of bvFTD. Lower ACE-III scores were associated with more advanced stages in both disorders. The ACE-III exhibited high discrimination between bvFTD vs. HC, and between AD vs. HC. Additionally, it was sensitive to detect hypometabolism in brain regions associated with bvFTD and AD. Conclusion: Our study contributes to the knowledge of the brain regions associated with ACE-III, thereby facilitating its interpretation, and highlighting its suitability for screening and monitoring. This study provides further validation of ACE-III in the context of AD and FTD.

Durable complete remission with local therapies after neoadjuvant and adjuvant nivolumab in recurrent/metastatic head and neck cancer.

Up to 10-15% of patients with first-line recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) present with platinum-refractory disease. The anti-PD1 nivolumab is the first therapeutic option in this setting achieving a 19.2% objective response rate and a 7.7-month median overall survival (OS). Given the poor prognosis of platinum-refractory patients, those showing slow progressive disease with no functional status deterioration should maintain nivolumab beyond progression in the absence of severe or unmanageable toxicities. Another strategy is to use local therapies such as radiotherapy and surgical tumor resection in cases of oligometastatic or oligoprogressive disease. Both strategies may significantly improve disease control and OS in these populations. We present the case of a patient with platinum-refractory disease treated with first-line nivolumab beyond progression who achieved a durable complete response after palliative radiation and surgical resection of five tumor lesions. To our knowledge, this is the first reported case of an R/M HNSCC treated with such a strategy outside a clinical trial and contributes to the evidence for combining anti-PD1 agents and local therapies in selected patients with R/M HNSCC.

Safety and preliminary activity of pembrolizumab-carboplatin-paclitaxel in heavily pretreated and/or fragile patients with PDL1-positive recurrent/metastatic head and neck cancer.

Novel chemo-immunotherapy (chemo-IO) combinations should be evaluated, which may be suitable for cisplatin-unfit or fluoropyrimide-ineligible patients with recurrent or metastatic squamous cell carcinoma of head and neck (R/M SCCHN) to guarantee higher and deeper responses than IO alone. The aim of the present study was to review our experience using pembrolizumab-carboplatin-paclitaxel (pembro + CP) in patients with R/M SCCHN. This was a retrospective study of patients with R/M SCCHN who received pembro + CP in any-line via a compassionate-use program. The present study evaluated safety using Common Terminology Criteria for Adverse Events v4.0, compliance, overall response rate (ORR) and disease control rate (DCR) using Response Evaluation Criteria in Solid Tumors 1.1, duration of treatment, progression-free survival (PFS) and overall survival (OS). Between March 2020 and August 2021, 10 patients were identified (median age, 64 years; female, 60%; Eastern Cooperative Oncology Group 2, 80%). A total of 8 patients received pembro + 3-weekly carboplatin-paclitaxel (3wkCP). A total of 2 patients received pembro + weekly carboplatin-paclitaxel (wkCP). Patients received a median of 3 lines (range, 0-6) of systemic therapy prior to pembro + CP and 80% received IO in previous lines. Grade 1-2 adverse events (AEs) occurred in 100% of patients. Grade 3-5 AEs occurred in 30% of patients [all grade 3 (anemia, neutropenia, thrombopenia, hypertension)]. The mean numbers of pembro + wkCP and pembro + 3wkCP cycles were 2.5 and 6. The ORR (n=7) was 14% (1/7) with one complete response. The DCR was 43% (3/7). The median PFS (n=7) and OS (n=10) times since pembro + CP were 5 months (95% CI, 1-9) and 6 months (95% CI, 0.5-14), respectively. In this small retrospective series of heavily pretreated patients, pembro + CP was well tolerated, and compliance was high. Studies should be conducted to prospectively evaluate the safety and efficacy of this combination in patients with R/M SCCHN.

Neuropsychological, Metabolic, and Connectivity Underpinnings of Semantic Interference Deficits Using the LASSI-L.

