The effect of fascin 1 inhibition on head and neck squamous cell carcinoma cells.

Fascin 1 plays important pro-metastatic roles in head and neck carcinoma (HNSCC) migration, invasion, and metastasis. However, limited advancement in targeting metastasis remains a major obstacle in improving HNSCC patients' survival. Therefore, we assessed the therapeutic potential of fascin 1 targeted inhibition and its potential prognostic value in HNSCC patients. Using in vitro and in vivo approaches, we investigated the effect of compound G2, a novel fascin 1 inhibitor, on HNSCC cells migration, invasion, and metastasis. High-throughput screening (HTS) was used to assess cytotoxic activity of compound G2 alone or combined with irradiation. We also evaluated the prognostic potential of fascin 1 in HNSCC patients. Interestingly, compound G2 reduced carcinoma cells migration and invasion in vitro and inhibited metastasis in vivo. Moreover, HTS revealed a modest cytotoxic activity of the compound G2 on HNSCC cell lines. Irradiation did not synergistically enhance the compound G2-mediated cytotoxic activity. Survival analyses showed that high fascin 1 immunoexpression, at the tumor invasive front, was associated with cancer-specific mortality in the advanced stages of HNSCC. Collectively, our findings suggest that fascin 1 represents a promising anti-metastatic therapeutic target and a useful prognostic marker in patients with HNSCC. Novel anti-metastatic agents could provide a valuable addition to cancer therapy.

Dizzy triathlete-evidence supporting vestibular etiology.

Dizziness during or after the swimming leg is a common complaint among triathletes. We hypothesized that the dizziness is caused by asymmetrical cooling of the vestibular organ. This caloric response is characterized by involuntary eye movements called nystagmus. Altogether, 125 triathletes completed an electronic questionnaire. Fifteen triathletes who had frequently experienced dizziness during the swimming leg agreed to take part in a cold water swimming test. The test comprised two cold water swimming legs, first without earplugs and then with earplugs to prevent a potential caloric response. Eye movements and possible nystagmus were recorded immediately after the swimming legs. A majority (87%, 109/125) of athletes had experienced dizziness during triathlon races or training. Of these, almost all (97%, 106/109) experienced it during or after swimming. Dizziness affected the triathlon performance in half of the athletes with dizziness (50%, 51/102). Fifteen athletes participated in a cold water swimming test. During the first leg (without earplugs), 11/15 athletes (73%) experienced dizziness. Of these, six had nystagmus (55%), four had uncertain nystagmus (36%), and one did not have nystagmus (9%). Only one of these athletes experienced dizziness during the second leg with earplugs. The prevalence of dizziness among triathletes is notable. A large part of the dizziness is likely to be caused by caloric reaction of the vestibular organ. We recommend earplug usage for triathletes suffering from dizziness during the swimming leg.

Sclerosing sialadenitis of the submandibular gland is rarely an immunoglobulin G4-related disease in the Finnish population.

Chronic sclerosing sialadenitis may represent one of many manifestations of an immunoglobulin G4-related disease. However, existing studies typically consist of small patient cohorts rarely conducted in Western populations. The clinical behavior of chronic sclerosing sialadenitis, including follow-up data, warrants further study. Thus, we aimed to determine whether chronic sclerosing sialadenitis always presents as IgG4-related disease or associates with autoimmune diseases and to determine which additional examinations patients may require. Between 2000 and 2017, 51 patients undergoing submandibular gland resection within the Helsinki University Hospital area were diagnosed with chronic sclerosing sialadenitis. We re-evaluated all specimens and performed immunostaining for IgG4. IgG and CD31 stainings were performed for IgG4-positive specimens. IgG4-related disease diagnosis was defined by the Boston consensus statement criteria. We revised clinical data, distributing a follow-up questionnaire to patients to register symptoms of IgG4-related disease or autoimmune disease during follow-up. The chronic sclerosing sialadenitis criteria were fulfilled in 34 patients, whereby 17 were diagnosed as non-sclerosing chronic sialadenitis. In 19 cases, a sialolith associated with a salivary gland lesion. In total, 12 of 51 cases were recognized as IgG4-positive, while two met the criteria for IgG4-related disease. These two cases belonged to the non-sclerosing chronic sialadenitis group, and both involved other organs. The histopathological features between chronic sclerosing sialadenitis and non-sclerosing chronic sialadenitis overlapped regarding the degree of fibrosis and inflammatory infiltrates. In the Finnish population, chronic sclerosing sialadenitis of the submandibular gland does not appear to present as IgG4-related disease. Non-sclerosing chronic sialadenitis can associate with IgG4-related disease. A histopathological distinction between chronic sclerosing sialadenitis and non-sclerosing chronic sialadenitis is not always unequivocal and the presence of a sialolith does not exclude IgG4-positivity. Therefore, immunostaining for IgG4 should be performed when dense plasma cell infiltration is present in either non-sclerosing chronic sialadenitis or chronic sclerosing sialadenitis.

