Cancer Translational Medicine

Review | Open Access

Vol.8 (2022) | Issue-3 | Page No: 76-86

DOI: https://doi-ds.org/doilink/09.2022-35525372/A1

Advances in Pathogenesis and Non-surgical Therapy of Cutaneous Basal Cell Carcinoma

Yichen Wu1, Jia Chen2*

Affiliations  

1. Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China

2. Department of Dermatopathology, Shanghai Skin Disease Hospital, Shanghai, China

*Corresponding Author

Address for correspondence: Prof. Jia Chen, Department of Dermatopathology, Shanghai Skin Disease Hospital, No.1278 Baode Road, Jing'an District, Shanghai 200040, China. E-mail: chenjia_doc@163.com


Important Dates  

Date of Submission:   18-May-2022

Date of Acceptance:   25-Jul-2022

Date of Publication:   29-Sep-2022

ABSTRACT

Basal cell carcinoma (BCC) is a low-grade malignant skin tumor originating from basal cells, which is closely related to UV radiation and tends to occur on the face. Fortunately, most of the tumors are localized and easily amenable to surgical resection. However, for those patients with specific areas of skin lesions and locally advanced as well as, in rare cases, metastatic BCC may pose a therapeutic challenge. Therefore, non-surgical treatment is needed as an important supplement or even the preferred option. In this review, we will outline the currently known pathogenesis and non-surgical therapy of BCC. With our understanding of the molecular basis of BCC, emerging targeted therapeutics such as Hedgehog pathway inhibitors, photodynamic therapy, and combined therapy are offering new avenues for the non-surgical treatment of BCC.

Keywords: Basal cell carcinoma, pathogenesis, therapy


INTRODUCTION

Basal cell carcinoma (BCC), also known as basal cell epithelioma, is the most common nonmelanoma skin cancer, accounting for 80% of cases.[1] A slowly growing tumor, BCC seldom metastasizes and has a benign evaluation, although some high-risk variants of BCC can lead to deadly results.[2] Currently, the preferred treatment plan for BCC is complete surgical resection. However, some patients are not suitable for this treatment due to age, health state, location of lesions, lesion generalization, and uncommon metastatic BCC, which can cause gradual disfigurement or even death. In recent years, many non-surgical treatments have emerged with further understanding of the pathogenesis of BCC. In this article, we discuss a brief overview of non-surgical therapies for BCC as well as emerging targeted therapeutics such as Hedgehog pathway inhibitors and immune modulators. These therapeutics have the potential to revolutionize the treatment of this common and important skin cancer.


THE PATHOGENESIS OF BCC

Hedgehog signaling pathway

During early embryonic development, the Hedgehog (HH) signaling pathway contributes to the formation of the neural tube, musculoskeletal system, hematopoietic cells, teeth, and skin. The mammalian Hedgehog family includes the Sonic Hedgehog (SHH), India Hedgehog (IHH), and Desert Hedgehog (DHH). IHH regulates chondrogenic differentiation and DHH is important for spermatogenesis and development of the neural fasciculus of peripheral nerves. Within the skin, the SHH pathway is primarily responsible for stem cell maintenance and controlling the development of hair follicles and sebaceous glands.[3] It has been suggested that BCC originates from stem cells permanently settled in the parietal epidermis and upper part of the hair follicle funnel.[4] Both in nevus-like basal cell carcinoma syndrome (NBCCS) or in sporadic basal cell carcinoma, aberrant activation of the SHH pathway plays a key role in tumor initiation, progression, and recurrence. Sonic Hedgehog ligands, patched 1 (PTCH1), smoothened (SMO), and GLI (glioma associated oncogene protein) are the key components of this pathway. Normally, PTCH1 acts as a regulatory molecule, reducing HH signaling by inhibiting the translocation of SMO cilia. When SHH ligand binds to PTCH1, the PTCH1-SHH complex is degraded by lysosomes which de-represses SMO, upregulating the downstream signaling cascade via several proteins, including SUFU (suppressor of fused). This ultimately leads to the release of GLI protein family members such as GLI1 (glioma associated oncogene protein-1). The GLI1 translocates to the cell nucleus and triggers the transcription of HH-dependent target genes, leading to the development of BCC.[5] Some studies have found that, somatic PTCH1 mutations can occur upto 75% of the time. It is generally well-established that heterozygous germline deletion of the PTCH1 molecular mechanism leads to NBCCS/Gorlin syndrome. Shift mutations in PTCH2 can also lead to NBCCS.[6] In addition, activating SMO mutations have been reported in approximately 10% - 20% of BCCs, demonstrating that activating mutations in SMO can induce BCC by activating the HH signaling pathway.[7]

TP53

The second most frequent factor associated with BCC pathogenesis is the mutations of the TP53 gene. The role of the vital tumor suppressor protein p53, encoded in the TP53 gene, is involved in cell cycle arrest and activation of programmed death. Somatic mutations in TP53 are common in BCC. A study has shown that TP53 mutations were found in 17 of 42 BCCs (40%).[8] P53 enhances apoptosis via repressing the BCL2 and inhibiting SMO proteins in the HH pathway.[3],[9] TP53 can interact with and repress GLI though it is not a part of the Hedgehog pathway. Therefore, mutations in TP53 further enhance Hedgehog signaling in BCC. In a mouse model studying BCC pathogenesis, P53 loss increased SMO expression sensitizing epidermal keratinocytes to the oncogenic effects of PTCH1 deletion, which in turn led to the development of BCC.[10] In addition, P53 could also enhance P21 protein function, inhibiting tumor formation.

DNA and histone methylation

Epigenetics plays a crucial role in transcriptional regulation. The expression of genes involved in essential cellular pathways can be altered by the aberrant epigenetic organization.[11] In addition to the PTCH1 and TP53, data from both The Cancer Genome Atlas (TCGA)[12] and the Catalogue of Somatic Mutations in Cancer (COSMIC)[13] suggest that histone methyltransferases are also among the most commonly mutated genes. A recent study results showed an association between advanced BCC and the histone methyltransferase EZH2. They assessed the expression levels of EZH2 in 30 less aggressive BCC subtypes and 30 more aggressive subtypes. EZH2 expression was significantly higher in the more aggressive BCC than in the less aggressive BCC and was positively correlated with BCC aggressiveness.[14],[15] This result suggests that EZH2 could serve as a potential target for inhibiting BCC progression and that EZH2-associated epigenetic marker profiles could serve as histological markers of BCC aggressiveness.