BACKGROUND: LASSI-L is a novel neuropsychological test specifically designed for the early diagnosis of Alzheimer's disease (AD) based on semantic interference. OBJECTIVE: To examine the cognitive and neural underpinnings of the failure to recover from proactive semantic and retroactive semantic interference. METHODS: One hundred and fifty-five patients consulting for memory loss were included. Patients underwent neuropsychological assessment, including the LASSI-L, and FDG-PET imaging. They were categorized as subjective memory complaints (SMC) (n=32), pre-mild cognitive impairment (MCI) due to AD (Pre-MCI) (n=39), MCI due to AD (MCI-AD) (n=71), and MCI without evidence of neurodegeneration (MCI-NN) (n=13). Voxel-based brain mapping and metabolic network connectivity analyses were conducted. RESULTS: A significant group effect was found for all the LASSI-L scores. LASSI-L scores measuring failure to recover from proactive semantic interference and retroactive semantic interference were predicted by other neuropsychological tests with a precision of 64.1 and 44.8%. The LASSI-L scores were associated with brain metabolism in the bilateral precuneus, superior, middle and inferior temporal gyri, fusiform, angular, superior and inferior parietal lobule, superior, middle and inferior occipital gyri, lingual gyrus, and posterior cingulate. Connectivity analysis revealed a decrease of node degree and centrality in posterior cingulate in patients showing frPSI. CONCLUSION: Episodic memory dysfunction and the involvement of the medial temporal lobe, precuneus and posterior cingulate constitute the basis of the failure to recover from proactive semantic interference and retroactive semantic interference. These findings support the role of the LASSI-L in the detection, monitoring and outcome prediction during the early stages of AD.

Neural basis of visuospatial tests in behavioral variant frontotemporal dementia.

Background: Recent models of visuospatial functioning suggest the existence of three main circuits emerging from the dorsal ("where") route: parieto-prefrontal pathway, parieto-premotor, and parieto-medial temporal. Neural underpinnings of visuospatial task performance and the sparing of visuospatial functioning in bvFTD are unclear. We hypothesized different neural and cognitive mechanisms in visuospatial tasks performance in bvFTD and AD. Methods: Two hundred and sixteen participants were enrolled for this study: 72 patients with bvFTD dementia and 144 patients with AD. Visual Object and Space Perception Battery Position Discrimination and Number Location (VOSP-PD and VOSP-NL) and Rey-Osterrieth Complex Figure (ROCF) were administered to examine visuospatial functioning, together with a comprehensive neuropsychological battery. FDG-PET was acquired to evaluate brain metabolism. Voxel-based brain mapping analyses were conducted to evaluate the brain regions associated with visuospatial function in bvFTD and AD. Results: Patients with AD performed worst in visuospatial tasks in mild dementia, but not at prodromal stage. Attention and executive functioning tests showed higher correlations in bvFTD than AD with ROCF, but not VOSP subtests. Visuospatial performance in patients with bvFTD was associated with bilateral frontal regions, including the superior and medial frontal gyri, supplementary motor area, insula and middle cingulate gyrus. Conclusion: These findings support the role of prefrontal and premotor regions in visuospatial processing through the connection with the posterior parietal cortex and other posterior cortical regions. Visuospatial deficits should be interpreted with caution in patients with bvFTD, and should not be regarded as hallmarks of posterior cortical dysfunction.

GA-MADRID: design and validation of a machine learning tool for the diagnosis of Alzheimer's disease and frontotemporal dementia using genetic algorithms.

Artificial Intelligence aids early diagnosis and development of new treatments, which is key to slow down the progress of the diseases, which to date have no cure. The patients' evaluation is carried out through diagnostic techniques such as clinical assessments neuroimaging techniques, which provide high-dimensionality data. In this work, a computational tool is presented that deals with the data provided by the clinical diagnostic techniques. This is a Python-based framework implemented with a modular design and fully extendable. It integrates (i) data processing and management of missing values and outliers; (ii) implementation of an evolutionary feature engineering approach, developed as a Python package, called PyWinEA using Mono-objective and Multi-objetive Genetic Algorithms (NSGAII); (iii) a module for designing predictive models based on a wide range of machine learning algorithms; (iv) a multiclass decision stage based on evolutionary grammars and Bayesian networks. Developed under the eXplainable Artificial Intelligence and open science perspective, this framework provides promising advances and opens the door to the understanding of neurodegenerative diseases from a data-centric point of view. In this work, we have successfully evaluated the potential of the framework for early and automated diagnosis with neuroimages and neurocognitive assessments from patients with Alzheimer's disease (AD) and frontotemporal dementia (FTD).

Design and Verbal Fluency in Alzheimer's Disease and Frontotemporal Dementia: Clinical and Metabolic Correlates.