Cauliflower ear among Finnish high-level male wrestlers and judokas is prevalent and symptomatic deformity.

Our research aimed to study the prevalence, concerns, and treatment practices related to cauliflower ear among Finnish wrestlers and judokas. In total, 32 Finnish wrestlers and 31 judokas completed a questionnaire at training sessions or at a competition. All participants were adults competing at the national or international levels. We also took lateral digital photographs of participants' ears. A senior author graded the overall appearance of the auricles on a scale from 0 to 5 (0 = normal auricle, 5 = extreme cauliflower ear). Cauliflower ear was more prevalent among male athletes (84%, 46/55) than female athletes (0%, 0/8, P < .001). Almost all (96%) had sought treatment for an auricular hematoma. The most prevalent treatment modality was needle aspiration (96%). Most (76%) had received treatment from individuals not representing the healthcare profession. Only one athlete reported receiving successful treatment. No complications from treatment were reported. Almost all participants (96%) reported some symptom from the cauliflower ear, typically pain. None regretted their cauliflower ear(s), and 41% of athletes with cauliflower ear considered it desirable. Cauliflower ear is a common and symptomatic deformity among high-level Finnish wrestlers and judokas. Despite the symptoms, it is accepted and sometimes even desired among the athletes.

Prognostic impact of tumour-stroma ratio in early-stage oral tongue cancers.

AIMS: Oral tongue squamous cell carcinoma (OTSCC) has a relatively poor outcome, and there is a need to identify better prognostic factors. Recently, tumour-stroma ratio (TSR) has been associated with prognosis in several cancers. The aim of this multi-institutional study was to evaluate the prognostic value of TSR from original haematoxylin and eosin (HE)-stained tumour-resection slides in a series of early-stage (cT1-2N0) OTSCC patients. METHODS AND RESULTS: A TSR cutoff value of 50% was used to divide the patients into stroma-rich (≥50%) and stroma-poor (<50%) groups. The relationships between TSR and clinicopathological characteristics of 311 early-stage OTSCC cases were analysed. The prognostic value of TSR in OTSCC was calculated separately and in combination with a previously published cancer cell budding and depth of invasion (BD) prognostic model. A total of 89 cases (28.6%) belonged to the stroma-rich group. In a multivariate analysis, the stroma-rich group had worse disease-free survival, with a hazard ratio (HR) of 1.81 [95% confidence interval (CI) 1.17-2.79, P = 0.008], and higher cancer-related mortality (HR 1.71, 95% CI 1.02-2.86, P = 0.03). The combination of the highest-risk parameter scores of TSR and the BD model showed significant correlations with recurrence rate (HR 3.42, 95% CI 1.71-6.82, P = 0.004) and cancer-related mortality (HR 11.63, 95% CI 3.83-35.31, P < 0.001). CONCLUSIONS: We conclude that TSR is a simple histopathological feature that is useful for prognostication of early-stage OTSCC, and suggest that TSR analyses in association with BD score could be included in routine clinical pathology reports for HE-stained slides.

Treponema denticola chymotrypsin-like proteinase is present in early-stage mobile tongue squamous cell carcinoma and related to the clinicopathological features.

