Submandibular gland involvement in oral cavity squamous cell carcinoma: a retrospective multicenter study.

BACKGROUND: The submandibular gland (SMG) is routinely excised during neck dissection. Given the importance of the SMG in saliva production, it is important to understand its involvement rate by cancer tissue and the feasibility of its preservation. METHODS: Retrospective data were collected from five academic centers in Europe. The study involved adult patients affected by primary oral cavity carcinoma (OCC) undergoing tumor excision and neck dissection. The main outcome analyzed was the SMG involvement rate. A systematic review and a meta-analysis were also conducted to provide an updated synthesis of the topic. RESULTS: A total of 642 patients were enrolled. The SMG involvement rate was 12/642 (1.9%; 95% CI 1.0-3.2) when considered per patient, and 12/852 (1.4%; 95% CI 0.6-2.1) when considered per gland. All the glands involved were ipsilateral to the tumor. Statistical analysis showed that predictive factors for gland invasion were: advanced pT status, advanced nodal involvement, presence of extracapsular spread and perivascular invasion. The involvement of level I lymph nodes was associated with gland invasion in 9 out of 12 cases. pN0 cases were correlated with a reduced risk of SMG involvement. The review of the literature and the meta-analysis confirmed the rare involvement of the SMG: on the 4458 patients and 5037 glands analyzed, the involvement rate was 1.8% (99% CI 1.1-2.7) and 1.6% (99% CI 1.0-2.4), respectively. CONCLUSIONS: The incidence of SMG involvement in primary OCC is rare. Therefore, exploring gland preservation as an option in selected cases would be reasonable. Future prospective studies are needed to investigate the oncological safety and the real impact on quality of life of SMG preservation.

Oral cavity carcinoma in patients with and without a history of lichen planus: A comparative analysis.

BACKGROUND: Oral potentially malignant disorders (OPMD) are associated with the risk of malignant transformation (MT) into oral cavity carcinoma (OCC). Oral lichen planus (OLP) is one of the most common OPMDs in western countries. Although there is a substantial amount of research on progression to cancer, a specific analysis of the clinical characteristics and prognosis of cancer developed in patients with a history of OLP versus patients without a history of OLP has not been investigated so far. METHODS: Retrospective evaluation of 82 patients treated for OCC with a known history of OLP compared to a representative sample of 82 patients treated for OCC without a known history of LP. Comparative analyses were performed on age at presentation, sex, TNM staging, clinical characteristics, pathology characteristics, 2- and 5-year overall survival (OS), and disease-free survival (DFS). RESULTS: It was shown that patients with a history of LP were significantly younger at first presentation than patients without a history of LP (mean age difference 6.7 years, 95% CI 3.1-10.3, p < 0.05). Also, patients with a history of OLP were in higher proportion females. The main pathological stage at presentation was significantly lower in the OLP group (p < 0.05). The 2-year survival analysis showed that DFS and OS were significantly lower in patients without a known history of OLP, with a hazard ratio (HR) of 3.1 (95% CI 1.4-6.8) and HR of 2.6 (95% CI 1.3-5.3), respectively. The 5-year survival analysis showed that DFS and OS were significantly lower in patients without a known history of OLP, with a hazard ratio of 3.1 (95% CI 1.6-6.2) and of 2.9 (95% CI 1.5-5.6), respectively. CONCLUSIONS: Cancer arising from OLP has peculiar characteristics compared to cancer in naïve patients. It most commonly affects younger patients, women, and nonsmokers. It is usually diagnosed at earlier stages and appears to have less aggressive behavior at presentation. Moreover, when 2- and 5-year survival is analyzed, it appears that patients in OLP group have an overall and a disease-free survival advantage. These results suggest that cancer from OLP is less aggressive and thus has a potential biological difference with cancer arising in non-OLP patients. Further clinical and basic investigations are needed to confirm the results of this study.

Myomucosal island flap in the reconstruction of oral cavity defects: Description of the surgical technique.

Multiple options are available for the reconstruction of the defects of the oral cavity. Among these, the facial artery myomucosal island flap (FAMMIF) is a pedicled flap composed by cheek mucosa, submucosa, and part of the buccinator muscle. The FAMMIF is ideal for the reconstruction of small-to-moderate defects of the oral cavity and the oropharynx. This is due to low operating time, low morbidity, and good functional and aesthetic results. A step-by-step description of the flap harvesting is presented, with particular attention to flap design, identification of the vessels, harvesting of the myomucosal island, tunnel preparation for its passage in the neck and back to the oral cavity, and closure of the cheek donor site with the buccal fat pad.

