Oral Cavity Squamous Cell Carcinoma: Review of Pathology, Diagnosis, and Management.

Squamous cell carcinoma of the oral cavity presents a significant global health burden, primarily due to risk factors such as tobacco smoking, smokeless tobacco use, heavy alcohol consumption, and betel quid chewing. Common clinical manifestations of oral cavity cancer include visible lesions and sores, often accompanied by pain in advanced stages. Diagnosis relies on a comprehensive assessment involving detailed history, physical examination, and biopsy. Ancillary imaging studies and functional evaluations aid in accurate staging and facilitate treatment planning. Prognostic information is obtained from histopathological factors, such as tumor grade, depth of invasion, lymphovascular invasion, and perineural invasion. Notably, lymph node metastasis, found in approximately half of the patients, carries significant prognostic implications. Effective management necessitates a multidisciplinary approach to optimize patient outcomes. Surgical resection is the backbone of treatment, aimed at complete tumor removal while preserving functional outcomes. Adjuvant therapies, including radiation and chemotherapy, are tailored according to pathological factors. Further work in risk stratification and treatment is necessary to optimize outcomes in squamous cell carcinoma of the oral cavity.

Population Pharmacokinetics and Dosing Simulations for Aripiprazole 2-Month Ready-to-Use Long-Acting Injectable in Adult Patients With Schizophrenia or Bipolar I Disorder.

A ready-to-use (RTU) long-acting injectable (LAI) formulation of aripiprazole monohydrate for administration once every 2 months, available in 960 mg (Ari 2MRTU 960) or 720 mg doses, has been developed for the treatment of schizophrenia or bipolar I disorder. A previously developed and validated population pharmacokinetic model for characterizing aripiprazole plasma concentrations following administration of oral aripiprazole or aripiprazole once-monthly (AOM) intramuscular injection was expanded to include the RTU LAI formulation of aripiprazole (Ari RTU LAI). Overall, 8899 aripiprazole pharmacokinetic samples from 1191 adults from 10 clinical trials were included in the final combined analysis data set. Aripiprazole plasma concentration-time profiles were simulated for various Ari RTU LAI initiation and maintenance scenarios in 1000 virtual patients. Diagnostic plots demonstrated that the final population pharmacokinetic model, which incorporated data for oral aripiprazole, AOM, and Ari RTU LAI, adequately described aripiprazole concentrations following Ari RTU LAI administration. Absorption of Ari RTU LAI was modeled by a parallel zero-order and lagged first-order process. Simulations across multiple scenarios were performed to inform dosing recommendations, including various treatment initiation regimens for a 2-monthly formulation of Ari RTU LAI in patients with or without prior stabilization on oral aripiprazole, and for patients switching from AOM. Additional simulations accounted for missed/delayed doses, cytochrome (CYP) 2D6 metabolizer status, and concomitant use of CYP2D6 or CYP3A4 inhibitors. Overall, simulations across a variety of scenarios demonstrated an Ari RTU LAI pharmacokinetic exposure profile that was comparable to AOM, with a longer dosing interval.

Phosphine substitution and linkage isomerization in cyclopentadienylruthenium bis(triphenylphosphine)thiocyanide and selenocyanide, CpRu(PPh3)2NCS and CpRu(PPh3)2SeCN.

The reaction between CpRu(PPh3)2NCS (1a) and PMePh2 yields CpRu(PPh3)(PMePh2)NCS (2a) while CpRu(PPh3)(PMePh2)Cl reacts with SCN- to form the S-bonded isomer, CpRu(PPh3)(PMePh2)SCN (2b). Compound 1a and the linkage isomers of 2 were characterized by X-ray crystallography. The kinetics of the reaction between 1a and PMePh2 under pseudo-first order conditions in THF and in fluorobenzene to form 2a are consistent with a dissociative interchange mechanism. Activation parameters for the reaction are: ΔH† = 15.7 ± 0.6 kcal mol-1 and ΔS† = -35 ± 2 cal mol-1 K-1 in THF vs. ΔH† = 24.8 ± 1.2 kcal mol-1 and ΔS† = -6 ± 4 cal mol-1 K-1 in C6H5F. In the presence of added SCN-, the rate of phosphine substitution is unchanged but a mixture of 2a and 2b is observed. The selenocyanate derivative, CpRu(PPh3)2SeCN (3b), crystallizes as the Se-bonded linkage isomer. Compound 3b reacts with PMePh2 under pseudo-first order conditions in fluorobenzene to form CpRu(PPh3)(PMePh2)SeCN (4b) at a much faster rate than 1a with activation parameters: ΔH† = 30.9 ± 4.8 kcal mol-1 and ΔS† = 22.4 ± 15.9 cal mol-1 K-1 with no evidence for linkage isomerization to the N-bonded products.

