Hallmarks of cancer resistance.

This review explores the hallmarks of cancer resistance, including drug efflux mediated by ATP-binding cassette (ABC) transporters, metabolic reprogramming characterized by the Warburg effect, and the dynamic interplay between cancer cells and mitochondria. The role of cancer stem cells (CSCs) in treatment resistance and the regulatory influence of non-coding RNAs, such as long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), are studied. The chapter emphasizes future directions, encompassing advancements in immunotherapy, strategies to counter adaptive resistance, integration of artificial intelligence for predictive modeling, and the identification of biomarkers for personalized treatment. The comprehensive exploration of these hallmarks provides a foundation for innovative therapeutic approaches, aiming to navigate the complex landscape of cancer resistance and enhance patient outcomes.

Cellular Aging and Senescence in Cancer: A Holistic Review of Cellular Fate Determinants.

This comprehensive review navigates the complex relationship between cellular aging, senescence, and cancer, unraveling the determinants of cellular fate. Beginning with an overview of cellular aging's significance in cancer, the review explores processes, changes, and molecular pathways influencing senescence. The review explores senescence as a dual mechanism in cancer, acting as a suppressor and contributor, focusing on its impact on therapy response. This review highlights opportunities for cancer therapies that target cellular senescence. The review further examines the senescence-associated secretory phenotype and strategies to modulate cellular aging to influence tumor behavior. Additionally, the review highlights the mechanisms of senescence escape in aging and cancer cells, emphasizing their impact on cancer prognosis and resistance to therapy. The article addresses current advances, unexplored aspects, and future perspectives in understanding cellular aging and senescence in cancer.

Predictive, preventive, and personalized medicine in breast cancer: targeting the PI3K pathway.

Breast cancer (BC) is a multifaceted disease characterized by distinct molecular subtypes and varying responses to treatment. In BC, the phosphatidylinositol 3-kinase (PI3K) pathway has emerged as a crucial contributor to the development, advancement, and resistance to treatment. This review article explores the implications of the PI3K pathway in predictive, preventive, and personalized medicine for BC. It emphasizes the identification of predictive biomarkers, such as PIK3CA mutations, and the utility of molecular profiling in guiding treatment decisions. The review also discusses the potential of targeting the PI3K pathway for preventive strategies and the customization of therapy based on tumor stage, molecular subtypes, and genetic alterations. Overcoming resistance to PI3K inhibitors and exploring combination therapies are addressed as important considerations. While this field holds promise in improving patient outcomes, further research and clinical trials are needed to validate these approaches and translate them into clinical practice.

Lateral approach is a more aesthetical option for radical resection of BSCC: assessment of its surgical, oncological, functional, and aesthetic outcomes.

BACKGROUND: The purpose of this study was to introduce a modified lateral approach for combined radical resection of buccal squamous cell carcinoma (BSCC) and evaluate its surgical, oncological, functional, and aesthetic outcomes in comparison with the conventional lower-lip splitting approach. METHODS: This single-center study retrospectively reviewed 80 patients with BSCC, of which 37 underwent the lateral approach and 43 underwent the conventional approach. Surgical, functional, oncological, and aesthetic evaluations, as well as follow-ups, were recorded and compared. RESULTS: Compared to the conventional approach group, the lateral approach group had a longer surgical time (P = 0.000), but there was no significant difference in other surgical and oncological parameters. Moreover, the scar in the head and neck had a significantly discreet appearance in the lateral approach group, whose satisfaction was better than those in the conventional approach group (P = 0.000). Other oral function parameters, postoperative mouth-opening, and 3-year survival rate were not significantly different between the two groups. CONCLUSION: The lateral approach could provide superior aesthetic results while maintaining equal surgical, functional, and oncological outcomes compared to the conventional approach for radical resection of BSCC.

[Influence of mandibulotomy approaches on oral function following radical resection of tongue carcinoma].