BACKGROUND: Certain periodontopathogenic bacteria have been linked to cancers. Treponema denticola (Td) is associated with severe periodontitis. Chymotrypsin-like proteinase (CTLP), a major virulence factor of Td, can degrade various host proteins and peptides, and modulate inflammatory responses. However, the role of Td in the tongue carcinogenesis remains unknown. This study aimed to investigate the presence of Td-CTLP in early-stage mobile tongue squamous cell carcinoma (MTSCC) and its relation to clinical and pathological characteristics. METHODS: The immunopositivity of Td-CTLP was assessed in samples obtained from 60 patients with MTSCC and associated with their clinicopathological data. Additionally, Td-CTLP expression was compared with immunoexpression of matrix metalloproteinases (MMP-8 and MMP-9), toll-like receptors (TLR-2, TLR-4, TLR-7 and TLR-9), c-Myc, Ki-67, Bmi-1 and Snail. RESULTS: Treponema denticola-chymotrypsin-like proteinase was present in 95% of MTSCC tumours of which many (40.4%) showed high immunopositivity. Td-CTLP positivity was significantly associated with invasion depth, tumour diameter and the expression of TLR-7, TLR-9 and c-Myc. High Td-CTLP immunopositivity in younger patients (≤ 60 years old) predicted early relapse. CONCLUSION: Our data indicate that Td and its CTLP are present in early-stage MTSCC carcinoma and may contribute to carcinogenesis, and therefore provide novel perspectives into intervention and therapeutic measures of MTSCC.

Toll-like receptors 2, 4, and 9 in primary, metastasized, and recurrent oral tongue squamous cell carcinomas.

BACKGROUND: Toll-like receptors (TLRs) are pattern-recognizing proteins involved in innate immunity and they seem to regulate both cancer progression and inhibition. In oral cancer, TLR activation has been linked to invasion. To define the role of TLR-2, TLR-4, and TLR-9 in oral tongue squamous cell carcinoma (OTSCC), we studied their expression in vivo in OTSCC tumor samples, as well as in vitro in cell invasion model. METHODS: We used immunohistochemistry to compare the expression of TLR-2, TLR-4, and TLR-9 in 21 primary Stage I-II OTSCCs, neck metastases, and recurrent tumors. In addition, we used myoma organotypic invasion assay to evaluate the effect of GIT27 (4,5-dihydro-3-phenyl-5-isoxasoleaceticacid) on the invasion of the HSC-3 OTSCC cell line. RESULTS: TLR-2, TLR-4, and TLR-9 were expressed in most tumors. Nuclear TLR-2 expression occurred more often in primary tumors than in neck metastases or recurrent tumors of the neck, whereas nuclear TLR-4 expression and cytoplasmic TLR-9 expression were higher in primary tumors than in local recurrent tumors. GIT27 did not affect the invasion of HSC-3 OTSCC cells, but a myoma organotypic invasion assay revealed that the expression of TLR-2 and TLR-4 was stronger in deeper-invading cells. CONCLUSIONS: TLR-2, TLR-4, and TLR-9 were expressed in primary tumors, neck metastases as well as in recurrent tumors of OTSCC. Thus, these receptors seem to play a role in both the development and progression of tongue carcinoma. These TLRs may also contribute to the invasive potential of OTSCC.

Does securin expression have significance in prognostication of oral tongue cancer? A pilot study.

The proliferation marker, securin, is involved in the progression of many carcinomas. However, its expression in oral tongue squamous cell carcinoma (OTSCC) has not been previously studied. We examined securin expression by immunohistochemistry in OTSCC. A total of 93 cases treated for OTSCC were included in this study. Expression of securin in OTSCC was studied by immunohistochemistry of tissue microarrays (52 cases) and routine tumor sections (41 cases). Securin overexpression is significantly associated with higher tumor grade (P = 0.03). Overexpression of securin was observed more frequently in advanced stages of OTSCC than in earlier stages but the difference was not statistically significant. These findings suggest that overexpression of securin in OTSCC may be important during progression of this cancer. No significant association was found between securin expression and the prognosis of OTSCC.

Cancer of the tongue - early detection improves the prognosis.

Approximately 30 to 40% of all patients with tongue cancer still succumb to the disease in five years. Early diagnosis of the disease is of vital importance, because treatment will in that case cause considerably less harm. The diagnosis is confirmed with a histological specimen, which should be taken from every suspicious lesion, and can easily be taken under local anesthesia with a punch. Already when seeking treatment, as many as 25 % of patients with tongue cancer have neck metastases, which influence the prognosis. Heavy use of tobacco and alcohol are the most important risk factors of tongue cancer.

Toll-like receptor 9 mediates invasion and predicts prognosis in squamous cell carcinoma of the mobile tongue.