Aberrant DNA methylation in association with abnormal gene expression is another hallmark of cancer. Brinkhuizen et al. tested the DNA methylation status, using MSP (methylation-specific polymerase) chain reaction, of 9 oncogenes and one oncogene promoter region in 112 BCC patients and 124 healthy controls. Results showed that SHH, adenomatous polyposis coli (APC), secreted frizzled-related protein 5 (SFRP5), and RAS-associated structural domain family 1 (RASSF1) genes were significantly hypermethylated in BCC.[16]

The Hippo-Yap signaling pathway

The Hippo pathway, which plays an essential role in tissue growth restriction, consists of a series of kinases. Dysfunctional regulation of the Hippo-Yap pathway has been reported in BCC from RNA sequencing research, with up-regulated YAP (Yes-associated protein) triggering proliferation of basal keratinocytes. LATS1 gene encodes one of the kinases in the Hippo pathway. Premature stop mutations in these LATS1 genes have been reported in 16% of BCC. Additionally, LATS2 gene (analog of LATS) mutations have been observed in 12% of tumors.[17]

MYCN/FBXW7 signaling

MYCN is a transcriptional activator, probably downstream of the HH pathway, involved in cell proliferation and differentiation.[17] Missense mutations have been detected in 30% of BCC, mainly within the MYC box1 region that interacts with FBXW7, a tumor suppressor, which triggers N-MYC ubiquitin degradation. But this is usually prevented by mutations in the box1 structural domain.[7]

TERT

The TERT gene encodes telomerase which is an enzyme that adds protective repeat sequences to telomeres.[18] Increasing telomere length immortalizes cells, prevents aging and allows excessive cellular replication that are characteristic features of 90% of malignant tumors, including BCC.[19]

DPH3-OXNAD1 bidirectional promotor

Bidirectional promoters of the DPH3 and OXNAD1 genes are shown to be the common sites of somatic mutations in BCC, with Typical UV-signature mutations observed in most of the BCC samples.[20] The DPH3 gene is required to produce diphthamide, a modified histidine residue in eukaryotic elongation factor 2 that helps maintain translation fidelity.[21]

Other possible driver genes

Other genes suggested as possible driver genes for BCC include PPP6C, STK19, KRAS, and PIK3CA. Additional genes found to be mutated at lower frequencies in BCC include RB1, KNSTRN, CASP8, RAC1, ARID1A, CSMD1/2, PREX2, GRIN2A, and NOTCH1/2.[7],[22] Whether these genes are the primary drivers of BCC development or just secondary mutations remains unclear.


THERAPEUTICS FOR BCC

Therapeutic options currently available have been divided into Surgical treatments, Systemic Therapy, Topical Therapy and Physical Therapy. Each method is elaborated here and Table 1 lists all the methods including their advantages and disadvantages.

Surgical treatments

The main surgical treatments include surgical excision and Mohs microsurgery (MMS). Surgical excision aims to resect tumors as completely as possible based on strict adherence to the contraindications and indications for surgery. Therefore, in addition to removing the periphery of the visible tumor border, standard surgery also requires the removal of a particular area of clinically uninvolved skin tissue. Since BCC occurs mainly on the head and face, excizing excessive skin tissue hinders repair of skin defects and negatively affects the patient's appearance.[23]

MMS is used to define the degree of tumor infiltration and microscopic resection. It is not appropriate for locally advanced and metastatic BCC or eyelid BCC due to the orbital soft tissues, even though it guarantees that no tumor cells remain at the cut edge and maximizes the preservation of normal tissues. Intraoperative frozen sections are prone to false-negative results and do not ensure clean tumor resection, locally advanced and metastatic BCC requires radiation therapy or systemic therapy.[24] Recently, a Meta-analysis involving all the therapeutic options for BCC showed a recurrence rate of 3.2% at 5 years in patients treated with MMS and 5.2% with Surgical excision.[25] Surgical resection is highly invasive, especially when a local flap or implant reconstruction is recommended. Moreover, it tends to leave scars, cause hyperpigmentation and hypopigmentation, and cannot achieve the desired cosmetic results. As for small primary BCC of the trunk or extremities lacking invasive clinical or histopathological features, MMS is not indicated because other procedures have similar efficacy, whereas MMS is time-consuming, expensive, and requires higher equipment requirements.[26]

Non-surgical treatments

Prior treatment modalities emphasized on platinum-based therapies. Single or combination platinum-containing agents are effective in advanced BCC. Case reports of patients with BCC have shown responses to the combination of platinum-containing agents such as cisplatin and paclitaxel, cisplatin and vincristine, cisplatin and cyclophosphamide, carboplatin and paclitaxel.[27],[28] In cisplatin-based treatment, the overall response rates of metastatic BCC are as high as 77%.[27] However, most patients eventually relapse and die because of this disease. Thus, some emerging small-molecule inhibitors that showed good efficacy and high security have been the focus of recent therapeutic advancements. In the following portion, we make an introduction about them in detail.[29]

Hedgehog signaling pathway inhibitors

Hedgehog signaling pathway inhibitors can effectively target the treatment of locally advanced BCC and metastatic BCC, especially small molecule-targeted SMO inhibitors, which reflect better anti-BCC effects.