OBJECTIVE: This study aimed to compare the influences of postoperative oral function in patients with median or paramedian mandibulotomy during the radical resection of tongue carcinoma and to provide evidence for the choice of osteotomy location for mandibulotomy. METHODS: The clinical data of 126 patients who underwent combined radical neck dissection with mandibulectomy and glossectomy followed by simultaneous reconstruction were analyzed retrospectively. The patients were divided into two groups according to the position of mandibulotomy: median mandibulotomy group (median group, n=60) and paramedian mandibulotomy group (paramedian group, n=66). The fourth edition of the University of Washington Quality of Life Questionnaire (UW-QOL) was used to compare the differences in oral functions, such as swallowing, mastication, and speech, between the two groups during regular follow-up. SPSS 24.0 software package was used for statistical analysis, and P<0.05 was considered statistically significant. RESULTS: Six months after the operation, no significant differences in swallowing, mastication, and speech functions were found between the median and paramedian groups. However, the swallowing and speech functions in the paramedian group were better than those in the median group 1 year after the operation (P<0.05), whereas no statistical difference in mastication function was observed between the two groups. CONCLUSIONS: Evaluation of the postoperative oral function results showed that paramedian mandibulotomy was a better surgical approach than median mandibulotomy. Paramedian mandibulotomy is worth prioritizing in the radical resection of tongue carcinoma.

[Application of the nasolabial fold "smile" incision approach in posterior buccal cancer ablation].

OBJECTIVE: This study investigated the feasibility and clinical result of radical resection of posterior buccal carcinoma by using the facial nasolabial fold "smile" incision approach. METHODS: From August 2016 to March 2017, 23 patients with posterior buccal carcinoma were included in this study and underwent radical surgery. Upon finishing the cervical lymph node dissection, an arc-shaped incision was made at 1 cm lateral to the ipsilateral angulus oris, extending along the nasolabial fold upward to the inferolateral margin of the nasal alar while downward in direct continuity with the neck dissection incision. RESULTS: Satisfactory exposure and easy resection of the primary tumor with negative surgical margin were achieved in all 23 patients. After 12-22 months of follow-up (16.5 months on average), all patients recovered favorably, and no local recurrence or distant metastasis was observed. Mouth opening was restored to normal in all cases. The scars were hidden in the nasolabial fold, thus named "smile" incision. CONCLUSIONS: For posterior buccal cancer patients, the facial "smile" incision approach can satisfy the need of surgical exposure, facilitate operative performance, and preserve the annular integrity of the lips without affecting the radical tumor ablation, thereby maintaining a favorable mouth opening. With these advantages, the "smile" incision approach is considered worthy of being popularized in clinical application.

A comparative study between submandibular-facial artery island flaps (including perforator flap) and submental artery perforator flap: A novel flap in oral cavity reconstruction.

OBJECTIVE: The purpose of this study was to introduce submandibular-facial artery island flaps (S-FAIF), including the perforator flap, and to evaluate their application for intraoral reconstruction in comparison with submental artery perforator flaps (SMAPF). METHODS: Ninety-six patients who underwent intraoral reconstruction using an S-FAIF (n = 34) or SMAPF (n = 62) after cancer resection were recruited in this study. The flap characteristics (viz., pedicle length, flap size, venous drainage pattern, and harvest time), short-term outcomes (viz., flap partial loss, intraoral wound dehiscence, fistula, and wound infection), and long-term morbidity (viz., facial nerve palsy, neck motion restriction, and hair growth) were compared. RESULTS: Nine S-FAIFs were authentic perforator flaps pedicled by level Ⅰ facial artery perforators, while the rest were island flaps based on level Ⅱ facial artery perforators. The survival rates of S-FAIF and SMAPF were both 100 percent. Flap partial loss occurred in two patients in each group. The pedicle length of S-FAIF was shorter than that of SMAPF (p < 0.001). Statistics analysis revealed no significant difference regarding flap size, venous drainage pattern, short-term outcomes, neck motion restriction, or facial nerve palsy between the groups. S-FAIF required less harvest time (p < 0.001) and experienced less hair growth when compared to SMAPF (p = 0.011). CONCLUSIONS: The S-FAIF is a robust and reliable novel flap and on par with SMAPF for reconstruction of small and medium-sized intraoral defects. It is preferred to SMAPF when technical requirements for flap harvest and hair problems are considered. It should be supplemented to the armamentarium for intraoral reconstruction.

Role of PFKFB3 and CD163 in Oral Squamous Cell Carcinoma Angiogenesis.

