Supraclavicular Artery Island Flap for Head and Neck Oncologic Reconstruction: 15-year Experience, Past, Present, Future.

Head and neck reconstruction poses unique challenges due to the complex structure of the region. Primary goals include soft-tissue coverage, adequate color and texture match, and minimal donor-site morbidity. Local and musculocutaneous regional flaps have largely been replaced with fasciocutaneous free flaps (FFF) over recent years. The supraclavicular artery island flap (SCAIF), a locoregional, fasciocutaneous, axially-based flap, has been shown to produce similar outcomes to FFF. We present our 15-year experience using the SCAIF for head and neck reconstruction, discuss its evolution, and provide case examples for its range of indications. Methods: Retrospective chart review identified 128 patients who underwent reconstruction of the head and neck with the SCAIF between the years 2006-2021 at Tulane University Medical Center. Patient demographics, lengths of stay, operative times, surgical indications, and complications were recorded. Results: The cohort mean age was 66.9 years. Mean lengths of stay and follow-up times were 6.9 days and 9.1 months, respectively. The most common indications for SCAIF reconstruction were recurrent radiated neck disease (n=27, 21.1%), pharyngeal wall defects (n=23, 18.0%), and parotidectomy defects (n=21, 16.4%). Overall complication rate was 17.2%. Partial thickness flap loss (5.5%), contained pharyngeal leak (3.2%), and distal tip necrosis (2.4%) were the most common complications. No functional donor site morbidity was encountered. Conclusions: The SCAIF is a versatile, fasciocutaneous, axially-based flap able to produce similar outcomes to FFF in the reconstruction of the head and neck region while reducing costs, lengths of stay, operative times, and donor site morbidity.

Cervical Necrotizing Fasciitis, Diagnosis and Treatment of a Rare Life-Threatening Infection.

IMPORTANCE: Necrotizing fasciitis is a relatively uncommon and potentially life-threatening soft tissue infection, with morbidity and mortality approaching 25% to 35%, even with optimal treatment. The challenge of diagnosis for necrotizing soft tissue infections (NSTIs) is their rarity, with the incidence of approximately 1000 cases annually in the United States. Given the rapid progression of disease and its similar presentation to more benign processes, early and definitive diagnosis is imperative. FINDINGS: Signs and symptoms of NSTIs in the early stages are virtually indistinguishable from those seen with abscesses and cellulitis, making definitive diagnosis difficult. The clinical presentation will depend on the pathogen and its virulence factors which ultimately determine the area and depth of invasion into tissue. There are multiple laboratory value scoring systems that have been developed to support the diagnosis of an NSTI. The scoring system with the highest positive (92%) and negative (96%) predictive value is the laboratory risk indicator for necrotizing fasciitis (LRINEC). The score is determined by 6 serologic markers: C-reactive protein (CRP), total white blood cell (WBC) count, hemoglobin, sodium, creatinine, and glucose. A score ≥ 6 is a relatively specific indicator of necrotizing fasciitis (specificity 83.8%), but a score <6 is not sensitive (59.2%) enough to rule out necrotizing fasciitis. In terms of imaging, computed tomography (CT) imaging, while more sensitive (80%) than plain radiography in detecting abnormalities, is just as nonspecific. Computed tomography imaging of NSTIs demonstrates fascial thickening (with potential fat stranding), edema, subcutaneous gas, and abscess formation. Magnetic resonance imaging (MRI) has demonstrated sensitivity of 100% and specificity of 86%, though MRI may not show early cases of fascial involvement of necrotizing fasciitis. CONCLUSIONS AND RELEVANCE: Necrotizing soft tissue infections are rapidly progressive and potentially fatal infections that require a high index of clinical suspicion to promptly diagnose and aggressive surgical debridement of affected tissue in order to ensure optimal outcomes.Prompt surgical and infectious disease consultation is necessary for the treatment and management of these patients. While imaging is useful for further characterization, it should not delay surgical consultation. Necrotizing soft tissue infection remains a clinical diagnosis, although plain radiography, CT imaging, and ultrasound can provide useful clues. In general, the management of these patients should include rapid diagnosis, using a combination of clinical suspicion, laboratory data (LRINEC score), and imaging (MRI being the recommended imaging modality), prompt infectious disease and surgical consultation, surgical debridement, and delayed reconstruction. Laboratory findings that can more strongly suggest a diagnosis of NSTI include elevated CRP, elevated WBC, low hemoglobin, decreased sodium, and increased creatinine. Imaging findings include fascial thickening (with potential fat stranding), edema, subcutaneous gas, and abscess formation. Broad-spectrum antibiotics should be started in all cases of suspected NSTI. Surgical debridement, however, remains the lynchpin for treatment of cervical necrotizing fasciitis.