Small molecule-targeted SMO inhibitors

Vismodegib and Sonidegib are currently approved for the treatment of BCC, while BMS-833923, LY2940680, Saridegib, and TAK-441 are still in clinical development.[30] Vismodegib is a small molecule drug that binds to SMO and inhibits its activity, thereby inhibiting the GLI2 transcription factor and therefore blocking the expression of the HH signaling pathway, making it effective for the treatment of BCC. In phase III clinical study of Vismodegib in BCC,150 mg orally once daily for 28 d as a treatment cycle, in 482 patients who met the criteria for efficacy evaluation in solid tumors, 155 patients (32%) showed a complete response, 158 patients (33%) had a partial response and 128 patients (27%) with stable disease. It is shown that Vismodegib could be a novel treatment option for locally invasive and metastatic BCC.[31] According to another study by Tang et al. who divided 41 patients with NBCS into two groups, Vismodegib group and placebo group, Vismodegib resulted in tumor shrinkage of BCC in NBCS and suppression of neoplastic BCC at the same time.[32]

Sonidegib has been approved by both the EMA and FDA for patients who experienced a relapse after surgery or radiation therapy for locally advanced BCC or were not candidates for these treatments.[33] In a multicenter, randomized, double-blind phase II trial, 230 subjects were randomized into Sonidegib 200 mg group (i.e., 79 on oral Sonidegib 200 mg daily) and the Sonidegib 800 mg group (i.e., 151 on oral Sonidegib 800 mg daily), of whom 194 were patients with locally advanced BCC and 36 were patients with metastatic BCC. Results showed that 43% of patients taking 200 mg orally and 38% of those taking 800 mg achieved an objective response, while the response rates in the metastatic BCC group were 15% and 17%, respectively.[34] Thus, compared to advanced BCC, the efficiency of Sonidegib was lower in metastatic BCC. In Phase I clinical study of Saridegib, similar results were observed.[35] Metastatic BCC cannot be treated as effectively as primary BCC due to a low PTCH1 mutation and has a different phenotype and genotype. New therapeutic approaches are therefore needed to treat this disease.[36]  

Small molecule-targeted SMO inhibitors have great promise for the treatment of BCC. But at the same time, some limitations exist as well. (I) Drug resistance. Most patients will develop resistance within a few months. (II) Metastatic BCC is relatively insensitive to Hedgehog inhibitors, and more new targets need to be identified. (III) Inhibition of the HH pathway by SMO may lead to the activation of another pathway and the creation of other tumors. In a study of 104 patients with advanced BCC treated with Vismodegib, squamous cell carcinoma occurred in 11% of patients, which may be related to this mechanism.[37] (IV) In some cases, adverse effects such as muscle spasms, rheumatic pain, alopecia, fatigue, and weight reduction may occur during treatment, which should be managed and prevented in the clinic.

Other Hedgehog signaling pathway inhibitors      

Pathway inhibitors that target the SMO protein are being developed and used in the clinic. In spite of this, the development of resistance caused by point mutations in SMO limits the therapeutic application of SMO inhibitors. Moreover, different mechanisms exist which activate HH signaling in cancer cells that bypass SMO. Therefore, identifying the HH inhibitors that modulate proteins as potential targets while avoiding the problem of resistance is of great interest. Studies have focused on antagonists of GLI1, a transcription factor downstream of the HH pathway. A recent study showed that Pipinib reduces the incidence of disease by selectively inhibiting phosphatidylinositol 4-kinase IIIβ (PI4KB) and suppressing GLI-mediated transcription and expression of the HH target genes, PTCH1 and GLI1, by blocking SMO localization to cilia. Thus, inhibition of PI4KB followed by a reduction in phosphatidyl‐4‐phosphate levels could serve as an alternative approach to inhibit SMO function and HH signaling.[38]

Inhibition of the downstream effector GLI by arsenic trioxide and the antifungal drug itraconazole is also considered a weak HH pathway inhibitor. An open-label, exploratory phase II trial of oral itraconazole for the treatment of BCC by Kim et al. Found that itraconazole reduced cell proliferation by 45%, HH pathway activity by 65%, and tumor area by 24%. Another study reported the application of standard-dose or reduced dose of Vismodegib (150 mg, 1-2 times a week) in combination with itraconazole for 2 cases of recurrent facial BCC, both showing clinical remission after 16 months of follow-up.[39] Further, combination therapy may reduce the dose of HH pathway inhibitors and reduce adverse effects, which are still being explored.[40] A preliminary study of five patients with metastatic BCC treated with the combination of arsenic trioxide and itraconazole showed a reduction in GLI1 mRNA levels by 75% from baseline after 3 months of treatment. However, there was no significant reduction in tumor size.[41] In addition, Sohn et al. showed results from a trial of topical itraconazole for basal cell nevus syndrome that, at the maximum soluble concentration of 0.7%, itraconazole gel did not reduce GLI1 mRNA levels or the size of BCC tumors. Nevertheless, this trial did not rule out that other formulations of itraconazole at higher concentrations could be more effective. Therefore, the efficacy of topical itraconazole in BCC needs to be further investigated.[42]

Programmed cell death receptor 1 (PD-1) inhibitor    

Another potential target for the treatment of BCC is immunotherapy since skin immune cells have an anti-tumor effect, and PD-1 is an immune checkpoint receptor located on lymphocytes, which, when activated by PD-1 ligands, triggers downregulation of immune function, leading to a decrease in immune tolerance. Markers predicting the effectiveness of PD-1 inhibitor therapy include programmed death factor ligand-1 (PD-L1) amplification in tumor cells and high tumor mutational burden (TMB), both of which are met in BCC. BCC has one of the highest mutational burdens of any human malignancy. In general, tumors with a high mutational burden are more responsive to PD-1 blockade.[43] Cemiplimab is a monoclonal antibody drug against the PD-1 target monoclonal antibody drug.[44] In an open-label, multi-center, single-arm, phase 2 trial, 84 patients with a histologically confirmed diagnosis of locally advanced basal cell carcinoma (Intolerant to previous HHI therapy or having no better than stable disease after 9 months on HHI therapy) were treated with intravenous infusions of Cemiplimab 350 mg over 30 minutes every 3 weeks for up to 93 weeks or until progression or unacceptable toxicity. This study demonstrated the safety and effectiveness of Cemiplimab as systemic therapy for locally advanced BCC and is the first immunotherapy drug for patients with locally advanced BCC after HHI therapy or for whom HHIs are not appropriate.[45] The recommended dose of Cemiplimab is 350 mg intravenously over 30 minutes every 3 weeks. Other PD-1 inhibitors, such as pembrolizumab, showed an objective response rate of 38% after 18 weeks in a study of 16 patients with advanced BCC.[46]

mTOR signaling pathway inhibitor

The mammalian target of rapamycin (mTOR) is a serine/threonine-protein kinase closely associated with cell growth, metabolism, and aging. It acts through two signaling complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Studies have shown that the mTOR pathway is highly expressed in BCC.[47] HH signals crossed over mTOR via SOX9 and showed that the SOX9-mTOR axis is a target protein downstream of SMO that enhances tumor clearance in BCC patients.[48] Therefore, drugs targeting mTOR have a therapeutic effect on progressive BCC. For example, Everolimus (mTORC1 inhibitor), an immunosuppressive agent and a proliferation signal inhibitor, targets mTOR exhibits substantial anti-neoplastic activity, principally against BCCs. Oral daily dose of 1.5 - 3 mg for 12 weeks or longer induces partial to complete BCC regression.[49]