6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3), an enzyme producing fructose 2, 6-bisphosphate (F-2, 6-BP), serves as a switch to activate phosphofructokinase-1, and is a critical enzyme for endothelial glycolysis, mediating circadian control of carcinogenesis. Also, tumor-associated macrophages (TAMs) play an important role in the progression and prognosis of numerous cancers. However, the role and clinical significance of PFKFB3 and TAMs in oral squamous cell carcinoma (OSCC) have not been elucidated. The present study was designed to investigate the correlation between PFKFB3 expression, CD163+ TAMs infiltration and tumor angiogenesis in OSCC by tissue microarray. Tissue microarrays containing 117 OSCC specimens and 56 matched paracarcinoma tissues were studied by immunohistochemistry. The expression levels of PFKFB3, CD163 and CD31 were significantly increased in OSCC specimens as compared with normal oral mucosa (P<0.05), and PFKFB was signifcantly correlated with tumor differentiation and tumor size (P<0.05), and CD163 was significantly correlated with areca nut chewing habit among OSCC tissues (P<0.05). Furthermore, Pearson's correlation analysis revealed that PFKFB3 was signifcantly correlated with both CD163 and CD31 (P<0.05), meanwhile CD163 was signifcantly correlated with CD31 (P<0.001), suggesting PFKFB3 may promote angiogenesis in tumor progression and metastases by regulating CD163+ TAMs infiltration in OSCC.

Twist-related protein 1 enhances oral tongue squamous cell carcinoma cell invasion through ß-catenin signaling.

Accumulating evidence suggests that ß­catenin signaling may be involved in oral tongue squamous cell carcinoma (OTSCC) cell invasion. Abnormal activation of twist­related protein 1 (TWIST1 or TWIST) has been identified in several types of human cancer. A recent study showed that overexpression of TWIST is associated with a poor prognosis in patients with OTSCC and may enhance OTSCC cell invasion. This study investigated the effect of TWIST on ß­catenin signaling in OTSCC cells and its impact on OSTCC cell invasion. Stable overexpression of TWIST, with or without knockdown of ß­catenin, and stable knockdown of TWIST were performed in SCC­4 and TCA8113 human OTSCC cells. Overexpression of TWIST in SCC­4 and TCA8113 cells increased ß­catenin signaling luciferase reporter activity, mRNA levels of the ß­catenin signaling target genes, c­Myc and c­Jun levels, soluble ß­catenin level, the phosphorylation status of glycogen synthase kinase­3ß (GSK­3ß) at serine 9, matrix metalloproteinase­2 (MMP­2) expression and cell invasion. Knockdown of TWIST had the opposite effect. All of these changes, with the exception of phosphorylation of GSK­3ß, were eliminated by stable knockdown of ß­catenin. In addition, the phosphatidylinositol 3­kinase (PI3K) inhibitor, LY294002 abrogated the enhancing effects of TWIST on mRNA levels of c­Myc and c­Jun, soluble ß­catenin levels, MMP­2 expression, cell invasion and GSK­3ß phosphorylation. In conclusion, the present study demonstrated that TWIST enhances cell invasion and MMP­2 expression in OTSCC cells through ß­catenin signaling, probably via a PI3K­dependent mechanism. This study provides novel insights into the molecular mechanisms underlying OTSCC progression.

Anterior tibial artery perforator flap for reconstruction of intraoral defects.

PURPOSE: The present clinical study assessed the feasibility of using an anterior tibial artery perforator (ATAP) flap for the reconstruction of an intraoral defect after ablative surgery for oral cancer. PATIENTS AND METHODS: A cohort of consecutive patients with oral cancer requiring reconstruction of an intraoral defect using an ATAP flap were enrolled after ablative surgery for oral cancer and ipsilateral neck dissection. RESULTS: Twelve patients had primary oral squamous cell carcinoma (8 with tongue cancer and 4 with buccal cancer). All patients received intraoral defect repair using an ATAP flap from the lower left leg. The flap measured 7 × 4 to 8 × 6 cm(2). Flap thickness was approximately 4.8 mm (3 to 6 mm). Anastomosis of all ATAP flaps was straightforward because of the long and high-caliber vessel pedicle. All flaps survived and yielded excellent esthetic results for intraoral reconstruction. No major complications occurred in any patient. CONCLUSION: The main advantages of the ATAP flap included the thin and pliable tissue characteristics and a long and high-caliber pedicle. For small and medium-size intraoral defects, the ATAP flap is a reliable alternative to the radial forearm free flap.