The effect of race, socioeconomic status, and comorbidity on patients afflicted with COVID 19: A Local Perspective.

PURPOSE: The aim of this study is to further examine the associations of race, socioeconomic factors, and comorbidity with COVID-19 health outcomes. METHODS: This is a retrospective cohort study of 309 PCR confirmed COVID-19 positive adults who presented to Tulane Medical Center in New Orleans, LA, from March 9 to May 29, 2020. The primary outcomes investigated were need for invasive mechanical ventilation (IMV) and in-hospital mortality. A multivariate analysis was performed to determine socioeconomic and medical risk factors for IMV and in-hospital mortality. RESULTS: Compared to white patients, Black patients were more likely to present younger, female, obese, unemployed, and underinsured. However, when controlled for common risk factors, Black and white patients had similar risk for IMV and mortality. Increased age (≥65 years), obesity, and increased comorbidity were associated with increased risk for IMV and mortality. CONCLUSIONS: Race and socioeconomic factors may increase risk for COVID-19 infection but did not affect health outcomes within the hospital setting. Therefore, the higher rates of COVID-19 infection and mortality in vulnerable populations may be better explained by lower socioeconomic status, with subsequent higher comorbidity, in these populations. Community health initiatives should be prioritized in response to the COVID-19 pandemic.

Risk of SARS-CoV-2 Transmission During Flexible Laryngoscopy: A Systematic Review.

IMPORTANCE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reportedly infected otolaryngologists disproportionately in the early parts of the coronavirus disease 2019 pandemic. Recommendations from national and international health organizations suggest minimizing the use of flexible laryngoscopy as a result. OBJECTIVE: To review evidence on the risks of aerosolization and transmission of SARS-CoV-2 from patients to health care personnel during endoscopy of the upper aerodigestive tract. EVIDENCE REVIEW: A comprehensive review of literature was performed on April 19, 2020, using the PubMed/MEDLINE (1966-April 2020), Embase (1975-April 2020), and Web of Science (1900-April 2020) databases. All English-language primary research studies were included if they assessed the transmission of SARS-CoV-2 or SARS-CoV-1 during procedures in the upper aerodigestive tract. The primary outcome measure was disease transmission among health care workers. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used for accuracy of reporting. FINDINGS: The queries for SARS-CoV-2 and SARS-CoV-1 identified 6 articles for systematic review. No studies included in this review provided data for SARS-CoV-2 transmission during flexible laryngoscopy. A total of 204 of 1264 health care workers (16.1%) had procedure-specific infections of SARS-CoV-1 or SARS-CoV-2. Among those, 53 of 221 (24.0%) were exposed during intubation, 1 of 15 (6.7%) during bronchoscopy, and 1 of 1 (100%) during endoscopy-assisted intubation. CONCLUSIONS AND RELEVANCE: A substantial lack of research precludes formal conclusions about the safety of flexible laryngoscopy and transmission of SARS-CoV-2 from patients to health care workers. The use of appropriate precautionary measures and personal protective equipment appears to reduce the risk of transmission. Given the uncertainty in transmission and the known benefits of safety precautions, upper airway endoscopy may be reasonable to perform if precautionary steps are taken.

Knowledge Gaps among Patients and Providers in HPV-Related Oropharyngeal Cancer: A Systematic Review.