OBJECTIVE: Cognitive processes underlying verbal and design fluency, and their neural correlates in patients with Alzheimer's disease (AD) and behavioural variant Frontotemporal Dementia (bvFTD) remain unclear. We hypothesised that verbal and design fluency may be associated with distinct neuropsychological processes in AD and FTD, showing different patterns of impairment and neural basis. METHODS: We enrolled 142 participants including patients with AD (n = 80, mean age = 74.71), bvFTD (n = 34, mean age = 68.18), and healthy controls (HCs) (n = 28, mean age = 71.14), that underwent cognitive assessment and 18F-fluorodeoxyglucose positron emission tomography imaging. RESULTS: Semantic and phonemic fluency showed the largest effect sizes between groups, showing lower scores in bvFTD than AD and HCs, and lower scores in AD than HC. Both AD and bvFTD showed a lower number of unique designs in design fluency in comparison to HC. Semantic fluency was correlated with left frontotemporal lobe in AD, and with left frontal, caudate, and thalamus in bvFTD. Percentage of unique designs in design fluency was associated with the metabolism of the bilateral fronto-temporo-parietal cortex in AD, and the bilateral frontal cortex with right predominance in bvFTD. Repetitions in AD were correlated with bilateral frontal, temporal, and parietal lobes, and with left prefrontal cortex in bvFTD. CONCLUSIONS: Our findings demonstrate differential underlying cognitive processes in verbal and design fluency in AD and bvFTD. While memory and executive functioning associated with fronto-temporo-parietal regions were key in AD, attention and executive functions correlated with the frontal cortex and played a more significant role in bvFTD during fluency tasks.

Incidental Findings Suggestive of COVID-19 Pneumonia in Oncologic Patients Undergoing 18F-FDG PET/CT Studies: Association Between Metabolic and Structural Lung Changes.

Although the novel coronavirus disease 2019 (COVID-19) can present as nonspecific clinical forms, subclinical cases represent an important route of transmission and a significant source of mortality, mainly in high-risk subpopulations such as cancer patients. A deeper knowledge of the metabolic shift in cells infected with severe acute respiratory syndrome coronavirus 2 could provide new insights about its pathogenic and host response and help to diagnose pulmonary involvement. We explored the potential added diagnostic value of 18F-FDG PET/CT scans in asymptomatic cancer patients with suspected COVID-19 pneumonia by investigating the association between metabolic and structural changes in the lung parenchyma. Methods:18F-FDG PET/CT studies acquired between February 19 and May 29, 2020, were reviewed to identify those cancer patients with incidental findings suggestive of COVID-19 pneumonia. PET studies were interpreted through qualitative (visual) and semiquantitative (measurement of SUVmax) analysis evaluating lung findings. Several characteristic signs of COVID-19 pneumonia on CT were described as COVID-19 Reporting and Data System (CO-RADS) categories (1-6). After comparing the SUVmax of pulmonary infiltrates among different CO-RADS categories, we explored the best potential cutoffs for pulmonary SUVmax against CO-RADS categories as the gold standard result to eliminate the possibility that the diagnosis of COVID-19 pneumonia exists. Results: On multimodal PET/CT imaging, CT signs classified as CO-RADS category 5 or 6 were found in 16 of 41 (39%) oncologic patients. SUVmax was higher in patients with categories 5 and 6 than in patients with category 4 (6.17 ± 0.82 vs. 3.78 ± 0.50, P = 0.04) or categories 2 and 3 (3.59 ± 0.41, P = 0.01). A specificity of 93.8% (95% CI, 71.7%-99.7%) and an accuracy of 92.9% were obtained when combining a CO-RADS score of 5 or 6 with an SUVmax of 2.45 in pulmonary infiltrates. Conclusion: In asymptomatic cancer patients, the metabolic activity in lung infiltrates is closely associated with several combined tomographic changes characteristic of COVID-19 pneumonia. Multimodal 18F-FDG PET/CT imaging could provide additional information during early diagnosis in selected predisposed patients during the pandemic. The prognostic implications of simultaneous radiologic and molecular findings in cancer patients and other subpopulations at high risk for COVID-19 pneumonia deserve further evaluation in prospective research.

Identification of the main components of spontaneous speech in primary progressive aphasia and their neural underpinnings using multimodal MRI and FDG-PET imaging.