[Expression of the activating receptor NKG2D on peripheral blood mononuclear cells in patient with oral squamous cell carcinoma and its clinical significance].

PURPOSE: To investigate the expression of activating receptor NKG2D(natural killer group 2,member D) on peripheral blood mononuclear cells(PBMCs) in patients with oral squamous cell carcinoma(OSCC) and its clinicopathological significance. METHODS: The expression of NKG2D on PBMCs in 54 OSCC patients and 20 healthy controls were assessed by flow cytometry. The data was analyzed with SPSS16.0 software package for independent-sample t test and one-way ANOVA test. RESULTS: The positive rate of assay for NKG2D on PBMCs in OSCC patients (12.49±5.26)% was lower than that of the controls (22.93±8.14)% (P<0.05). And which was significantly different among different clinicopathological parameters such as tumor size and disease stage(P<0.05), but no significant difference was found among different gender, age, tumor location, tumor differentiation and cervical lymph node status (P>0.05). CONCLUSIONS: The NKG2D expression on PBMCs in OSCC patients was lower than that of healthy controls and was correlated with tumor size and disease stage.

Clinico-pathological significance of MHC-I type chain-associated protein A expression in oral squamous cell carcinoma.

The current research concerns the clinicopathological significance of MHC class I chain-related protein A (MICA) expression in oral squamous cell carcinomas (OSCCs). The expression and location of MICA protein in 14 normal oral mucous and 45 cancerous and para-cancerous tissues were assessed by immunohistochemistry and levels of MICA mRNA expression in 29 cancerous and para-cancerous tissues were determined by the real-time polymerase chain reaction. Data were analyzed with the SPSS16.0 software package. MICA was found to be located in the cytoplasm and plasma membrane. Expression was higher in para-cancerous than in cancerous tissues (P<0.05). However, no statistical difference was found between the following: 1) para-cancerous tissue with normal mucosa; 2) normal mucosa with cancerous tissue;and 3) among different clinicopathological parameters in OSCC (P>0.05). The level of MICA mRNA was higher in OSCCs than in para-cancerous tissues, and was correlated with the regional lymph node status and disease stage (P<0.05). The levels of MICA protein and mRNA expression differ among normal oral mucosa, para-cancerous tissue, and cancerous tissue. MICA may contribute to the tumorigenesis and progression of OSCC.

[Antitumor immune response of MHC class I chain-related gene A modified oral squamous cell carcinoma vaccine: an experimental study in mice].

PURPOSE: To investigate the vaccine potency of MHC class I chain-related gene A (MICA) modified oral squamous cell carcinoma cells. METHODS: Oral squamous cell carcinoma Tb cells transfected with eukaryotic expression vector pEGFP-N1-MICA and overexpressing MICA protein were inactivated by 120Gy irradiation and vaccinated human peripheral blood leucocytes reconstituted SCID (Hu-PBL/SCID)mice via intra-peritoneal injection, and the non-transfected or blank vector transfected Tb cells were used as the controls. The inhibition effect on tumorigenicity of subcutaneously challenged Tb cells in vaccinated Hu-PBL/SCID mice was detected.The expression of NKG2D and the cytotoxicity in vitro to Tb cells of peripheral blood mononuclear cells (PBMCs) and spleen cells were measured by flow cytometry and lactate dehydrogenase (LDH) release assay. SPSS16.0 software package was used for statistical analysis. RESULTS: MICA gene modified Tb tumor vaccine resulted in remarkable loss of tumor size and tumor weight in vaccinated Hu-PBL/SCID mice. Flow cytometry and lactate dehydrogenase (LDH) release assay showed MICA gene modified Tb tumor vaccine up-regulated the expression of NKG2D on PBMC and spleen cells and enhanced the cytotoxicity to tumor cells. Significant difference was found between MICA-transfected vaccine and non-transfected and blank vector-transfected vaccine (P<0.05). CONCLUSIONS: MICA gene modified oral squamous cell carcinoma vaccine can enhance the ability of antitumor immune response,and MICA may be considered as a promising immunotherapy target of oral squamous cell carcinoma.