OBJECTIVE: To describe the level of knowledge of human papillomavirus (HPV) and HPV-associated oropharyngeal squamous cell carcinoma (OPSCC) among the general population and health care providers. DATA SOURCES: Systematic search was performed on December 20, 2018, using MEDLINE (1966 to December 2018), EMBASE (1975 to December 2018), Web of Science (1900 to December 2018), and CENTRAL (1996 to December 2018) databases. English-language literature involving human subjects was used, and studies were limited to case series, case-control, cohort, and randomized controlled trial designs. REVIEW METHODS: Studies were included if they assessed knowledge of HPV and HPV-associated OPSCC. The primary outcome measure was the knowledge of HPV-associated OPSCC among the general population and with health care providers. Meta-analysis of proportions was attempted using random-effects model. The PRISMA guidelines were used for accuracy of reporting. RESULTS: Thirty-two studies were included with 17,288 participants. There was a high degree of heterogeneity preventing completion of a meta-analysis. Knowledge of HPV and HPV-associated OPSCC varied between the general population and health care providers. The proportion of the general population and health care providers with knowledge of HPV ranged from 16% to 75% and 21% to 84%, respectively. Knowledge of HPV-associated OPSCC was greater in health care providers and ranged from 22% to 100% compared with the general population, which ranged from 7% to 57%. CONCLUSION: There is a knowledge gap of HPV-associated OPSCC for both the general population and health care providers. Additional education may not only increase awareness but may also result in prevention and earlier detection.

A novel gene panel for prediction of lymph-node metastasis and recurrence in patients with thyroid cancer.

BACKGROUND: Although well-differentiated papillary thyroid cancer may remain indolent, lymph node metastases and the recurrence rates are approximately 50% and 20%, respectively. No current biomarkers are able to predict metastatic lymphadenopathy and recurrence in early stage papillary thyroid cancer. Hence, identifying prognostic biomarkers predicting cervical lymph-node metastases would prove very helpful in determining treatment. METHODS: The database of the Cancer Genome Atlas included 495 papillary thyroid cancer samples. Using this database, we developed a machine learning model to define a gene signature that could predict lymph-node metastasis (N0 or N1). Kruskal-Wallis tests, univariate and multivariate logistic and Cox regression models, and Kaplan-Meier analyses were performed to correlate the gene signature with clinical outcomes. RESULTS: We identified a panel of 25 genes and constructed a risk score that can differentiate N0 and N1 papillary thyroid cancer samples (P < .001) with a sensitivity of 86%, a specificity of 62%, a positive predictive value of 93%, and a negative predictive value of 42%. This panel represents an independent biomarker to predict metastatic lymphadenopathy (OR = 8.06, P < .001) specifically in patients with T1 lesions (OR = 7.65, P = .002) and disease-free survival (HR = 2.64, P = .043). CONCLUSION: This novel 25-gene panel may be used as a potential prognostic marker for accurately predicting lymph-node metastasis and disease-free survival in patients with early-stage papillary thyroid cancer.

Tumor necrosis factor-α triggers opposing signals in head and neck squamous cell carcinoma and induces apoptosis via mitochondrial- and non-mitochondrial-dependent pathways.

Head and neck squamous cell carcinoma (HNSCC) remains one of the most common malignancies worldwide. Although the treatment outcomes of HNSCC have improved in recent years, the prognosis of patients with advanced-stage disease remains poor. Current treatment strategies for HNSCC include surgery as a primary therapy, while radio-, chemo-, and biotherapeutics can be applied as second-line therapy. Although tumor necrosis factor-α (TNF-α) is a potent tumor suppressor cytokine, the stimulation of opposing signals impairs its clinical utility as an anticancer agent. The aim of this study was to elucidate the mechanisms regulating TNF-α­induced opposing signals and their biological consequences in HNSCC cell lines. We determined the molecular mechanisms of TNF-α-induced opposing signals in HNSCC cells. Our in vitro analysis indicated that one of these signals triggers apoptosis, while the other induces both apoptosis and cell survival. The TNF-α-induced survival of HNSCC cells is mediated by the TNF receptor-associated factor 2 (TRAF2)/nuclear factor (NF)-κB-dependent pathway, while TNF-α-induced apoptosis is mediated by mitochondrial and non-mitochondrial-dependent mechanisms through FADD-caspase-8-caspase-3 and ASK-JNK-p53-Noxa pathways. The localization of Noxa protein to both the mitochondria and endoplasmic reticulum (ER) was found to cause mitochondrial dysregulation and ER stress, respectively. Using inhibitory experiments, we demonstrated that the FADD­caspase-8­caspase-3 pathway, together with mitochondrial dysregulation and ER stress-dependent pathways, are essential for the modulation of apoptosis, and the NF-κB pathway is essential for the modulation of anti-apoptotic effects/cell survival during the exposure of HNSCC cells to TNF-α. Our data provide insight into the mechanisms of TNF-α-induced opposing signals in HNSCC cells and may further help in the development of novel therapeutic approaches with which to minimize the systemic toxicity of TNF-α.