BACKGROUND: Toll-like receptor 9 (TLR9) is a cellular receptor, which recognizes bacterial and host-derived DNA. Stimulation of TLR9 induces cellular invasion via matrix metalloproteinase 13 (MMP-13). The aim of this study was to evaluate the role of TLR9 in invasion of oral tongue squamous cell carcinoma (OTSCC). METHODS: The effects of TLR9 ligands on oral squamous cell carcinoma cell lines were studied with invasion and migration assays, as well as in a myoma organotypic model. RESULTS: The TLR9 ligand, CpG-ODN, increased invasion and migration in OTSCC lines. These effects were reduced by TLR9 siRNA or inhibition with TLR9 antibodies. Immunohistochemical analysis of tissues from 195 patients with OTSCC revealed that TLR9 was expressed in 181/195 carcinomas. The expression of TLR9 was higher in the malignant cells than in the normal epithelium. High TLR9 expression was associated with high MMP-13 expression and poor differentiation. High TLR9 expression was also identified as an independent predictor of poor prognosis (HR 1.810, 95% CI [1.053-3.112]). CONCLUSION: Toll-like receptor 9 mediates OTSCC invasion and migration in vitro and is an independent prognostic factor of OTSCC. Inhibition of TLR9 may be a novel therapeutic opportunity in oral cancer.

Effect of head impacts and chemical irritation on elite athletes' olfaction.

Limited research exists on athletes' olfaction. As diet is an elementary part of an athlete's lifestyle and training, it is important to know whether the sport discipline itself carries a risk for olfactory impairment. The aim of this study was to evaluate whether elite swimmers (chemical irritation), boxers (head impact) or soccer players (head impact) are at risk for impaired olfaction. Elite-level male swimmers (n = 30), boxers (n = 35) and soccer players (n = 30) aged 18-40 years were recruited from Finnish sport clubs. Floorball players (n = 30) were recruited as a control group. All participants filled in a questionnaire about their training history, nasal and sinonasal diseases, asthma, nasal operations and traumas, smoking and self-evaluation of olfaction and taste function. Sniffin' Sticks odour identification test with 12 different odorants and anterior rhinoscopy were performed on all participants. The mean score from the smelling test did not differ between the sport groups. Sinonasal diseases and bronchial asthma were more common among swimmers than among the other athletes. Rhinitis symptoms were common among all athletes. Boxing, soccer or swimming does not seem to affect sense of smell. The majority of our participating elite athletes had normal olfaction, even if they had had a long history of active sports.Highlights Boxing, soccer or swimming does not seem to affect sense of smell.Rhinitis symptoms were prevalent among all elite athlete groups in our study.Athletes with hyposmia can perceive their own decreased olfaction.Swimmers have more bronchial asthma and sinus diseases than other athlete groups.

Prognostic significance of matrix metalloproteinase-2, -8, -9, and -13 in oral tongue cancer.

BACKGROUND: Oral tongue squamous cell carcinoma (OTSCC) often metastasizes to cervical lymph nodes. Mechanisms of this disease progression are not fully known. We aimed at finding new predictive markers for diagnosis and disease monitoring. METHODS: Seventy-three consecutive T1N0M0 and T2N0M0 OTSCC patients treated at Helsinki University Central Hospital, Helsinki, Finland, in 1992-2002 were included. Tissue array blocks were prepared from primary tumors and immunostained. Immunoexpression of matrix metalloproteinase (MMP)-2, -8, -9, and -13 was compared with patient characteristics and outcome. RESULTS: Nuclear expression of MMP-13, but not cytoplasmic expression of MMP-2, -8, and -9, was associated with invasion depth (P = 0.017) and tumor size (P = 0.008). Furthermore, high nuclear MMP-13 expression was predictive of poor outcome (P = 0.042). CONCLUSION: Our results suggest that especially MMP-13 may be regarded as a prognostic biomarker in OTSCC.

Do tonsils regrow after partial tonsillectomy? - Histology of regrown tonsils and predisposing factors for tonsillar regrowth.