Response-Based Dosing for Ponatinib: Model-Based Analyses of the Dose-Ranging OPTIC Study.

Optimizing Ponatinib Treatment in CP-CML (OPTIC) was a randomized, phase II dose-optimization trial of ponatinib in chronic phase-chronic myeloid leukemia (CP-CML) resistant to ≥ 2 tyrosine kinase inhibitors or with T315I mutation. Patients were randomized to starting doses of 45-, 30-, or 15-mg ponatinib once daily. Patients receiving 45- or 30-mg reduced to 15-mg upon achievement of ≤ 1% BCR::ABL1IS (≥ molecular response with 2-log reduction (MR2)). The exposure-molecular response relationship was described using a four-state, discrete-time Markov model. Time-to-event models were used to characterize the relationship between exposure and arterial occlusive events (AOEs), grade ≥ 3 neutropenia, and thrombocytopenia. Increasing systemic exposures were associated with increasing probability of transitioning from no response to ≥ MR1, and from MR1 to ≥ MR1, with odds ratios of 1.63 (95% confidence interval (CI), 1.06-2.73) and 2.05 (95% CI, 1.53-2.89) for a 15-mg dose increase, respectively. Ponatinib exposure was a significant predictor of AOEs (hazard ratio (HR) 2.05, 95% CI, 1.43-2.93, for a 15-mg dose increase). In the exposure-safety models for neutropenia and thrombocytopenia, exposure was a significant predictor of grade ≥ 3 thrombocytopenia (HR 1.31, 95% CI, 1.05-1.64, for a 15-mg dose increase). Model-based simulations predicted a clinically meaningful higher rate of ≥ MR2 response at 12 months for the 45-mg starting dose (40.4%) vs. 30-mg (34%) and 15-mg (25.2%). The exposure-response analyses supported a ponatinib starting dose of 45 mg with reduction to 15 mg at response for patients with CP-CML.

ED visits, hospital admissions and treatment breaks in head/neck cancer patients undergoing radiotherapy.

Objectives: Radiation therapy (RT) is an integral part of treatment of head/neck cancer (HNC) but is associated with many toxicities. We sought to evaluate sociodemographic, pathologic, and clinical factors associated with emergency department (ED) visits, hospital admissions (HA), and RT breaks in HNC patients undergoing curative-intent RT. Methods: We completed a Level 3 (Oxford criteria for evidence-based medicine) analysis of a cohort of HNC patients who underwent curative-intent RT at our institution from 2013 to 2017. We collected demographic characteristics and retrospectively assessed for heavy opioid use, ED visits or HA during RT as well as RT breaks. Treatment breaks were defined as total days to RT fractions ratio ≥1.6. Multivariable stepwise logistic regression analyses were done to determine the association of various sociodemographic, pathologic, and clinical characteristics with ED visits, HA and RT treatment breaks. Results: The cohort included 376 HNC patients (294 male, 82 female, median age 61). On multivariable analysis, significant factors associated with ED visits during RT were heavy opioid use and black race. Receipt of concomitant chemotherapy was the only factor associated with hospital admissions during RT. Advanced age, lower socioeconomic class, glandular site, and receipt of chemotherapy were all independently associated with RT breaks. Lower cancer stage and lack of substance abuse history were independently associated with lack of treatment breaks. Conclusion: HNC patients with factors such as heavy opioid use, Black race, receipt of concomitant chemotherapy, and lower socioeconomic class may require closer monitoring during RT.

Population pharmacokinetics and exposure-response of trilaciclib in extensive-stage small cell lung cancer and triple-negative breast cancer.