Primary Squamous Cell Carcinoma of the Thyroid.

Background: Primary squamous cell carcinoma of the thyroid (PSCCT) is a rare malignancy of the head and neck, with fewer than 60 cases reported in the literature. We report a case of PSCCT and provide a brief review of the literature. Case Report: A 66-year-old female with a history of a hemithyroidectomy for a benign thyroid lesion presented with 3 months of progressively worsening compressive symptoms and shortness of breath. Physical examination revealed right-sided thyromegaly and right-sided true vocal fold immobility. Preoperative imaging with ultrasound and computed tomography scan confirmed an enlarged right thyroid, as well as right anterior cervical lymphadenopathy, subglottic stenosis, and bilateral pulmonary nodules. Fine needle aspiration of the thyroid was suggestive of carcinoma. Intraoperative findings of gross tracheal invasion during a planned completion thyroidectomy prompted limited resection and impromptu tracheotomy. Histopathologic and immunohistochemical evaluation confirmed a squamous cell carcinoma of thyroid origin. Further oncologic workup with core lung biopsy and positron emission tomography scan demonstrated metastasis to the lung and cervical spine. Palliative chemotherapy was begun, but the patient died 1 week into therapy. Conclusion: PSCCT is a rare but aggressive malignancy of the head and neck. Histopathologic and immunohistochemical evaluations are essential for diagnosis. While locoregional surgery and radiation therapy may improve the length of survival, the prognosis of patients with PSCCT is poor. Physicians should be mindful of this unique but deadly disease process, as early diagnosis and rapid treatment initiation are essential to optimize treatment outcomes.

Association of Continued Preoperative Aspirin Use and Bleeding Complications in Patients Undergoing Thyroid Surgery.

IMPORTANCE: No evidence exists to direct the management of preoperative aspirin (acetylsalicylic acid) use in patients undergoing thyroid surgery. Nevertheless, a considerable number of patients interrupt receiving aspirin therapy during the preoperative period to minimize bleeding complications despite the increased risk of experiencing major adverse cardiac events. OBJECTIVE: To determine whether aspirin therapy continued preoperatively increases bleeding complications in patients undergoing thyroid surgery. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of a consecutive sample of 570 patients, aged 18 to 100 years, who underwent thyroid surgery for benign and malignant disease from January 1, 2010, to December 31, 2015, by a single surgeon at a tertiary referral hospital center in New Orleans, Louisiana. EXPOSURES: Patients receiving aspirin therapy and patients not receiving aspirin therapy (aspirin naive) preoperatively. MAIN OUTCOMES AND MEASURES: Comparison of estimated blood loss, substantial blood loss, operative hematoma, nonoperative hematoma, and recurrent laryngeal nerve injury. RESULTS: Of 570 patients who underwent thyroid surgery, 106 (18.6%) were performed in patients receiving aspirin; of these, 23 (21.7%) were men and 105 (99.1%) were older than 45 years. Those receiving aspirin therapy displayed a 14.4-year difference in age (95% CI, 11.6-17.1). The aspirin group displayed a 20.3% absolute increase (95% CI, 9.3-30.7) in African American patients. Aspirin therapy was not associated with a statistically significant or clinically meaningful increase in intraoperative blood loss (2.5 mL; 95% CI, -0.4 to 5.3). Aspirin therapy was associated with a statistically significant increase in total hematoma formation (3.3%; 95% CI, 0.4-9.0), but the results were inconclusive. Aspirin therapy was not associated with a statistically significant increase in recurrent laryngeal nerve injury (2.6%; 95% CI, -1.1 to 8.6), but the results were inconclusive. CONCLUSIONS AND RELEVANCE: These results suggest that aspirin therapy can be maintained prior to thyroid surgery without increased intraoperative bleeding. Further research with a larger sample size and more outcome events are required to make definitive conclusions regarding the association between aspirin use and complications, including hematoma and recurrent laryngeal nerve injury.