Topical therapy

Imiquimod

Imiquimod is a non-nucleoside heterocyclic amine drug, a small molecule immunomodulator that stimulates the body's immune system to recognize viral infections and tumors by inducing the body to produce cytokines such as IFN-α, TNF-α, and IL-12, ultimately eliminating the associated lesions.[50] Williams et al. conducted a randomized controlled study comparing standard surgical and imiquimod treatments. The absolute response rate for topical imiquimod was 83% at 5 years. Although clearly inferior to the 98% for excisional surgery, the cosmetic effect of imiquimod was outstanding compared to the surgical approach.[51] Karabulut et al. reported results from three patients treating large nodular BCC at the medial canthal area with 5% imiquimod cream, applied topically once daily, five times a week for 12 weeks, with no recurrence of the tumor at 3 years of follow-up after treatment.[52] Therefore, Imiquimod could serve as an alternative to surgical treatment in some specific sites.

5-fluorouracil

5-Fluorouracil (5-FU) is a pyrimidine analogue. The 5-FU metabolites get incorporated into DNA and RNA as faulty building blocks, thus inhibiting the activity of thymidylate synthase. These mechanisms lead to the inhibition of cell growth and apoptosis. Since these mechanisms are especially effective in tissues with high proliferation rates, there is a certain "bias" against malignant cells. The FDA has approved topical 5-FU for the treatment of superficial BCC and actinic keratoses. A study in 2013 assessing the effectiveness of photodynamic therapy compared with imiquimod or fluorouracil in patients with superficial BCC, showed that the treatment success rate of 72.8% for photodynamic, 80.1% for 5% fluorouracil, and 83.4% for imiquimod at 5 years.[53] In general, this trial demonstrated that from topical imiquimod could be a viable option for the treatment of superficial BCC.

Physical therapy

5-aminolevulinic acid photodynamic therapy

Photodynamic therapy uses visible light to activate photosensitizers 5-aminolevulinic acid or benzoporphyrin derivatives. These photosensitizers produce cytotoxic reactive oxygen species (ROS) through protoporphyrin IX, an intracellular reactive oxygen product, that gets activated by visible light after accumulation in the organelle cell membrane, leading to tumor cell damage and death. It also exerts its effects by indirectly destroying tumor blood vessels and triggering immune responses.[54],[55] Expert consensus on the clinical application of 5-aminolevulinic acid photodynamic therapy (ALA-PDT) as a clinical treatment for superficial basal cell carcinoma and nodular basal cell carcinoma that is not deeply invasive (< 2 mm). Zou et al. performed a meta-analysis comparing the efficacy and recurrence rates of PDT and surgery in 596 cases of nodular BCC, observing that PDT and surgery were comparable in terms of complete remission rates, however, an increased cumulative probability of recurrence was found for PDT compared to surgery.[56] Liu et al. divided 80 BCC into 2 groups, the control group underwent surgery alone while the observation group was treated with ALA-PDT combined with surgery.[57] The 1-year recurrence rate for the combined therapy group was 0 which also demonstrated a better long-term efficacy. In conclusion, ALA-PDT provides the advantage of specifically eliminating tumor cells while causing less damage to adjacent normal tissues, with equivalent efficacy to surgical therapy and better cosmetic results. However, combined therapy is recommended in clinical practice for improved treatment efficacy.[58]

Radiotherapy

Clinically, radiotherapy kills BCC tumors using superficial X-rays. Where surgical excision is not an option (medically/technically inoperable), radiotherapy offers an excellent alternative. Compared with surgical treatment, its advantages lie in killing tumor cells, preserving the shape and function of surrounding normal tissues without leaving scars, and having broad clinical application prospects. However, Radiotherapy may cause skin atrophy, capillary dilation, and depigmentation or pigmentation in the radiated field.[59] The 5-year cure rates according to a meta-analysis were 83% - 95% for radiation therapy.[60] Shan et al. treated 14 BCC patients with superficial X-rays, at a total dose of 45.6 - 53.2 Gy. The results showed that fourteen lesions in 14 patients disappeared, with no relapse after 2 years of follow-up. The main adverse effects were radiodermatitis and ulceration of the lesions, which disappeared within 1 month.[61] Superficial X-ray radiation therapy for BCC has a low recurrence rate, which is an ideal method for patients who are not suitable for surgical treatment. Furthermore, the efficacy of radiotherapy is linked to the extent of radiation and therefore the scope of radiotherapy should be strictly controlled. It is reported that small, low-risk BCC should be treated with a radiation field margin of 0.5 cm beyond the clinically apparent tumor, while high-risk BCC should be treated with wider margin of 1 to 1.5 cm.[62] Therefore, radiotherapy boundaries should be evaluated and paid attention to prevent side effects. For patients with advanced, aggressive facial BCC, radiation therapy may be given priority. Radiation therapy is contraindicated in Gorlin-Goltz syndrome since it induces secondary tumors. Different radiotherapy techniques have been developed to date, such as external beam radiotherapy and superficial brachytherapy. The choice between them has to consider many factors: tumor size, location, and infiltration depth.[63]

Electrochemotherapy

Electrochemotherapy (ECT) is a technique used to ablate malignant tumors by temporarily permeabilizing cells after exposing them to a brief pulsed electric field in combination with low doses of chemotherapeutics. The cell membrane gets temporarily destabilized by the local application of the electrical pulse leading to pore formation on the cell surface and allowing passive diffusion of drugs that are present locally to enter the cell. The National Institute for Health and Clinical Excellence in the United Kingdom deemed that ECT was a relatively safe treatment for primary BCC due to its simplicity of operation and less damage to surrounding normal tissues. A prospective randomized controlled trial was conducted by Clover et al. to compare the effectiveness of electrochemotherapy in combination with surgery for primary BCC.[64] After 60 days of treatment, all the lesions treated with ECT responded except for 8/69 (12%) who needed a second treatment to ensure a complete response. All patients who underwent surgical treatment showed complete histological clearance after primary excision, except two patients requiring a further wider excision. Five years after surgery, there were 5 recurrences in the ECT group and one recurrence in the surgery group. The overall complete response rate in the surgical group was 39/40 (97.5%). Another clinical trial evaluating the effectiveness of ECT in head and neck tumors, including BCC, showed that it was the best choice for small, primary, and early-stage tumors.[65] In conclusion, ECT can be an effective adjunct to surgical treatment of BCC, with reasonable durable response rates.