[Clinical application of heterogeneous acellular dermal matrix in the surgical treatment of oral submucous fibrosis].

PURPOSE: The aim of this study was to evaluate the clinical effect of heterogeneous acellular dermal matrix in the surgical treatment of advanced oral submucous fibrosis (OSF). METHODS: There were eight patients who had undergone surgical treatment of trismus caused by OSF. Surgery was performed under general anaesthesia given through a nasoendotracheal tube using a fibreoptic bronchoscope. All the fibrous bands on the buccal mucosa were incised and bluntly dissected to stretch the mouth opening. Based on the defect, heterogeneous acellular dermal matrix graft was applied directly on the bilateral wounds. A tie-over dressing technique was used to hold the graft firmly to its bed.The sutures and dressing material were removed on the tenth to fourteenth day after the operation. All the patients were asked to stretch the mouth opening 3 times daily and were followed up for at least 6 months. A modality of medical treatment including multiple micronutrient supplements and steroid injection therapy were carried out if necessary. The changes in the interincisal distances (IDs) were analyzed in the preoperative, intraoperative, and postoperative stages. The data was analyzed with SPSS16.0 software package for one-way ANOVA. RESULTS: The overall success rate was 100% without any or only partial graft loss. There were no immunologic reactions or significant complications.The mean preoperative, intraoperative, and final follow-up interincisal distances were 12.04, 35.46, and 29.33 mm, respectively. Evaluation of the changes in the IDs revealed statistically significant differences between the values recorded at the different stages.(P<0.05). CONCLUSIONS: Heterogeneous acellular dermal matrix may be a valuable biomaterial for repairing oral mucosal defects after surgery on the fibrous bands in patients with advanced OSF through covering and protecting wound surface early,which shortens the healing time of wound, decreases relapse of fibrosis and improve the restricted mouth opening.

[Dumbbell-shaped cervical spinal neurilemmoma presenting as neck mass: diagnosis and treatment].

PURPOSE: Cervical neurilemmoma originating from cervical spine could extend through foramen intervertebrale and displayed a radiographic features as a cervical intra- and extra-spinal dumbbell-shaped mass.Because of its early compressive spine cord, patients usually visited neurosurgery at first. In this paper, two patients of cervical intra- and extra-spinal dumbbell-shaped neurilemmoma visiting oral and maxillofacial surgery complained of upper cervical mass were reported, aiming to improve the diagnostic and therapeutic skill for oral and maxillofacial surgeons. METHODS: Two case of cervical dumbbell tumors who complained of a neck mass underwent surgery and were followed up by oral and maxillofacial surgeons .The pathogenesis,operative approach and prognosis were discussed by reviewing relevant literatures retrospectively. RESULTS: Both of the two patients' presenting symptoms were upper-cervical masses. Preoperative imaging suggested trans-cervical vertebra dumbbell masses.The tumors were removed through combining the posterior midline and lateral cervical approach, and a gross total resection was achieved.No evidence of recurrence was noted after one-year of follow-up. CONCLUSIONS: The initial symptom of cervical intra- and extra-spinal dumbbell-shaped neurilemmoma may be a cervical mass and inconspicuous compressive spine cord. Analysis is essentially devoted to the radicality of tumor resection, nerve root preservation, relation to the vertebral artery, and compromise of spinal stability.The surgical resection of dumbbell-shaped cervical spinal neurilemmoma can pose a formidable challenge.

[Reconstruction of oral and maxillofacial defects using free anterolateral thigh flaps in patients with malignant tumors].

PURPOSE: To explore the value of free anterolateral thigh flaps in the reconstruction of oral and maxillofacial defects following radical resection of malignant tumors. METHODS: Seventy-six cases of oral and maxillofacial malignant tumor from December 2007 to June 2009, including 32 tongue carcinomas, 16 buccal carcinomas, 10 carcinomas of floor of mouth, 9 gingival carcinomas, 8 oropharyngeal carcinomas and 1 skin carcinoma, underwent radical resection. Free anterolateral thigh flaps were used to reconstruct the defects. The postoperative effect and flap success rate were evaluated. RESULTS: Among 76 cases, 74 flaps survived completely with satisfied configuration, only 2 flaps had complete necrosis. The survival rate was 97.3%. No complications were observed in the donor site. CONCLUSIONS: The free anterolateral thigh flap is an ideal choice for reconstruction of oral and maxillofacial defects, as it has many advantages such as reliable blood supply, large size available, and little donor site morbidity.