Racial and regional disparity in liver transplant allocation.

BACKGROUND: Sources of liver transplant disparities are not understood adequately, particularly in terms of race and region. METHODS: Fixed effects multivariate logistic regression augmented by modified forward and backward stepwise regression of transplanted patients from the United Network for Organ Sharing Standard Transplant Analysis and Research database (1985-2016) was performed to assess causal inference of such disparities. RESULTS: In the study sample (N = 258,602), significant disparities in the odds of receiving a liver were found: African Americans odds ratio 1.12 (95% confidence interval, 1.08-1.17), Asians 1.12 (95% confidence interval, 1.07-1.18), females 0.80 (95% confidence interval, 0.78-0.83), and malignancy 1.18 (95% confidence interval, 1.13-1.22). Region 7 (IL, MN, ND, SD, and WI) was set as the reference level since its transplantation rate most closely approximated the sex and race-matched rate of the national post-Share 35 average. Significant racial disparities by region were identified using Caucasian Region 7 as the reference: Hispanic Region 9 (New York, West Vermont) 1.22 (1.02-1.45), Hispanic Region 1 (New England) 1.26 (1.01-1.57), Hispanic Region 4 (Oklahoma, TX) 1.23 (1.05-1.43), and Asian Region 4 (Oklahoma, TX) 1.35 (1.05-1.73). CONCLUSION: Despite numerous adjustments to liver allocation, we identified with causal inference statistics on a large dataset spanning ≥30 years there remain racial and regional overweighting.

Prognostic Role of BRAFV600E Cellular Localization in Melanoma.

BACKGROUND: Approximately half of cutaneous melanoma tissues harbor BRAFV600E mutations, resulting in a constitutive activation of the mitogen-activated protein kinase (MAPK) pathway. Nuclear-cytoplasmic transport machinery is dysregulated in neoplastic cells and alters the key regulatory proteins that can lead to tumor progression and drug resistance. The significance of nuclear localization of BRAFV600E has not been fully understood. We examined the clinical significance of intracellular localization of BRAFV600E in cutaneous melanoma. STUDY DESIGN: Immunohistochemical analysis of BRAFV600E was performed on formalin-fixed, paraffin-embedded specimens of cutaneous melanoma (n = 91). Staining intensity was graded in a blinded manner. Correlations to clinical factors were analyzed by Fisher's exact test and 2-tailed t-test. Localization of BRAFV600E was determined in melanoma cells, and we investigated their resistance to BRAFV600E-specific inhibitor according to nuclear localization in both in vitro and in vivo models. RESULTS: We included 91 patients, of whom 32% (29 of 91) had cytoplasmic BRAFV600E. Nuclear BRAFV600E was observed in 30% (27 of 91). Overall, BRAFV600E expression correlated with TNM stage (p = 0.011), mitotic activity (p = 0.010), and ulceration (p = 0.045). Nuclear BRAFV600E expression correlated with overall clinical stage (p < 0.001), tumor size (p < 0.001), regional lymph node (p < 0.017), depth of invasion (p = 0.005), Clark level (p < 0.001), mitotic activity (p < 0.001), ulceration (p < 0.001), and margin status (p = 0.017). On a cellular level, BRAFV600E was identified in the nucleus, and its translocation was serum dependent. Our in vitro and in vivo data revealed sequestration of BRAFV600E in the cytosol-sensitized resistant cells to vemurafenib; nuclear retention of BRAFV600E was associated with aggressiveness and drug resistance. CONCLUSIONS: Nuclear localization of BRAFV600E is associated with melanoma aggressiveness. Further multi-institutional studies are warranted to confirm the clinical relevance of nuclear localization of BRAFV600E.

Bortezomib sensitizes thyroid cancer to BRAF inhibitor in vitro and in vivo.