The Impact of the COVID-19 Pandemic on Head and Neck Cancer Diagnosis in the Piedmont Region, Italy: Interrupted Time-Series Analysis.

Background: The COVID-19 pandemic has likely affected the most vulnerable groups of patients and those requiring time-critical access to healthcare services, such as patients with cancer. The aim of this study was to use time trend data to assess the impact of COVID-19 on timely diagnosis and treatment of head and neck cancer (HNC) in the Italian Piedmont region. Methods: This study was based on two different data sources. First, regional hospital discharge register data were used to identify incident HNC in patients ≥18 years old during the period from January 1, 2015, to December 31, 2020. Interrupted time-series analysis was used to model the long-time trends in monthly incident HNC before COVID-19 while accounting for holiday-related seasonal fluctuations in the HNC admissions. Second, in a population of incident HNC patients eligible for recruitment in an ongoing clinical cohort study (HEADSpAcE) that started before the COVID-19 pandemic, we compared the distribution of early-stage and late-stage diagnoses between the pre-COVID-19 and the COVID-19 period. Results: There were 4,811 incident HNC admissions in the 5-year period before the COVID-19 outbreak and 832 admissions in 2020, of which 689 occurred after the COVID-19 outbreak in Italy. An initial reduction of 28% in admissions during the first wave of the COVID-19 pandemic (RR 0.72, 95% CI 0.62-0.84) was largely addressed by the end of 2020 (RR 0.96, 95% CI 0.89-1.03) when considering the whole population, although there were some heterogeneities. The gap between observed and expected admissions was particularly evident and had not completely recovered by the end of the year in older (≥75 years) patients (RR: 0.88, 0.76-1.01), patients with a Romano-Charlson comorbidity index below 2 (RR 0.91, 95% CI: 0.84-1.00), and primary surgically treated patients (RR 0.88, 95% CI 0.80-0.97). In the subgroup of patients eligible for the ongoing active recruitment, we observed no evidence of a shift toward a more advanced stage at diagnosis in the periods following the first pandemic wave. Conclusions: The COVID-19 pandemic has affected differentially the management of certain groups of incident HNC patients, with more pronounced impact on older patients, those treated primarily surgically, and those with less comorbidities. The missed and delayed diagnoses may translate into worser oncological outcomes in these patients.

Implant Dental Rehabilitation of Fibula-Free Flap Reconstructed Jaws.

BACKGROUND: The possibility of placing dental fixtures in the reconstructed regions allows us to overcome the problems related to dental rehabilitation with removable prosthesis. The aim of this study was to assess the clinic-radiological outcome in a series of patients who underwent fibula flap jaws reconstruction and rehabilitation with implant-supported prosthesis with a minimum follow-up of 24 months. MATERIAL AND METHODS: The study included 10 patients who underwent reconstruction with fibula free flap between 2010 and 2018. Albrektsson criteria were used to define the implant survival. The follow-up evaluation was performed according to a standardized protocol including clinical examination, radiological evaluation (panoramic radiograph) and patient interview. RESULTS: A total of 45 implants were positioned.The time between mandibular reconstruction and implant placement ranged from 13 months to 39 months.The prosthesis used was fixed in 6 cases and supported overdenture in 4 cases.No implant failure was observed.Regarding implant survival no infections were observed in these series. Nine patients out of 10 had no pain and signs of mobility. Seven patients out of 10 had absence of peri-implant radiolucency at the panoramic radiograph.One patient presented with an overgrowth of granulomatous soft tissue around the implant abutments that caused pain. CONCLUSIONS: Implant placed in vascularized bone grafts are a safe and reliable opportunity to rehabilitate patients following mandibular resection. The results of this series demonstrate a high survival rate for implants placed in reconstructed mandibles with an improvement of the quality of life.

Different Presentation and Outcomes in the Surgical Treatment of Advanced MRONJ in Oncological and Nononcological Patients Taking or Not Corticosteroid Therapy.