OBJECTIVES: It has been suggested that after partial tonsillectomy, referred here as tonsillotomy (TT), the remaining tonsillar tissue might be altered, leading to scarring or chronic tonsillitis. The objectives were to compare the histology of regrown tonsillar tissues with native tonsils and to assess the incidence of reoperations and predictive factors for tonsillar regrowth after TT. METHODS: Tonsillar tissues of 1) children that underwent TT and later requiring resurgery and 2) children operated on for the first time with TT were prospectively analysed. To assess the incidence of resurgery because of tonsillar regrowth and predictive factors for tonsillar regrowth, the data covering TTs and tonsillectomies performed in 2009-2020 were retrospectively retrieved. RESULTS: Altogether 11 children formed the regrowth group, with the control group consisting of 19 children. In the histological analysis of tonsillar tissues, neutrophil infiltration in the epithelium and crypts and severe lymphoplasmacytic infiltration in the epithelium were significantly more frequent in samples of the regrowth group relative to the control group. The number of germinal centres was greater in the regrowth group. In the retrospective analysis of 3141 children, the incidence of resurgery after primary TT was 1.9%. Logistic regression analysis showed that age was the only significant predisposing factor for resurgery. CONCLUSION: Inflammatory cells were present more often in regrown tonsillar tissues but there was no evidence of severe chronic inflammation or scarring in the regrown tonsils. The risk of resurgery after TT was low. Young age predisposed to tonsillar regrowth, no other risk factors were found.

Monopolar tonsillotomy versus cold dissection tonsillectomy in children: Prospective study on postoperative recovery.

OBJECTIVES: To compare postoperative self-reported recovery results with monopolar tonsillotomy and cold dissection tonsillectomy in children. To evaluate the feasibility of the monopolar technique in tonsillotomy. METHODS: Children <12 years undergoing tonsillotomy or tonsillectomy between April 2018 and March 2020 who (with a caregiver) were willing to participate in a two-week follow-up formed the study group. They filled in a questionnaire about pain-related outcomes, return to normal activities, weight changes, complications, and length of home care. RESULTS: Altogether 166 patients were recruited; 103 (62%) returned the questionnaire. The first pain-free day with tonsillotomy was day 5 and with tonsillectomy day 11. After tonsillotomy, patients returned to normal activities faster, e.g. they were able to eat normally 6.5 days earlier than tonsillectomy patients. During the first postoperative week weight dropped after tonsillectomy, but not after tonsillotomy. The length of home care was 6 days with tonsillotomy and 10 days with tonsillectomy. The incidence of postoperative hemorrhage (including minor bleedings at home) was 14% after tonsillotomy and 32% after tonsillectomy. Hemorrhages needing interventions were 0% with tonsillotomy and 2% with tonsillectomy. CONCLUSION: Children operated on with monopolar tonsillotomy recovered faster and had less postoperative hemorrhage than those undergoing tonsillectomy. They were able to return earlier to daycare/school and their caregivers back to work. Recovery results with monopolar tonsillotomy were equal to other tonsillotomy techniques reported in the literature, hence the monopolar technique can be considered an alternative method to perform tonsillotomy.

The expression and prognostic relevance of CDH3 in tongue squamous cell carcinoma.

P-cadherin (CDH3) is a cell-to-cell adhesion molecule that regulates several cellular homeostatic processes in normal tissues. Lack of CDH3 expression is associated with aggressive behavior in oral squamous cell carcinoma (OSCC). Previous studies have shown that CDH3 is downregulated in high-grade OSCC and its reduced expression is predictive for poorer survival. The aim of this study was to evaluate the expression and prognostic relevance of CDH3 in tongue squamous cell carcinoma (TSCC). A retrospective series of 211 TSCC and 50 lymph node samples were stained immunohistochemically with polyclonal antibody (anti-CDH3). CDH3 expression was assessed semi-quantitatively with light microscopy. Fisher's exact test was used to compare patient and tumor characteristics, and the correlations were tested by Spearman correlation. Survival curves were drawn by the Kaplan-Meier method and analyzed by the log-rank test. Univariate and multivariate Cox regression was used to estimate the association between CDH3 expression and survival. CDH3 expression did not affect TSCC patient's disease-specific survival or overall survival. Strong CDH3 expression in the primary tumor predicted poor disease-specific and overall survival in patients with recurrent disease. CDH3 expression in lymph nodes without metastasis was negative in all cases. CDH3 expression was positive in all lymph node metastases with extranodal extension. In contrast to previous report about the prognostic value of CDH3 in OSCC, we were not able to validate the result in TSCC.

Changing trends in pediatric tonsil surgery.