Combined therapy

Commonly used combination therapies include photodynamic combined with imiquimod, surgical combined with drug, radiation therapy or ALA-PDT.[66],[67] The laser immunotherapy (LIT), a combination of laser and immunotherapeutic agents, has recently been reported to have multiple potential advantages, including enabling topical delivery of immunological agents, as well as laser-based amplification of immunotherapeutic agents. Studies on LIT show direct anti-tumor effects as well as systemic adaptive immunity which is characterized by prevention of tumor recurrence and regression in distant untreated tumors. These findings imply that LIT can be used as adjuvant therapy for BCC patients who have failed to respond to single laser therapy or immunotherapy. Nevertheless, LIT remains an experimental strategy and further research in the field is warranted.[68] In addition, radiation combined with herbal medicine has also achieved progress. Zhang et al. showed that the Integrated Chinese and Western medicine, where they combined CO2 with Chinese herbal medicine to treat BCC, was superior to laser treatment alone.[69] External use of traditional Chinese medicine on laser wounds accelerates wound healing and reduce the proliferation of scarring since they are known to resolve decay and regenerat muscle, clears heat and detoxification and acts as anti-cancer agents. It enables to kill residual tumor cells, even improves the healing rate, and reduces the recurrence rate.[70]

Others

Include gene therapy: gene therapy aims to correct or compensate for genetic defects by introducing an exogenous gene with the corresponding function to a cell with a functional defect. The occurrence of BCC is associated with multiple mutations, including K-ras, H-ras, N-myc, nm-23, and C-erb2. Numerous experimental studies have been conducted on gene therapy for BCC, and further research progress is expected. In addition, there are many other treatments like nanopulse therapy, cryotherapy, EGFR inhibitor Cetuximab, VEGFR inhibitor pazopanib, PI3K inhibitor Buparlisib (BKM120), and so on.

Table 1. Summary of therapies of Cutaneous Basal Cell Carcinoma and their advantages and disadvantages
Table 1. Summary of therapies of Cutaneous Basal Cell Carcinoma and their advantages and disadvantages


CONCLUSION

The molecular basis of BCC is complex, including genetic susceptibility and multiple somatic mutations. Recent advances in sequencing technology have allowed us to better understand the mutated genes and implicated molecular pathways. The non-surgical treatments discussed in this article are also based on these insights gained over the past decade into the molecular pathogenesis of BCC. As our knowledge of the disease continues to improve, we look forward to more innovative treatments emerging.

 

FINANCIAL SUPPORT AND SPONSORSHIP

Nil.

CONFLICTS OF INTEREST

There are no conflicts of interest.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

Not applicable.


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Weixia Li1, Kunpeng Liu1, Dechen Lin2, Xin Xu2, Haizhen Lu3, Xinyu Bi4, Mingrong Wang2


Extracorporeal Photopheresis for Steroid‑refractory Chronic Graft‑versus‑host Disease After Allogeneic Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta‑Analysis

Runzhe Chen1, Baoan Chen1, Peter Dreger2, Michael Schmitt2, Anita Schmitt2


Glucans and Cancer: Historical Perspective

Petr Sima1, Luca Vannucci1, Vaclav Vetvicka2


Implications of Circadian Rhythm Regulation by microRNAs in Colorectal Cancer

Song Wu1, Andrew Fesler2, Jingfang Ju2


BCL2 Family, Mitochondrial Apoptosis, and Beyond

Haiming Dai1, X. Wei Meng2, Scott H. Kaufmann2


Quantum Dot‑based Immunohistochemistry for Pathological Applications

Li Zhou1, Jingzhe Yan2, Lingxia Tong3, Xuezhe Han4, Xuefeng Wu5, Peng Guo6


CD24 as a Molecular Marker in Ovarian Cancer: A Literature Review

Lu Huang1, Weiguo Lv2, Xiaofeng Zhao1


Etiological Trends in Oral Squamous Cell Carcinoma: A Retrospective Institutional Study

Varsha Salian, Chethana Dinakar, Pushparaja Shetty, Vidya Ajila


Effect of Irinotecan Combined with Cetuximab on Liver Function in Patients with Advanced Colorectal Cancer with Liver Metastases

Yan Liang1, Yang Li2, Xin Li3, Jianfu Zhao4


The Role of Precision Medicine in Pancreatic Cancer: Challenges for Targeted Therapy, Immune Modulating Treatment, Early Detection, and Less Invasive Operations

Khaled Kyle Wong1, Zhirong Qian2, Yi Le3


Targeting Signal Transducer and Activator of Transcription 3 for Colorectal Cancer Prevention and Treatment with Natural Products

Weidong Li1,2*, Cihui Chen3*, Zheng Liu2, Baojin Hua1


The Potential of Wnt Signaling Pathway in Cancer: A Focus on Breast Cancer

Mahnaz M. Kazi, Trupti I. Trivedi, Toral P. Kobawala, Nandita R. Ghosh


Imaging‑driven Digital Biomarkers

Enrico Capobianco


Target‑Matching Accuracy in Stereotactic Body Radiation Therapy of Lung Cancer: An Investigation Based on Four‑Dimensional Digital Human Phantom

Jing Cai1,2, Kate Turner2, Xiao Liang2, W. Paul Segars2,3, Chris R. Kelsey1, David Yoo1, Lei Ren1,2, Fang‑Fang Yin1,2


Downregulation of Death‑associated Protein Kinase 3 and Caspase‑3 Correlate to the Progression and Poor Prognosis of Gliomas

Ye Song, Tianshi Que, Hao Long, Xi’an Zhang, Luxiong Fang, Zhiyong Li, Songtao Qi


Hyaluronic Acid in Normal and Neoplastic Colorectal Tissue: Electrospray Ionization Mass Spectrometric and Fluor Metric Analysis