BACKGROUND: Primary progressive aphasia (PPA) is a clinical syndrome characterized by gradual loss of language skills. This study aimed to evaluate the diagnostic capacity of a connected speech task for the diagnosis of PPA and its variants, to determine the main components of spontaneous speech, and to examine their neural correlates. METHODS: A total of 118 participants (31 patients with nfvPPA, 11 with svPPA, 45 with lvPPA, and 31 healthy controls) were evaluated with the Cookie Theft picture description task and a comprehensive language assessment protocol. Patients also underwent 18F-fluorodeoxyglucose positron emission tomography and magnetic resonance imaging studies. Principal component analysis and machine learning were used to evaluate the main components of connected speech and the accuracy of connected speech parameters for diagnosing PPA. Voxel-based analyses were conducted to evaluate the correlation between spontaneous speech components and brain metabolism, brain volumes, and white matter microstructure. RESULTS: Discrimination between patients with PPA and controls was 91.67%, with 77.78% discrimination between PPA variants. Parameters related to speech rate and lexical variables were the most discriminative for classification. Three main components were identified: lexical features, fluency, and syntax. The lexical component was associated with ventrolateral frontal regions, while the fluency component was associated with the medial superior prefrontal cortex. Number of pauses was more related with the left parietotemporal region, while pauses duration with the bilateral frontal lobe. The lexical component was correlated with several tracts in the language network (left frontal aslant tract, left superior longitudinal fasciculus I, II, and III, left arcuate fasciculus, and left uncinate fasciculus), and fluency was linked to the frontal aslant tract. CONCLUSION: Spontaneous speech assessment is a useful, brief approach for the diagnosis of PPA and its variants. Neuroimaging correlates suggested a subspecialization within the left frontal lobe, with ventrolateral regions being more associated with lexical production and the medial superior prefrontal cortex with speech rate.

"Brain Fog" by COVID-19 or Alzheimer's Disease? A Case Report.

Cognitive symptoms after COVID-19 have been increasingly recognized several months after the acute infection and have been designated as "brain fog." We report a patient with cognitive symptoms that started immediately after COVID-19, in which cerebrospinal fluid biomarkers were highly suggestive of Alzheimer's disease. Our case highlights the need to examine patients with cognitive symptoms following COVID-19 comprehensively. A detailed assessment combining clinical, cognitive, and biomarker studies may help disentangle the underlying mechanisms associated with cognitive dysfunction in each case. The investigation of neurodegenerative processes in an early stage, especially in older patients, is probably warranted.

Major pathological response and durable locoregional control after neoadjuvant pembrolizumab-carboplatin-paclitaxel in head and neck cancer.

Head and neck cancers are increasingly being diagnosed in elderly patients, where standard curative-intent, therapeutic options are often too aggressive for frail, malnourished and heavily comorbid patients. Since the incorporation of immune checkpoint inhibitors (ICIs) a few small studies have reported promising safety and efficacy with ICIs in the neoadjuvant locally-advaced setting. We present the case of an elderly, frail and comorbid patient, with a high-PDL1 expressing and very locally-advanced unresectable oral cavity cancer, that was treated with the combination of pembrolizumab and weekly carboplatin and paclitaxel, achieving a major pathological response, that permitted to de-escalate adjuvant therapy after surgery and is free of locoregional relapse 7 months after surgery. This is, to our knowledge, the first patient treated with neoadjuvant chemo-immunotherapy outside a clinical trial in SCCHN.

Personalized Repetitive Transcranial Magnetic Stimulation for Primary Progressive Aphasia.

BACKGROUND: Primary progressive aphasia (PPA) is a neurodegenerative syndrome for which no effective treatment is available. OBJECTIVE: We aimed to assess the effect of repetitive transcranial magnetic stimulation (rTMS), using personalized targeting. METHODS: We conducted a randomized, double-blind, pilot study of patients with PPA receiving rTMS, with a subgroup of patients receiving active- versus control-site rTMS in a cross-over design. Target for active TMS varied among the cases and was determined during a pre-treatment phase from a list of potential regions. The primary outcome was changes in spontaneous speech (word count). Secondary outcomes included changes in other language tasks, global cognition, global impression of change, neuropsychiatric symptoms, and brain metabolism using FDG-PET. RESULTS: Twenty patients with PPA were enrolled (14 with nonfluent and 6 with semantic variant PPA). For statistical analyses, data for the two variants were combined. Compared to the control group (n = 7), the group receiving active-site rTMS (n = 20) showed improvements in spontaneous speech, other language tasks, patient and caregiver global impression of change, apathy, and depression. This group also showed improvement or stabilization of results obtained in the baseline examination. Increased metabolism was observed in several brain regions after the therapy, particularly in the left frontal and parieto-temporal lobes and in the precuneus and posterior cingulate bilaterally. CONCLUSION: We found an improvement in language, patient and caregiver perception of change, apathy, and depression using high frequency rTMS. The increase of regional brain metabolism suggests enhancement of synaptic activity with the treatment. TRIAL REGISTRATION: NCT03580954 (https://clinicaltrials.gov/ct2/show/NCT03580954).

Incidental 68Ga-DOTATOC PET/CT Uptake in Hemorrhagic Transformation of Stroke in a Patient With Cervical Paraganglioma.