OBJECTIVES: We analyzed trends in tonsil surgery over a 10-year period in a single tertiary care hospital and evaluated the effects of these changes on use of hospital services and healthcare costs. METHODS: This was a retrospective cohort study based on data from databases at the Department of Otorhinolaryngology, Helsinki University Hospital, Helsinki, Finland. Children under 16 years of age with tonsillectomy (TE) or tonsillotomy (TT) performed during 2007-2016 were included in the study. RESULTS: In 10 years, 4979 tonsil surgeries were performed on 4951 children: TE in 3170 (64%) and TT in 1781 (36%) children. The total number of tonsil surgeries stayed nearly constant. TT operations commenced in the study hospital in 2009 and from 2012 onwards have been more common than TE procedures. Altogether 279 patients visited the emergency department because of complications; TE patients had 9.0 visits/100 surgeries and TT patients 1.8 visits/100 surgeries. The most common complication was postoperative hemorrhage: 200 cases (6.3%) in the TE group and 11 cases (0.6%) in the TT group. During the two-year follow-up after tonsil surgery the total costs of healthcare services were significantly lower in the TT group than in the TE group. CONCLUSION: Considerable changes have occurred in tonsil surgery in children during the 10-year study period; TT is today performed more often than TE. As a consequence, complications, readmissions to hospital, and number of patients treated in the operating room because of postoperative hemorrhage have decreased, lowering the costs of healthcare.

MMP-7 expression may influence the rate of distant recurrences and disease-specific survival in HPV-positive oropharyngeal squamous cell carcinoma.

The objective of this study was to determine if matrix metalloproteinase-7 (MMP-7) expression is related to human papilloma virus (HPV) status, clinical parameters, and outcome in oropharyngeal squamous cell carcinoma (OPSCC). Tumor tissue specimens from 201 OPSCC patients treated with curative intent were available for immunohistochemistry, and the samples were stained with monoclonal MMP-7 antibody. All the patients were followed up at least 3 years or until death. MMP-7 expression did not differ between HPV-positive and HPV-negative patients. MMP-7 was not prognostic among patients with HPV-negative OPSCC. In the HPV-positive subgroup, patients with moderate, high, or very high MMP-7 expression had significantly worse 5-year disease-specific survival (DSS) (56.6%) than patients with absent, or low MMP-7 expression (77.2%), and MMP-7 expression appeared as a prognostic factor in the multivariate analysis. In addition, among HPV-positive OPSCC with moderate, high, or very high MMP-7 expression, the 5-year distant recurrence-free survival was significantly lower (69.6%) than in those who had low or absent MMP-7 expression (97.5%). Our results suggest that among HPV-positive OPSCC patients, high MMP-7 expression is related to worse 5-year DSS and increased rate of distant recurrences.

Small oral tongue cancers (≤ 4 cm in diameter) with clinically negative neck: from the 7th to the 8th edition of the American Joint Committee on Cancer.

One of the main changes in the 8th edition of the American Joint Committee on Cancer (AJCC) for staging of oral cancer is the inclusion of depth of invasion (DOI) in the T category. However, cancers in different oral subsites have variable behavior, with oral tongue squamous cell carcinoma (OTSCC) being the most aggressive one even at early stage. Thus, it is necessary to evaluate the performance of this new T category in homogenous cohort of early OTSCC. Therefore, we analyzed a large cohort of patients with a small (≤ 4 cm) OTSCC to demonstrate the differences in T stage between the AJCC 7th and 8th editions. A total of 311 early-stage cases (AJCC 7th) of OTSCC were analyzed. We used 5 mm and 10 mm DOI for upstaging from T1 to T2 and from T2 to T3 respectively, as in the AJCC 8th. We further reclassified the cases according to our own proposal suggesting 2 mm to upstage to T2 and 4 mm to upstage to T3. According to AJCC 7th, there were no significant differences in the survival analysis. When we applied the 8th edition, many cases were upstaged to T3 and thus associated with worse disease-specific survival (HR 2.37, 95% CI 1.12-4.99) and disease-free survival (HR 2.12, 95% CI 1.09-4.08). Based on our proposal, T3 cases were associated with even worse disease-specific survival (HR 4.19, 95% CI 2.27-7.74). The 8th edition provides better survival prediction for OTSCC than the 7th and can be further optimized by lowering the DOI cutoffs.