AIMS: Trilaciclib is a first-in-class, intravenous cyclin-dependent kinase 4/6 inhibitor that provides multilineage protection from chemotherapy-induced myelosuppression. This analysis aimed to characterize the population pharmacokinetics (PK) of trilaciclib, identify potential covariates influencing trilaciclib PK, and evaluate exposure-response relationships in extensive-stage small cell lung cancer (ES-SCLC) and triple-negative breast cancer (TNBC) trials. METHODS: Population PK analysis was performed using data from healthy volunteers (n = 72), patients with ES-SCLC (n = 111) and patients with TNBC (n = 14). Exposure-response analyses were conducted to investigate the impact of trilaciclib exposure (AUC) on myeloprotective efficacy, antitumour efficacy and safety. Logistic regression and Cox regression models were used for binary and time-to-event endpoints, respectively. RESULTS: Trilaciclib PK was described by a three-compartment model. Sex, body surface area, baseline albumin concentration and age were identified as significant covariates on trilaciclib PK but did not have clinically relevant impact on exposure. Based on exposure-response analyses, lower and higher exposures of trilaciclib at clinical doses (200-280 mg/m2 ) were associated with similar myeloprotective effects. Trilaciclib exposure did not impact the antitumour effects of chemotherapy. Higher exposure to trilaciclib was associated with higher probabilities of headache, phlebitis/thrombophlebitis and injection site reactions. CONCLUSION: No dose adjustments are required based on the covariates tested. Trilaciclib resulted in optimal myeloprotective effects with no impact on antitumour effects of chemotherapy. However, higher exposure increased the probabilities of adverse events. The data further support selection of the recommended phase 2 dose (trilaciclib 240 mg/m2 ).

Stereotactic Body Radiotherapy for Localized Kidney Cancer.

PURPOSE OF REVIEW: Stereotactic body radiation therapy (SBRT) is increasingly utilized in the management of localized kidney cancers, particularly for patients who are not surgical candidates. Herein, we provide a narrative review of SBRT in the management of localized kidney cancers. RECENT FINDINGS: Recent prospective studies and multi-institutional retrospective studies highlight the safety and efficacy of SBRT in the management of renal tumors, a disease previously thought to be radioresistant. Studies have shown that local control is greater than 90% with rare grade 3 or 4 toxicity and no grade 5 toxicity. SBRT can be utilized successfully in the treatment of large kidney tumors (> 5 cm). New techniques such as MRI-guided radiation therapy may further improve the therapeutic ratio. However, randomized clinical trials are necessary to confirm the optimal dosing schedule and compare outcomes with nephrectomy, which remains the standard of care in suitable patients. Advances in SBRT have made this modality a safe and effective treatment option in the management of localized kidney cancers.

A Case of Glioblastoma, Isocitrate Dehydrogenase Wild Type, With Widely Disseminated Osseous Metastasis.

Glioblastoma, isocitrate dehydrogenase (IDH) wild type, is an aggressive primary brain malignancy with a poor prognosis, despite treatment including surgery, chemotherapy, and radiation therapy. Few patients with glioblastoma develop metastasis outside the neuroaxis, likely due to disease progression in the brain prior to extraneural dissemination. The driving mutations of tumors in patients with extraneural metastases are not well described. In this case, we present a severe case of extraneural metastatic glioblastoma, as well as the genetic mutations of the tumor.

Factors associated with the use of salvage whole brain radiation therapy versus salvage stereotactic radiosurgery after initial stereotactic radiosurgery for brain metastases.

Objectives: Patients undergoing stereotactic radiosurgery (SRS) for brain metastases require additional radiation for relapse. Our objective is to determine the factors associated with salvage SRS versus whole brain radiation therapy (WBRT) for salvage of first intracranial failure (ICF) after upfront SRS. Method: We identified a cohort of 110 patients with brain metastases treated with SRS in the definitive or postoperative setting followed by subsequent salvage WBRT or SRS at least one month after initial SRS. Clinical and demographic characteristics were retrospectively recorded. Results: 78 Patients received SRS and 32 patients received WBRT at the time of first ICF. On multivariate analysis (MVA) factors associated with decreased use of salvage SRS were male gender (p=0.044) and local progression (p<0.001). Conclusions: Local progression and male gender were the strongest factors associated with selection of salvage WBRT. Possible etiologies of this difference could be provider or patient driven, but warrant further exploration.

Erring Characteristics of Deformable Image Registration-Based Auto-Propagation for Internal Target Volume in Radiotherapy of Locally Advanced Non-Small Cell Lung Cancer.