ABSTRACT: We present a case of a 75-year-old woman with clinical suspicion of stroke whose cranial CT showed ischemic changes in right precentral region, without visible vascular occlusion, and a right vagal lesion suggestive of paraganglioma. Two weeks later, 68Ga-DOTATOC PET/CT with IV iodine-based contrast administration (Biograph 6 True Point equipment; Siemens) was performed for characterization of this lesion and staging. Intraparenchymal 68Ga-DOTATOC uptake was visualized in right frontal lobe suggestive of hemorrhagic transformation of the previous stroke.

Validation technique and improvements introduced in a new dedicated brain positron emission tomograph (CareMiBrain).

The goal of developing a PET dedicated to the brain (CareMiBrain) has evolved from its initial approach to diagnosis and monitoring of dementias, to the more ambitious of creating a revolutionary clinical pathway for the knowledge and personalized treatment of multiple neurological diseases. The main innovative feature of CareMiBrain is the use of detectors with continuous crystals, which allow a high resolution determination of the depth of annihilation photons interaction within the thickness of the scintillation crystal. The technical validation phase of the equipment consisted of a pilot, prospective and observational study whose objective was to obtain the first images (40 patients), analyze them and make adjustments in the acquisition, reconstruction and correction parameters, comparing the image quality of the CareMiBrain equipment with that of the whole-body PET/CT. Thanks to the team meetings and the joint analysis of the images, it was possible to detect its weak points and some of its causes. The calibration, acquisition and processing processes, as well as the reconstruction, were optimized, the number of iterations was set to achieve the best signal-to-noise ratio, the random correction was optimized and a post-processing algorithm was included in the reconstruction algorithm. The main technical improvements implemented in this phase of technical validation carried out through collaboration of the Services of Nuclear Medicine and Neurology of the Hospital Clínico San Carlos with the Spanish company Oncovision will be exposed in a project financed with funds from the European Union (Horizon 2020 innovation program, 713323).

Safety and Efficacy of Cetuximab-Based Salvage Chemotherapy After Checkpoint Inhibitors in Head and Neck Cancer.

BACKGROUND: There are still few data on the activity and safety of cetuximab-based salvage chemotherapy after immunotherapy (SCAI) in patients with squamous cell cancer of the head and neck (SCCHN). MATERIALS AND METHODS: This was a retrospective study of patients with SCCHN who received cetuximab-based SCAI after programmed cell death protein 1 or programmed cell death ligand 1(PD[L]1) inhibitors. Overall response rate (ORR) and disease control rate (DCR) with SCAI and with last chemotherapy before immunotherapy (LCBI) by RECIST 1.1, percentage change from baseline in target lesions (PCTL), progression-free survival (PFS), overall survival (OS), treatment compliance, and toxicity were evaluated. RESULTS: Between March 2016 and November 2019, 23 patients were identified. SCAI consisted of cetuximab-based combinations (3-weekly cisplatin-5FU-cetuximab [n = 2], weekly paclitaxel-cetuximab [n = 17], weekly cisplatin-cetuximab [n = 2], weekly carboplatin-paclitaxel-cetuximab [n = 2]). ORR was 56.5% (11 partial response, 2 complete response). DCR was 78.3%. Among 13 objective responders, median best PCTL was -53.5% (range, -30% to -100%). Median OS and PFS were 12 months and 6 months, respectively. In 10 patients receiving LCBI, ORR to LCBI was 40%, whereas ORR to SCAI achieved 60%. In LCBI-treated patients, median PFS with LCBI was 8 months and median PFS and OS with SCAI were 7 months and 12 months, respectively. Reduced dose intensity of the chemotherapy and cetuximab components occurred in 82.6% and 52.2% of the patients. Grade 1 or 2 adverse events (AEs) occurred in all patients. Grade 3 or 4 AEs developed in 65%, being grade 3 in all of them except in one patient (grade 4 neutropenia). There were no treatment-related deaths. CONCLUSION: Cetuximab-based salvage chemotherapy after PD(L)1 inhibitors associated with high response rates and deep tumor reductions with a manageable safety profile. Subsequent lines of therapy may explain the long survival achieved in our series. These results invite to design studies to elucidate the best therapeutic sequence in patients with SCCHN in the immunotherapy era. IMPLICATIONS FOR PRACTICE: Cetuximab-based salvage chemotherapy (SCAI) achieved high response rates in patients with recurrent/metastatic squamous cell cancer of the head and neck (SCCHN) after progression to PD-1/PD-L1 inhibitors. Objective response rate was higher than and progression-free survival was comparable to that of chemotherapy administered before immunotherapy (IO). In most patients, SCAI consisted of weekly, well-tolerated regimens. These observations have implications for current practice because of the limited evidence to date in SCCHN and the scant therapeutic options in this disease and invite to elucidate which may be the best treatment sequence for patients with head and neck cancer in the IO era.