Ana Paula Cleto Marolla1, Jaques Waisberg2, Gabriela Tognini Saba2, Demétrius Eduardo Germini2, Maria Aparecida da Silva Pinhal1


Melanoma Antigen Gene Family in the Cancer Immunotherapy

Fengyu Zhu1, Yu Liang1, Demeng Chen2, Yang Li1


Combined Chronic Lymphocytic Leukemia and Pancreatic Neuroendocrine Carcinoma: A Collision Tumor Variation

Kaijun Huang1, Panagiotis J. Vlachostergios1, Wanhua Yang2, Rajeev L. Balmiki3


Antiproliferative and Apoptotic Effect of Pleurotus ostreatus on Human Mammary Carcinoma Cell Line (Michigan Cancer Foundation‑7)

Krishnamoorthy Deepalakshmi, Sankaran Mirunalini


Impact of Age on the Biochemical Failure and Androgen Suppression after Radical Prostatectomy for Prostate Cancer in Chilean Men

Nigel P. Murray1,2, Eduardo Reyes1,3, Nelson Orellana1, Cynthia Fuentealba1, Omar Jacob1


Carcinoma of Unknown Primary: 35 Years of a Single Institution’s Experience

Rana I. Mahmood1,2, Mohammed Aldehaim1,3, Fazal Hussain4, Tusneem A. Elhassan4,
Zubeir A. Khan5, Muhammad A. Memon6


Metformin in Ovarian Cancer Therapy: A Discussion

Yeling Ouyang1, Xi Chen2, Chunyun Zhang1, Vichitra Bunyamanop1, Jianfeng Guo3


The Progress in Molecular Biomarkers of Gliomas

Jing Qi1, Hongwei Yang2, Xin Wang2, Yanyang Tu1


Correlation between Paclitaxel Tc > 0.05 and its Therapeutic Efficacy and Severe Toxicities in Ovarian Cancer Patients

Shuyao Zhang1*, Muyin Sun2*, Yun Yuan3*, Miaojun Wang4*, Yuqi She1*, Li Zhou5, Congzhu Li5, Chen Chen1, Shengqi Zhang4


Identifying Gaps and Relative Opportunities for Discovering Membrane Proteomic Biomarkers of Triple‑negative Breast Cancer as a Translational Priority

Bhooma Venkatraman


The Molecular Mechanism and Regulatory Pathways of Cancer Stem Cells

Zhen Wang1, Hongwei Yang2, Xin Wang2, Liang Wang3, Yingduan Cheng4, Yongsheng Zhang5, Yanyang Tu1,2


Nanoparticle Drug Delivery Systems and Three‑dimensional Cell Cultures in Cancer Treatments and Research

Wenjin Shi1, Ding Weng2,3, Wanting Niu2,3


Choline Kinase Inhibitors Synergize with TRAIL in the Treatment of Colorectal Tumors and Overcomes TRAIL Resistance

Juan Carlos Lacal1, Ladislav Andera2


MicroRNA Regulating Metabolic Reprogramming in Tumor Cells: New Tumor Markers

Daniel Otero‑Albiol, Blanca Felipe‑Abrio


Biomarkers of Colorectal Cancer: A Genome‑wide Perspective

José M. Santos‑Pereira1, Sandra Muñoz‑Galván2


Nicotinamide Adenine Dinucleotide+ Metabolism Biomarkers in Malignant Gliomas

Manuel P. Jiménez‑García, Eva M. Verdugo‑Sivianes, Antonio Lucena‑Cacace


Patient-derived Xenografts as Models for Personalized Medicine Research in Cancer

Marco Perez, Lola Navas, Amancio Carnero


Genome‑wide Transcriptome Analysis of Prostate Cancer Tissue Identified Overexpression of Specific Members of the Human Endogenous Retrovirus‑K Family

Behnam Sayanjali1,2


Clinical Utility of Interleukin‑18 in Breast Cancer Patients: A Pilot Study

Reecha A. Parikh, Toral P. Kobawala, Trupti I. Trivedi, Mahnaz M. Kazi, Nandita R. Ghosh


Current and Future Systemic Treatment Options for Advanced Soft‑tissue Sarcoma beyond Anthracyclines and Ifosfamide

Nadia Hindi1,2, Javier Martin‑Broto1,2


The Genomic Organization and Function of IRX1 in Tumorigenesis and Development

Pengxing Zhang1, Hongwei Yang2, Xin Wang2, Liang Wang3, Yingduan Cheng4, Yongsheng Zhang5, Yanyang Tu1,2


Stem Cell‑based Approach in Diabetes and Pancreatic Cancer Management

Yi‑Zhou Jiang1, Demeng Chen2


Mutation Detection with a Liquid Biopsy 96 Mutation Assay in Cancer Patients and Healthy Donors

Aaron Yun Chen, Glenn D. Braunstein, Megan S. Anselmo, Jair A. Jaboni, Fernando Troy Viloria, Julie A. Neidich, Xiang Li, Anja Kammesheidt


The Application of Estrogen Receptor‑1 Mutations’ Detection through Circulating Tumor DNA in Breast Cancer

Binliang Liu, Yalan Yang, Zongbi Yi, Xiuwen Guan, Fei Ma


Circulating MicroRNAs and Long Noncoding RNAs: Liquid Biomarkers in Thoracic Cancers

Pablo Reclusa1, Anna Valentino1, Rafael Sirera1,2, Martin Frederik Dietrich3, Luis Estuardo Raez3, Christian Rolfo1


Exosomes Biology: Function and Clinical Implications in Lung Cancer

Martin Frederik Dietrich1, Christian Rolfo2, Pablo Reclusa2, Marco Giallombardo2, Anna Valentino2, Luis E. Raez1


Circulating Tumor DNA: A Potential Biomarker from Solid Tumors’ Monitor to Anticancer Therapies

Ting Chen1,2, Rongzhang He1,3, Xinglin Hu1,3,4, Weihao Luo1, Zheng Hu1,3, Jia Li1, Lili Duan1, Yali Xie1,2, Wenna Luo1,2, Tan Tan1,2, Di‑Xian Luo1,2


Novel Molecular Multilevel Targeted Antitumor Agents

Poonam Sonawane1, Young A. Choi1, Hetal Pandya2, Denise M. Herpai1, Izabela Fokt3,
Waldemar Priebe3, Waldemar Debinski1


Fish Oil and Prostate Cancer: Effects and Clinical Relevance

Pei Liang, Michael Gao Jr.