Purpose: Respiratory motion of locally advanced non-small cell lung cancer (LA-NSCLC) adds to the challenge of targeting the disease with radiotherapy (RT). One technique used frequently to alleviate this challenge is an internal gross tumor volume (IGTV) generated from manual contours on a single respiratory phase of the 4DCT via the aid of deformable image registration (DIR)-based auto-propagation. Through assessing the accuracy of DIR-based auto-propagation for generating IGTVs, this study aimed to identify erring characteristics associated with the process to enhance RT targeting in LA-NSCLC. Methods: 4DCTs of 19 patients with LA-NSCLC were acquired using retrospective gating with 10 respiratory phases (RPs). Ground-truth IGTVs (GT-IGTVs) were obtained through manual segmentation and union of gross tumor volumes (GTVs) in all 10 phases. IGTV auto-propagation was carried out using two distinct DIR algorithms for the manually contoured GTV from each of the 10 phases, resulting in 10 separate IGTVs for each patient per each algorithm. Differences between the auto-propagated IGTVs (AP-IGTVs) and their corresponding GT-IGTVs were assessed using Dice coefficient (DICE), maximum symmetric surface distance (MSSD), average symmetric surface distance (ASSD), and percent volume difference (PVD) and further examined in relation to anatomical tumor location, RP, and deformation index (DI) that measures the degree of deformation during auto-propagation. Furthermore, dosimetric implications due to the analyzed differences between the AP-IGTVs and GT-IGTVs were assessed. Results: Findings were largely consistent between the two algorithms: DICE, MSSD, ASSD, and PVD showed no significant differences between the 10 RPs used for propagation (Kruskal-Wallis test, ps > 0.90); MSSD and ASSD differed significantly by tumor location in the central-peripheral and superior-inferior dimensions (ps < 0.0001) while only in the central-peripheral dimension for PVD (p < 0.001); DICE, MSSD, and ASSD significantly correlated with the DI (Spearman's rank correlation test, ps < 0.0001). Dosimetric assessment demonstrated that 79% of the radiotherapy plans created by targeting planning target volumes (PTVs) derived from the AP-IGTVs failed prescription constraints for their corresponding ground-truth PTVs. Conclusion: In LA-NSCLC, errors in DIR-based IGTV propagation present to varying degrees and manifest dependences on DI and anatomical tumor location, indicating the need for personalized consideration in designing RT internal target volume.

Application of Super Photoacids in Controlling Dynamic Processes: Light-Triggering the Self-Propulsion of Oil Droplets.

The dynamic control of pH-responsive systems is at the heart of many natural and artificial processes. Here, we use photoacids, molecules that dissociate only in their excited state and transfer their proton to nearby proton acceptors, for the dynamic control of processes. A problem arises when there is a need to protonate highly acidic acceptors. We solve this problem using super photoacids that have an excited-state pKa of -8, thus enabling them to protonate very weak proton acceptors. The process that we target is the light-triggered self-propulsion of droplets, initiated by an excited-state proton transfer (ESPT) from a super photoacid donor to a surfactant acceptor situated on the surface of the droplet with a pKa of ∼0. We first confirm using steady-state and time-resolved spectroscopy that a super photoacid can undergo ESPT to the acidic surfactant, whereas a "regular" photoacid cannot. Next, we show self-propulsion of the droplet upon irradiating the solvated super photoacid. We further confirm the protonation of the surfactant on the surface of the droplet using transient surface tension measurements. Our system is the first example of the application of super photoacids to control dynamic processes and opens new possibilities in the field of light-triggered dynamic systems.

Survival and Yield of Surveillance Imaging in Long-Term Survivors of Brain Metastasis Treated with Stereotactic Radiosurgery.

OBJECTIVES: The optimal frequency of surveillance brain magnetic resonance imaging (MRI) in long-term survivors with brain metastases after stereotactic radiosurgery (SRS) is unknown. Our aim was to identify the optimal frequency of surveillance imaging in long-term survivors with brain metastases after SRS. METHODS: Eligible patients were identified from a cohort treated with SRS definitively or postoperatively at our institution from 2014 to 2019 with no central nervous system (CNS) failure within 12 months from SRS. Time to CNS disease failure diagnosis and cost per patient were estimated using theoretical MRI schedules of 2, 3, 4, and 6 months starting 1 year after SRS until CNS failure. Time to diagnosis was calculated from the date of CNS progression to the theoretical imaging date on each schedule. RESULTS: This cohort included 55 patients (median follow-up from SRS: 2.48 years). During the study period, 20.0% had CNS disease failure (median: 2.26 years from SRS treatment). In this cohort, a theoretical 2-month, 3-month, 4-month, and 6-month MRI brain surveillance schedule produced a respective estimated time to diagnosis of CNS disease failure of 1.11, 1.74, 1.65, and 3.65 months. The cost of expedited diagnosis for the cohort (dollars/month) for each theoretical imaging schedule compared with a 6-month surveillance schedule was $6600 for a 2-month protocol, $4496 for a 3-month protocol, and $2180 for a 4-month protocol. CONCLUSIONS: Based on cost-benefit, a 4-month MRI brain schedule should be considered in patients with metastatic disease to the brain treated definitively or postoperatively with SRS without evidence of CNS recurrence at 1 year.