Although overall survival rate for patients with thyroid cancer (TC) is high, there is an alarming 10-year recurrence rate of up to 30% conferring a ~50% survival among these high-risk patients. The BRAFV600E mutation is estimated to be present in over 50% of papillary thyroid cancer (PTC) cases besides being associated with carcinogenesis and poor prognosis. We assessed the status of NF-κB, Ki-67, cyclin D1 and BRAFV600E in TC tissues and TC cell lines using immunohistochemistry and Western blot analysis. Concurrently, we evaluated the outcomes of combined targeting of the proteasome pathway in addition to selective BRAF inhibitors in cases of PTC. In this study, BRAFV600E-bearing TC cells were treated with BRAFV600E inhibitor, Vemurafenib alone or in combination with the proteasome inhibitor, Bortezomib. The combination of both drugs showed synergistic effects as evidenced by cell growth inhibition (P < 0.05), increased G2-phase cell cycle arrest and induced apoptosis (P < 0.05). In our TC xenograft model, the combination of Vemurafenib and Bortezomib significantly reduced tumor size (P < 0.05) and expression of the markers of cell growth and proliferation, Ki-67 and cyclin D1 (P < 0.001), when compared to monotherapy. Further analysis demonstrated that treatment with Bortezomib sensitized TC cells to Vemurafenib via mitochondrial dysregulation and apoptosis of TC cells, as evidenced by the increase in the expression of p53, Noxa protein, the loss of mitochondrial membrane potential, cytochrome c release and Poly (ADP-ribose) polymerase cleavage. Our results demonstrate a strong clinical potential for the combination of the Bortezomib and the BRAF inhibitor Vemurafenib as an efficient therapeutic approach for the treatment of TC.

Liver transplantation in New Orleans: parity in a world of disparity?

BACKGROUND: Racial disparity in access to liver transplantation among African Americans (AA) compared to Caucasians (CA) has been well described. The aim of this investigation was to examine the presentation of AA liver transplant recipients in a socioeconomically challenged region. METHODS: 680 adult liver transplant candidates and 233 resultant recipients between 2007 and 2015 were analyzed using univariate and multivariate analyses to evaluate factors significant for transplantation. RESULTS: Percentages of wait list patients transplanted were similar between CA and AA (34.9% vs. 32.2%, p = 0.5205). AA were younger (50.4 ± 1.8 vs. 56.3 ± 0.7 yrs, p = 0.0003) with higher average MELD scores (22.9 ± 1.6 vs. 19.4 ± 0.7, p = 0.0230). Overall patient mortality was similar (AA 22.7% vs. CA 26.3%, p = 0.5931). A multiple linear regression showed that male gender was strongly associated with transplantation. CONCLUSIONS: Equal access to liver transplantation remains challenging for racial minorities. At our institution, AA were accepted and transplanted at an equivalent rate as CA despite a higher AA population, HCV rate and diagnosed HCC. AA were younger and sicker at the time of transplant, but overall had similar outcomes compared to CA. Our study highlights the need for studies to delineate the underpinnings of disparity in transplantation access.

Immunohistochemistry as an accurate tool for evaluating BRAF-V600E mutation in 130 samples of papillary thyroid cancer.

BACKGROUND: BRAFV600E mutation has been investigated by immunohistochemistry and has shown high sensitivity and specificity. We aim to investigate the accuracy of immunohistochemistry versus molecular testing of BRAFV600E in papillary thyroid cancer using a large number of polymerase chain reaction-positive BRAFV600E papillary thyroid cancer tissues. METHODS: We stained 130 formalin-fixed papillary thyroid cancer specimens using the VE1 antibody: 100 BRAFV600E positive and 30 BRAFV600E negative confirmed by PCR. The sensitivity, specificity, and predictive values of the antibody were assessed. RESULTS: Immunohistochemistry of BRAFV600E showed 98.0% sensitivity, 93.3% specificity, and positive and negative predictive values of 98.0% and 93.3%, respectively. Of 100 patients with BRAFV600E PCR-positive samples, 97 (97.0%) had cytoplasmic weak (4.0%), moderate (17.0%), and strong (76.0%) immunostaining. In BRAFV600E PCR-negative samples, cytoplasmic staining was not detected in 93.3% (28/30) of papillary thyroid cancer tissues. The receiver operating characteristic curve demonstrated a high validity and comparable immunohistochemistry method (area under the curve = 98.8%) compared with PCR testing. CONCLUSION: The use of VE1 immunohistochemistry for the detection of BRAFV600E in papillary thyroid cancer tissues is a clinically applicable method with high specificity, sensitivity, and positive and negative predictive values. The reliable use of BRAFV600E immunohistochemistry should promulgate the routine use of this method for BRAFV600E detection in papillary thyroid cancer tissues.