Stemness‑related Markers in Cancer

Wenxiu Zhao1, Yvonne Li2, Xun Zhang1


Autophagy Regulated by miRNAs in Colorectal Cancer Progression and Resistance

Andrew Fesler1, Hua Liu1, Ning Wu1,2, Fei Liu3, Peixue Ling3, Jingfang Ju1,3


Gastric Metastases Mimicking Primary Gastric Cancer: A Brief Literature Review

Simona Gurzu1,2,3, Marius Alexandru Beleaua1, Laura Banias2, Ioan Jung1


Possibility of Specific Expression of the Protein Toxins at the Tumor Site with Tumor‑specialized Promoter

Liyuan Zhou1,2, Yujun Li1,2, Changchen Hu3, Binquan Wang1,2


SKI‑178: A Multitargeted Inhibitor of Sphingosine Kinase and Microtubule Dynamics Demonstrating Therapeutic Efficacy in Acute Myeloid Leukemia Models

Jeremy A. Hengst1,2, Taryn E. Dick1,2, Arati Sharma1, Kenichiro Doi3, Shailaja Hegde4, Su‑Fern Tan5, Laura M. Geffert1,2, Todd E. Fox5, Arun K. Sharma1, Dhimant Desai1, Shantu Amin1, Mark Kester5, Thomas P. Loughran5, Robert F. Paulson4, David F. Claxton6, Hong‑Gang Wang3, Jong K. Yun1,2


A T‑cell Engager‑armed Oncolytic Vaccinia Virus to Target the Tumor Stroma

Feng Yu1, Bangxing Hong1, Xiao‑Tong Song1,2,3


Real‑world Experience with Abiraterone in Metastatic Castration‑resistant Prostate Cancer

Yasar Ahmed1, Nemer Osman1, Rizwan Sheikh2, Sarah Picardo1, Geoffrey Watson1


Combination of Interleukin‑11Rα Chimeric Antigen Receptor T‑cells and Programmed Death‑1 Blockade as an Approach to Targeting Osteosarcoma Cells In vitro

Hatel Rana Moonat, Gangxiong Huang, Pooja Dhupkar, Keri Schadler, Nancy Gordon,
Eugenie Kleinerman


Efficacy and Safety of Paclitaxel‑based Therapy and Nonpaclitaxel‑based Therapy in Advanced Gastric Cancer

Tongwei Wu, Xiao Yang, Min An, Wenqin Luo, Danxian Cai, Xiaolong Qi


Motion Estimation of the Liver Based on Deformable Image Registration: A Comparison Between Four‑Dimensional‑Computed Tomography and Four‑Dimensional-Magnetic Resonance Imaging

Xiao Liang1, Fang‑Fang Yin1,2, Yilin Liu1, Brian Czito2, Manisha Palta2, Mustafa Bashir3, Jing Cai1,2


A Feasibility Study of Applying Thermal Imaging to Assist Quality Assurance of High‑Dose Rate Brachytherapy

Xiaofeng Zhu1, Yu Lei1, Dandan Zheng1, Sicong Li1, Vivek Verma1, Mutian Zhang1, Qinghui Zhang1, Xiaoli Tang2, Jun Lian2, Sha X. Chang2, Haijun Song3, Sumin Zhou1, Charles A. Enke1


Role of Exosome microRNA in Breast Cancer

Wang Qu, Ma Fei, Binghe Xu


Recent Progress in Technological Improvement and Biomedical Applications of the Clustered Regularly Interspaced Short Palindromic Repeats/Cas System

Yanlan Li1,2*, Zheng Hu1*, Yufang Yin3, Rongzhang He1, Jian Hu1, Weihao Luo1, Jia Li1, Gebo Wen2, Li Xiao1, Kai Li1, Duanfang Liao4, Di-Xian Luo1,5


The Significance of Nuclear Factor‑Kappa B Signaling Pathway in Glioma: A Review

Xiaoshan Xu1, Hongwei Yang2, Xin Wang2, Yanyang Tu1


Markerless Four‑Dimensional‑Cone Beam Computed Tomography Projection‑Phase Sorting Using Prior Knowledge and Patient Motion Modeling: A Feasibility Study

Lei Zhang1,2, Yawei Zhang2, You Zhang1,2,3, Wendy B. Harris1,2, Fang‑Fang Yin1,2,4, Jing Cai1,4,5, Lei Ren1,2


The Producing Capabilities of Interferon‑g and Interleukin‑10 of Spleen Cells in Primary and Metastasized Oral Squamous Cell Carcinoma Cells-implanted Mice

Yasuka Azuma1,2, Masako Mizuno‑Kamiya3, Eiji Takayama1, Harumi Kawaki1, Toshihiro Inagaki4, Eiichi Chihara2, Yasunori Muramatsu5, Nobuo Kondoh1


“Eating” Cancer Cells by Blocking CD47 Signaling: Cancer Therapy by Targeting the Innate Immune Checkpoint

Yi‑Rong Xiang, Li Liu


Glycosylation is Involved in Malignant Properties of Cancer Cells

Kazunori Hamamura1, Koichi Furukawa2


Biomarkers in Molecular Epidemiology Study of Oral Squamous Cell Carcinoma in the Era of Precision Medicine

Qing‑Hao Zhu1*, Qing‑Chao Shang1*, Zhi‑Hao Hu1*, Yuan Liu2, Bo Li1, Bo Wang1, An‑Hui Wang1


I‑Kappa‑B Kinase‑epsilon Activates Nuclear Factor‑kappa B and STAT5B and Supports Glioblastoma Growth but Amlexanox Shows Little Therapeutic Potential in These Tumors

Nadège Dubois1, Sharon Berendsen2, Aurélie Henry1,2, Minh Nguyen1, Vincent Bours1,
Pierre Alain Robe1,2


Suppressive Effect of Mesenchymal Stromal Cells on Interferon‑g‑Producing Capability of Spleen Cells was Specifically Enhanced through Humoral Mediator(s) from Mouse Oral Squamous Cell Carcinoma Sq‑1979 Cells In Vitro