Medication-related osteonecrosis of the jaw (MRONJ) is a severe side effect caused by antiangiogenic antiresorptive drugs used to treat various oncological and non oncological diseases. The clinical and radiological characteristics of MRONJ depend on the type of causative drug, the time of administration, and its dosage. Proven systemic risk factors like anemia, uncontrolled diabetes, corticosteroid therapy, and chemotherapy in neoplastic diseases (e.g., high doses of methotrexate up to 30 mg daily) significantly increase the chances of acquiring MRONJ. The risk factors themselves can affect treatment outcomes. Although the main scientific societies have recently disseminated good practice rules on the patient's prevention, diagnosis, and management, there are still no guidelines on shared therapeutic strategies. In general, if conservative treatment fails, surgical treatment is considered, including local debridement, osteoplasty, and marginal or segmental osteotomy. In literature, cohorts of heterogeneous patients with MRONJ have been analyzed for a long time, resulting in a lack of uniformity of information and difficulties interpreting the data. According to the American Association of Oral and Maxillofacial Surgeons criteria, this retrospective study evaluates the surgical treatment outcomes of 64 patients with stage II-III MRONJ, evaluated at the Department of Maxillofacial Surgery of the University of Turin (Italy). The first objective of this retrospective study is to evaluate treatment results for stages II-III in all cases; the second objective is to evaluate the same results by dividing the sample into different cohorts of patients: first, based on the underlying pathology, i.e., oncological and non oncological, and secondly, based on the drug or combination of drugs they took.

Prospective assessment of taste impairment and nausea during radiotherapy for head and neck cancer.

Dysgeusia and nausea are common side effects observed in head and neck cancer patients treated with either exclusive radiotherapy or combined modality treatment. The aim of the present study was to prospectively evaluate dysgeusia, during treatment and follow-up, using the chemotherapy-induced taste alteration scale (CiTAS), a metrics based on 18-items exploring three dimensions (quantitative and qualitative changes in taste perception, and diet-related issues) identified through a four-factor analysis: decline in basic taste, discomfort, phantogeusia-parageusia, and general taste alterations. Moreover, we scored, according to Common Toxicity Criteria Adverse Events, nausea and other treatment-related toxicities. Since, ginger is traditionally used to prevent and/or treat nausea and vomiting, we prophylactically employed a ginger-based supplement named Naumix/Naugin (Gamfarma, Milan, Italy), to potentially mitigate both nausea and taste impairment. Using the CiTAS scale, we highlighted a progressive increase in all dysgeusia dimensions, peaking at the VII week of treatment and a subsequent partial late recovery. In particular, we observed a recovery for discomfort, phantogeusia-parageusia, and general taste alterations at 6 months. Grade 2 nausea, observed to be as low as 12.9% potentially due to the use of ginger, peaked at the III week of treatment. Finally, for patients experiencing nausea, the dysgeusia dimension of discomfort was also relevant.

Oral Localization of Kaposi Sarcoma: Clinical Presentation and Conservative Management.

Kaposi sarcoma (KS) caused by human herpes virus type-8 is the most frequent immunosuppression-associated malignancy worldwide and its treatment is still controversial. We report on the clinical management of a patient who developed oral KS after liver transplantation. The disease appeared 1 month after the transplant and recurred after 4 months. The patient represents, to our knowledge, a rare case that was treated successfully only by shifting a conventional immunosuppressive therapy to everolimus alone.

Prospective assessment of oral mucositis and its impact on quality of life and patient-reported outcomes during radiotherapy for head and neck cancer.

Oral mucositis (OM) is a common acute side effect during radiotherapy treatments for head and neck cancer (HNC), with a potential impact on patient's compliance to therapy, quality of life (QoL) and clinical outcomes. Its timely and appropriate management is of paramount importance. Several quantitative scoring scales are available to properly assess OM and its influence on patient-reported outcomes (PROs) and QoL. We prospectively assessed OM in a cohort of HNC patients submitted to radiation using the Oral Mucositis Assessment Scale (OMAS), while its impact on PROs and QoL was evaluated employing the Oral Mucositis Weekly Questionnaire-Head and Neck Cancer (OMWQ-HN) and the Functional Assessment of Cancer Therapy-Head and Neck Cancer (FACT-HN). Evaluation of OMAS scores highlighted a progressive increase in OM during treatment and a partial recovery after the end of radiation. These trends were correlated to PROs and QoL as evaluated with OMWQ-HN and FACT-HN questionnaires. In the present study, we provided a quantitative assessment of OM, PROs and QoL in HNC patient undergoing radiotherapy, potentially useful for future comparison.