[Alveolar soft part sarcoma of the tongue root: a case report].

Alveolar soft part sarcoma is a rare, aggressive malignancy of uncertain histological origin with a propensity for vascular invasion and distant metastasis. The case presented involves a 31-year-old woman with alveolar soft part sarcoma in the tongue root. The clinical features, pathogenesis, diagnosis and treatment were discussed.

[A case of nevoid basal cell carcinoma syndrome family].

Nevoid basal cell carcinoma syndrome is a rare autosomal dominant genetic disorder characterized by developmental abnormalities and tumorigenesis. In this paper, a case of nevoid basal cell carcinoma syndrome family was reported, and its incidence, pathogenesis, clinical features and methods of treatment were discussed by reviewing relevant literatures.

[Establishment and identification of biological characteristics of rat monoclone cell line Rca-B].

OBJECTIVE: To establish a monoclone cell line of squamous cell carcinoma (SCC) in rat buccal mucosa and to study its biological characteristics. METHODS: SCC in rat oral mucosa was induced by adding 4-nitroquinoline-1-oxide (4NQO) into the SD rats' drinking water, and the cancer cells were then cultured to obtain mixed cells in vitro. The mixed tumor cells were purified by mono cell cloning method. The biological characteristics of the cells were studied by microscope and electronic microscope observation, chromosome analysis, Methyl thiazolyl tetrazolium (MTT) test, flow cytometry assay and immunohistochemistry staining. Hypodermic inoculations of the cells in nude mice and injection of the cells by nude mice tail veins were performed to observe the tumor formation and long distance metastasis. RESULTS: The morphology proved that the cell line was squamous cell carcinoma cells, which were cultured from one cell. The population doubling time for passage 65 cells was 25.44 hours. The cells in S-phase accounted for 20.13% of the cell cycle. The chromosome modal number was 84. All the cells expressed the proteins of cytokeratin and vimentin. The xenograft rate and the tumor metastatic rate to the lung were 100% in nu/nu BALB/C mice, but the homograft rate was zero in SD Rats. CONCLUSIONS: Rca-B was a typical oral squamous cell carcinoma cell line derived from Sprague-Dawley rat buccal mucosa carcinoma, and the cell line has high metastatic potential and its biological characteristics were well ascertained.

[Modulation of Chinese prescription Shenyang on Th1/Th2 cytokines in serum of SD rats with squamous cell carcinoma of the tongue].

PURPOSE: Prospective research demonstrated that Chinese prescription Shenyang could prolong the survival time and improve the survival rate of patients with oral squamous cell carcinoma (SCC). But the mechanism was not clear. The purpose of this study was to investigate effect of Shenyang on the level of Th1/Th2 cytokines in serum of SD rats with SCC of tongue and clarify its mechanism. METHODS: Among 80 SD rats fed by 0.002% 4-nitroquinoline-1-oxide (4NQO) drinking water for 36 weeks, 61 with SCC of tongue had been found and randomly divided into 4 groups, namely Shenyang A, Shenyang B, positive and negative control group. Before and after high and low dosage of Shenyang, acanthopanax senticoside and water had been given for 15 days respectively, peripheral blood serum was collected. Secretion of Th1-type cytokines, such as IFN-gamma, IL-2, TNF-alpha and Th2-type cytokines, such as IL-4, IL-10 were detected by enzyme-linked immunosorbent assay (ELISA). Statistical analysis was made with paired t test. RESULTS: Shenyang significantly enhanced ,the serum levels of Th1-type cytokine, TNF-alpha and IL-2 (P<0.05), and decreased the expression of Th2-type cytokine, IL-4 and IL-10(P<0.05). Serum IFN-gamma had been increased to some extent. CONCLUSION: Reversing Th2 to Th1 cytokines and then enhancing the immunity may be one of the mechanisms in anti-tumor effect of Shenyang. Supported by Science and Technology Development Fund (No.014319359) of Shanghai Municipality.