A Single Axial Slice of the Sternocleidomastoids and Paravertebral Muscles Associated with Worse Local Progression-Free Survival and Severe Toxicity in Sarcopenic Head and Neck Cancer Patients Undergoing Radiotherapy.

Objective The objective of this study is to contrast the predictive ability of targeted muscle groups as radiographic proxies of sarcopenia on computerized tomography (CT) with body mass index (BMI) in head and neck cancer patients (H&NCP) undergoing radiation at a safety net hospital, and to evaluate sarcopenia with survival, local progression, toxicities and treatment delays. Methods A retrospective review included 52 H&NCP treated between 2017-2019. The posterior neck muscles (PN), sternocleidomastoids (SCM), and their summed volume (AM) were contoured at C3 on patients' pre-treatment CT scans, then normalized to obtain skeletal muscle index (MI) values. Pre-treatment BMI was also evaluated. Cutoffs for sarcopenia were determined by receiver operating characteristic curves. Overall survival and local recurrence-free survival were evaluated by Kaplan-Meier. Acute grade 3 or higher toxicities were evaluated by binomial logistic regression. Results Using all neck muscles (AM-MI) produced the best model for predicting outcomes, outperforming individual muscle groups and BMI. Local progression-free survival was worse in sarcopenic patients at 25.81 months versus 35.40 months (p=0.026). Acute grade 3 or higher toxicities were associated with sarcopenia (p=0.005). Conclusions In this small, retrospective single-institution experience at a safety net hospital, a single axial slice of the combined sternocleidomastoids and paravertebral muscles at C3 performed better than either muscle group alone or pre-treatment BMI at predicting oncologic outcomes.

Levels of Evidence for Radiation Therapy Recommendations in the National Comprehensive Cancer Network (NCCN) Clinical Guidelines.

PURPOSE: The National Comprehensive Cancer Network (NCCN) clinical guidelines influence medical practice, payor coverage, and standards of care. The levels of evidence underlying radiation therapy recommendations in NCCN have not been systematically explored. Herein, we aim to systematically investigate the NCCN recommendations pertaining to the categories of consensus and evidence (CE) for radiation therapy. METHODS AND MATERIALS: We evaluated the distribution of CE underlying current treatment recommendations for the 20 most prevalent cancers in the United States with at least 10 radiation therapy recommendations in the NCCN clinical guidelines. For context, the distribution of evidence in the radiation therapy guidelines was compared with that of systemic therapy using a χ2 test. The proportion of category I CE between radiation and systemic therapy was compared using a 2-proportion, 2-tailed z-test in total and for each disease site. A P value of < .05 was considered significant. RESULTS: Among all radiation therapy recommendations, the proportions of category I, IIA, IIB, and III CE were 9.7%, 80.6%, 8.4%, and 1.3%, respectively. When analyzed by disease site, cervix and breast cancer had the highest portion of category I CE (33% and 31%, respectively). There was no radiation therapy category I CE for hepatobiliary, bone, pancreatic, melanoma, and uterine cancers. There was a significant difference in the distribution of CE between the systemic therapy recommendations and the radiation therapy recommendations (χ2 statistic 64.16, P < .001). Overall, there was a significantly higher proportion of category I CE in the systemic therapy recommendations compared with the radiation therapy recommendations (12.3% vs 9.7%, P = .043). CONCLUSIONS: Only 9.7% of radiation therapy recommendations in NCCN guidelines are category I CE. The highest levels of evidence for radiation therapy are in breast and cervical cancers. Despite major advances in the field, these data underline that the majority of NCCN radiation therapy recommendations are based on uniform expert opinion and not on higher level evidence.

Radiomics Predicts for Distant Metastasis in Locally Advanced Human Papillomavirus-Positive Oropharyngeal Squamous Cell Carcinoma.