Management of acute skin toxicity with Hypericum perforatum and neem oil during platinum-based concurrent chemo-radiation in head and neck cancer patients.

Acute skin toxicity is a frequent finding during combined radiotherapy and chemotherapy in head and neck cancer patients. Its timely and appropriate management is crucial for both oncological results and patient's global quality of life. We herein report clinical data on the use of Hypericum perforatum and neem oil in the treatment of acute skin toxicity during concurrent chemo-radiation for head and neck cancer. A consecutive series of 50 head and neck cancer patients undergoing concomitant radio-chemotherapy with weekly cisplatin was analyzed. Treatment with Hypericum perforatum and neem oil was started in case of G2 acute skin toxicity according to the RTOG/EORTC scoring scale and continued during the whole treatment course and thereafter until complete recovery. The maximum detected acute skin toxicity included Grade 2 events in 62% of cases and G3 in 32% during treatment and G2 and G3 scores in 52 and 8%, respectively, at the end of chemo-radiation. Grade 2 toxicity was mainly observed during weeks 4-5, while G3 during weeks 5-6. Median times spent with G2 or G3 toxicity were 23.5 and 14 days. Patients with G3 toxicity were reconverted to a G2 profile in 80% of cases, while those with a G2 score had a decrease to G1 in 58% of cases. Time between maximum acute skin toxicity and complete skin recovery was 30 days. Mean worst pain score evaluated with the Numerical Rating Scale-11 was 6.9 during treatment and 4.5 at the end of chemo-radiotherapy. Hypericum perforatum and neem oil proved to be a safe and effective option in the management of acute skin toxicity in head and neck cancer patients submitted to chemo-radiation with weekly cisplatin. Further studies with a control group and patient-reported outcomes are needed to confirm this hypothesis.

Induction Chemotherapy and Sequential Concomitant Chemo-radiation in Locally Advanced Head and Neck Cancers: How Induction-phase Intensity and Treatment Breaks May Impact on Clinical Outcomes.

AIM: The purpose of the study was to assess outcomes of locally advanced head and neck (LAHNC) treated with induction chemotherapy (ICT) and subsequent concurrent chemo-radiation. PATIENTS AND METHODS: A total of 71 LAHNC patients were treated with 2-3 cycles of docetaxel, cisplatin and 5-fluorouracil as induction chemotherapy and subsequent concurrent chemoradiation with weekly cisplatin or carboplatin. Definitive radiotherapy was delivered with intensity-modulated radiation and a simultaneous integrated boost approach up to a total dose of 70 Gy in 35 fractions to the macroscopic primary and nodal disease. RESULTS: Actuarial 2-year OS, CSS, DFS, MFS, LC were 55.3% (95%CI=39.3-68.6), 58.6% (95%CI=41.9-72), 60.5% (95%CI=47.3-71.4), 87.3% (95%CI=76.2-93.5) and 74.7% (95%CI=61.5-83.9), respectively. On multivariate analysis undergoing to 3 vs. 2 cycles of TPF (HR=22.31; 95%CI=2.68-185.66; p=0.004) and radiotherapy treatment break >4 days (HR=1.28; 95%CI=1.06-1.55; p=0.01) negatively affected cancer-specific survival (CSS) with statistical significance. Achieving complete remission after ICT had a statistically significant impact on CSS (HR=0.9; 95%CI=0.01-0.54; p=0.009). Patients undergoing ICT with 3 cycles had more frequently treatment breaks compared to those submitted to 2 cycles (HR=1.36; 95%CI=1.06-1.73; p=0.01), and had statistically significant longer treatment break time (5.9+1.8 vs. 3+0.36; p=0.02). CONCLUSION: A shorter ICT phase may be a better option enhancing patients' tolerance during concurrent chemoradiation and affecting clinical outcomes.

Primary and secondary reconstruction of complex craniofacial defects using polyetheretherketone custom-made implants.