(1) Background and purpose: clinical trials have unsuccessfully tried to de-escalate treatment in locally advanced human papillomavirus positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) with the goal of reducing treatment toxicity. The aim of this study was to explore the role of radiomics for risk stratification in this patient population to guide treatment. (2) Methods: the study population consisted of 225 patients with locally advanced HPV+ OPSCC treated with curative-intent radiation or chemoradiation therapy. Appearance of distant metastasis was used as the endpoint event. Radiomics data were extracted from the gross tumor volumes (GTVs) identified on the planning CT, with gray level being discretized using three different bin widths (8, 16, and 32). The data extracted for the groups with and without distant metastasis were subsequently balanced using three different algorithms including synthetic minority over-sampling technique (SMOTE), adaptive synthetic sampling (ADASYN), and borderline SMOTE. From these different combinations, a total of nine radiomics datasets were derived. Top features that minimized redundancy while maximizing relevance to the endpoint were selected individually and collectively for the nine radiomics datasets to build support vector machine (SVM) based predictive classifiers. Performance of the developed classifiers was evaluated by receiver operating characteristic (ROC) curve analysis. (3) Results: of the 225 locally advanced HPV+ OPSCC patients being studied, 9.3% had developed distant metastases at last follow-up. SVM classifiers built for the nine radiomics dataset using either their own respective top features or the top consensus ones were all able to differentiate the two cohorts at a level of excellence or beyond, with ROC area under curve (AUC) ranging from 0.84 to 0.95 (median = 0.90). ROC comparisons further revealed that the majority of the built classifiers did not distinguish the two cohorts significantly better than each other. (4) Conclusions: radiomics demonstrated discriminative ability in distinguishing patients with locally advanced HPV+ OPSCC who went on to develop distant metastasis after completion of definitive chemoradiation or radiation alone and may serve to risk stratify this patient population with the purpose of guiding the appropriate therapy.

Emergent Radiotherapy for Leukemia-Induced Cranial Neuropathies Refractory to Intrathecal Therapy.

Neurologic symptoms from leukemic infiltration of the central nervous system are an oncologic emergency, and expeditious treatment is required to preserve function. We report the case of a 44-year-old patient with relapsed acute myeloid leukemia (AML) who developed sub-acute cranial neuropathies refractory to treatment with intrathecal (IT) chemotherapy. The patient was therefore treated with an emergent course of whole-brain radiotherapy, resulting in immediate improvement and subsequent resolution of cranial neuropathies. This case illustrates that while central nervous system involvement by AML is rare, radiotherapy remains an effective modality to avoid long-term morbidity in patients failing to respond to systemic or IT chemotherapy.

Opioid use patterns in patients with head and neck cancer receiving radiation therapy: Single-institution retrospective analysis characterizing patients who did not require opioid therapy.

BACKGROUND: We had previously analyzed the variables that determine the rates of opioid use at 1-year postradiotherapy in patients with head and neck cancer. Here we analyze the variables associated with opioid abstinence during and in the 12 months after radiotherapy at our institution. METHODS: We identified a cohort of patients with head and neck cancer who received radiotherapy as part of curative treatment at our institution. Logistic regression analyses were performed to determine socioeconomic and clinical factors associated with opioid abstinence. RESULTS: The cohort included 376 patients. On multivariable analysis, patients from an upper-income class (p = 0.004), black race (p = 0.004), older (p = 0.008), with dependent children (p < 0.001) or receiving surgery (p = 0.002) were more likely to abstain from opioids, while patients using analgesic mouthwash (p = 0.009) or higher pain scale (p = 0.002) were less likely. CONCLUSION: Socioeconomic and treatment characteristics are associated with opioid abstinence during and following radiation treatment in patients with head and neck cancer.

Retention of surface structure causes lower density in atomic layer deposition of amorphous titanium oxide thin films.

Size effects and structural modifications in amorphous TiO2 films deposited by atomic layer deposition (ALD) were investigated. As with the previously investigated ALD-deposited Al2O3 system we found that the film's structure and properties are strongly dependent on its thickness, but here, besides the significant change in the density of the films there is also a change in their chemical state. The thin near-surface layer contained a significantly larger amount of Ti+3 species and oxygen vacancies relative to the sample's bulk. We attribute this change in chemistry to the ALD specific deposition process wherein each different atomic species is deposited in turn, thereby forming a "corundum-like" structure of the near-surface layer resembling that found in the Al2O3 system. This, combined with the fact that each deposited layer starts out as a surface layer and maintains the surface structure over the next several following deposition cycles, is responsible for the overall decrease in the film density. This is the first time this effect has been shown in detail for TiO2, expending the previously discovered phenomenon to a new system and demonstrating that while similar effects occur, they can present in different ways for oxide systems with different structures and symmetries.