PURPOSE: The aim of this study was to evaluate the surgical outcomes using polyetheretherketone (PEEK) patient-specific prostheses produced by computer-aided design and manufacturing for primary and secondary reconstruction in patients with craniofacial defects. MATERIAL AND METHODS: The study included 13 patients who underwent reconstruction for craniofacial defects using PEEK patient-specific implants (PSI). Eight patients underwent single-step primary reconstruction using individual custom-made surgical guides and custom-made prostheses during the same surgery; five patients underwent delayed reconstruction. The material used to manufacture the implants was PEEK in 13 cases. All patients underwent esthetic examination, ophthalmological examination, and radiological evaluation during the preoperative and follow-up periods. The operation duration and short- and long-term complications were recorded. RESULTS: The shape and global position of the implants were satisfactory in each case. Fitting of the implant during surgery required extensive adaptation in 1 case and minor in 11 cases. Of 13 implants, 11 adequately restored a morphological complex area with satisfactory cosmetic results. No complications related to the implants were reported. CONCLUSION: Reconstruction for cranio-facial defects using PEEK computer-aided designed and manufactured implants is a promising new technique that allows for accurate restoration of the complex 3D anatomy of the craniofacial region.

To computer-aided design and manufacturing or not to computer-aided design and manufacturing? Free fibula flap with computer-aided technique for mandibular reconstruction.

AIM: The purpose of this study was to analyze the accuracy of computer-assisted free fibula flap for reconstruction of large mandibular defects for benign tumors. MATERIALS AND METHODS: Between December 2012 and January 2014, a total of 4 free osteocutaneous computer-assisted fibula flaps have been used in an equal number of patients for reconstruction of the mandible at the Division of Maxillofacial Surgery, Città della Scienza e della Salute Hospital, University of Turin. Inclusion criteria were large mandibular defects due to benign tumors. The computer-assisted fibula flap was chosen when 2 or more osteotomies were requested. Intraoperative complication, mean ischemia time, operative time, and morphologic outcomes were analyzed in all cases. After surgery, a postoperative computed tomography compared the virtual plan with the surgical results. RESULTS: All 3 flaps were harvested and transplanted successfully. For the free flaps examined in this work, no intraoperative complications were noted. Postoperative computed tomography showed high correspondence in terms of bone contour according to the virtual plan. The immediate and long-term morphologic results were satisfactory. CONCLUSIONS: Microsurgical mandible reconstruction using a computer-assisted fibula flap technique is the best available method to manage complex defects.

The Le Fort I osteotomy as surgical approach of an extensive pleomorphic adenoma of the palate.

Pleomorphic adenoma (PA) is the most common benign mixed salivary gland tumor. We describe here a peculiar case of a 72-year-old woman with a PA of the palate resected with palatal approach combined with Le Fort I osteotomy, adding to the currently limited scientific literature on intraoral approach for removal of extensive tumors of the midface. The Le Fort I osteotomy approach allows direct visualization of the tumor and ensures a wide excision, increasing safety and minimizing the possibility of recurrence.

Evaluation of plate-related complications and efficacy in fibula free flap mandibular reconstruction.

AIM: The objective of this study was to evaluate the incidence of plate-related complications after vascularized bony reconstruction of the mandible, comparing the plate type used. PATIENTS AND METHODS: Between 2004 and December 2012, a total of 41 free osteocutaneous fibula flaps have been used in an equal number of patients for reconstruction of the mandible, at the Division of Maxillofacial surgery, San Giovanni Battista Hospital, University of Turin. Malignant pathology was the most common indication for segmental mandibulectomy.Patient outcomes were retrospectively evaluated with special attention to plate complications such as plate fracture, exposure, infection, and bony nonunion.The types of reconstruction plates used were mandible plates 2.0, locking plates 2.0, miniplates (<2.0), and locking 2.4 plates. RESULTS: Mandible plates 2.0 were used in 14 patients, locking plates 2.0 in 12 patients, and locking 2.4 plates in 4 patients. The most commonly used plates were miniplates, which were used in 86 patients.A total of 5 plate complications occurred after 41 procedures in an equal number of patients.Two complications occurred in patients receiving 2.0 mandible plates (2/14). One complication occurred in patients receiving 2.0 locking plates (1/12). Two complications occurred in patients receiving miniplates (2/86). CONCLUSIONS: In our experience, miniplates are not associated to a high rate of complications comparing to other plates. The advantage of these plates and the low rate of complications make them our first choice for mandibular reconstructions.

Surgical management of synchronous central giant cell granuloma and ossifying fibroma of the mandible.

We describe the surgical management of an uncommon case of synchronous presentation of central giant cell granuloma and ossifying fibroma in the mandible. A mandibular resection was performed and a fibula-free flap was harvested to reconstruct the defect.

Ossifying fibroma affecting the mandibular condyle: report of an uncommon case.

We describe the surgical management of an uncommon case of ossifying fibroma affecting the mandibular condyle. A condylectomy was performed with an immediate temporomandibular joint reconstruction by a total temporomandibular joint prosthesis.

Surgical management of pathologic mandibular fractures.

BACKGROUND: The aim of this article was to present our experience in the management of pathologic mandibular fractures. METHODS: We conducted a retrospective analysis of 14 patients with pathologic mandibular fractures associated with osteoradionecrosis, bisphosphonate-related osteonecrosis of the jaw, benign/malignant lesions, osteomyelitis, idiopathic, or iatrogenic etiology. Data collected included age, sex, etiology, site, treatment, and outcome. RESULTS: Five patients had iatrogenic fractures, 3 patients had osteomyelitis, 2 had benign cystic lesion, and the remaining 4 had primary squamous cell carcinoma, histiocytosis, multiple myeloma, and bisphosphonate-related osteonecrosis of the jaw, respectively. Eleven fractures of 14 were treated using a 2.4-mm mandibular plate. CONCLUSIONS: Pathologic mandibular fractures may be challenging to treat because of their different etiology and peculiar local and general conditions, often requiring a more rigid fixation. In patients with poor medical conditions, simpler and more limited options may be preferred.

The platysma myocutaneous flap (PMF) for head and neck reconstruction: a retrospective and multicentric analysis of 91 T1-T2 patients.

The platysma myocutaneous flap (PMF) was first applied to intraoral reconstructions in 1978. PMF is not only an alternative to microvascular flaps but it also represents an excellent reconstructive choice especially in cases where free tissue transfer cannot be carried out. Failure and complications rate have been described as varying from 18 to 45% and this is why this flap should not be used in specific cases such as in the presence of cervical metastases and in cases of mandibulectomy and simultaneous reconstruction with alloplastic materials. The purpose of this study is to examine the experience and results obtained in three different and independent institutes where PMF has been adopted in 91 patients for head and neck cancer reconstructions. The authors report their departments' separate but simultaneous experiences with PMF for small and middle-size soft tissue defects in a 10-year period.

DNA repair gene expression level in peripheral blood and tumour tissue from non-small cell lung cancer and head and neck squamous cell cancer patients.

BACKGROUND: The nucleotide excision repair pathway is crucial for cellular DNA integrity and the ERCC1 helicase is also potentially involved in resistance to platinum-based chemotherapy, and high levels of ERCC1 mRNA in tumours have been associated with cisplatin resistance in different human cancers. The aim of this work was to investigate the correlation between DNA repair gene expression levels in tumour tissue, normal tissue and peripheral blood samples from patients with two common human cancers, non-small cell lung cancer (NSCLC) and squamous cell carcinoma of the head and neck (HNSCC), to test if blood gene expression could be a proxy for tumour tissue gene expression to predict response to platinum-based chemotherapy. METHODS: Using RT-qPCR we determined ERCC1, ERCC2, ERCC4, XPA, XPC, XRCC1, XRCC3, APEX, OGG1, MGMT mRNA levels in fresh NSCLC, normal lung and HNSCC tissue, as well as blood, from NSCLC and HNSCC patients who were treated surgically. RESULTS: Target gene expression in NSCLC and HNSCC tissue was higher than in blood. A statistically significant correlation (p<0.05) was found between target gene mRNA expression in tumour tissue and blood, in particular ERCC1, MGMT, XPC, XRCC1 and XRCC3 in NSCLC and APEX, ERCC1, ERCC2, ERCC4, XRCC1 and XRCC3 in HNSCC. CONCLUSIONS: The existence of a significant correlation between blood and tumour tissue expression of some genes of clinical interest, such as ERCC1 in NSCLC and HNSCC, could allow the introduction in clinical practice of a simple test that would measure mRNA levels of DNA repair genes in peripheral blood samples instead of tissue samples to determine prognostic and predictive factors in NSCLC and HNSCC patients.