Toshihiro Inagaki1,2, Masako Mizuno‑Kamiya3, Eiji Takayama1, Harumi Kawaki1, Eiichi Chihara4, Yasunori Muramatsu5, Shinichiro Sumitomo5, Nobuo Kondoh1


An Interplay Between MicroRNA and SOX4 in the Regulation of Epithelial–Mesenchymal Transition and Cancer Progression

Anjali Geethadevi1, Ansul Sharma2, Manish Kumar Sharma3, Deepak Parashar1


MicroRNAs Differentially Expressed in Prostate Cancer of African‑American and European‑American Men

Ernest K. Amankwah


The Role of Reactive Oxygen Species in Screening Anticancer Agents

Xiaohui Xu1, Zilong Dang2, Taoli Sun3, Shengping Zhang1, Hongyan Zhang1


Panobinostat and Its Combination with 3‑Deazaneplanocin‑A Induce Apoptosis and Inhibit In vitro Tumorigenesis and Metastasis in GOS‑3 Glioblastoma Cell Lines

Javier de la Rosa*, Alejandro Urdiciain*, Juan Jesús Aznar‑Morales, Bárbara Meléndez1,
Juan A. Rey2, Miguel A. Idoate3, Javier S. Castresana


Cancer Stem‑Like Cells Have Cisplatin Resistance and miR‑93 Regulate p21 Expression in Breast Cancer

Akiko Sasaki1, Yuko Tsunoda2, Kanji Furuya3, Hideto Oyamada1, Mayumi Tsuji1, Yuko Udaka1, Masahiro Hosonuma1, Haruna Shirako1, Nana Ichimura1, Yuji Kiuchi1


The Contribution of Hexokinase 2 in Glioma

Hui Liu1, Hongwei Yang2, Xin Wang3, Yanyang Tu1


The Mechanism of BMI1 in Regulating Cancer Stemness Maintenance, Metastasis, Chemo‑ and Radiation Resistance

Xiaoshan Xu, Zhen Wang, Nan Liu, Pengxing Zhang, Hui Liu, Jing Qi, Yanyang Tu


A Multisource Adaptive Magnetic Resonance Image Fusion Technique for Versatile Contrast Magnetic Resonance Imaging

Lei Zhang1,2, Fang‑Fang Yin1,2,3, Brittany Moore1,2, Silu Han1,2, Jing Cai1,2,4


Senescence and Cancer

Sulin Zeng1,2, Wen H. Shen2, Li Liu1


The “Wild”‑type Gastrointestinal Stromal Tumors: Heterogeneity on Molecule Characteristics and Clinical Features

Yanhua Mou1, Quan Wang1, Bin Li1,2


Retreatment with Cabazitaxel in a Long‑Surviving Patient with Castration‑Resistant Prostate Cancer and Visceral Metastasis

Raquel Luque Caro, Carmen Sánchez Toro, Lucia Ochoa Vallejo


Therapy‑Induced Histopathological Changes in Breast Cancers: The Changing Role of Pathology in Breast Cancer Diagnosis and Treatment

Shazima Sheereen1, Flora D. Lobo1, Waseemoddin Patel2, Shamama Sheereen3,
Abhishek Singh Nayyar4, Mubeen Khan5


Glioma Research in the Era of Medical Big Data

Feiyifan Wang1, Christopher J. Pirozzi2, Xuejun Li1


Transarterial Embolization for Hepatocellular Adenomas: Case Report and Literature Review

Jian‑Hong Zhong1,2, Kang Chen1, Bhavesh K. Ahir3, Qi Huang4, Ye Wu4, Cheng‑Cheng Liao1, Rong‑Rong Jia1, Bang‑De Xiang1,2, Le‑Qun Li1,2


Nicotinamide Phosphoribosyltransferase: Biology, Role in Cancer, and Novel Drug Target

Antonio Lucena‑Cacace1,2,3, Amancio Carnero1,2


Enhanced Anticancer Effect by Combination of Proteoglucan and Vitamin K3 on Bladder Cancer Cells

Michael Zhang, Kelvin Zheng, Muhammad Choudhury, John Phillips, Sensuke Konno


Molecular Insights Turning Game for Management of Ependymoma: A Review of Literature

Ajay Sasidharan, Rahul Krishnatry


IDH Gene Mutation in Glioma

Leping Liu1, Xuejun Li1,2


Challenges and Advances in the Management of Pediatric Intracranial Germ Cell Tumors: A Case Report and Literature Review

Gerard Cathal Millen1, Karen A. Manias1,2, Andrew C. Peet1,2, Jenny K. Adamski1


Assessing the Feasibility of Using Deformable Registration for Onboard Multimodality‑Based Target Localization in Radiation Therapy

Ge Ren1,2,3, Yawei Zhang1,2, Lei Ren1,2


Research Advancement in the Tumor Biomarker of Hepatocellular Carcinoma

Qing Du1, Xiaoying Ji2, Guangjing Yin3, Dengxian Wei3, Pengcheng Lin1, Yongchang Lu1,
Yugui Li3, Qiaohong Yang4, Shizhu Liu5, Jinliang Ku5, Wenbin Guan6, Yuanzhi Lu7


Novel Insights into the Role of Bacterial Gut Microbiota in Hepatocellular Carcinoma

Lei Zhang1, Guoyu Qiu2, Xiaohui Xu2, Yufeng Zhou3, Ruiming Chang4


Central Odontogenic Fibroma with Unusual Presenting Symptoms

Aanchal Tandon, Bharadwaj Bordoloi, Safia Siddiqui, Rohit Jaiswal


The Prognostic Role of Lactate in Patients Who Achieved Return of Spontaneous Circulation after Cardiac Arrest: A Systematic Review and Meta‑analysis

Dongni Ren1, Xin Wang2, Yanyang Tu1,2


Inhibitory Effect of Hyaluronidase‑4 in a Rat Spinal Cord Hemisection Model

Xipeng Wang1,2, Mitsuteru Yokoyama2, Ping Liu3


Research and Development of Anticancer Agents under the Guidance of Biomarkers

Xiaohui Xu1, Guoyu Qiu1, Lupeng Ji2, Ruiping Ma3, Zilong Dang4, Ruling Jia1, Bo Zhao1


Idiopathic Hypereosinophilic Syndrome and Disseminated Intravascular Coagulation

Mansoor C. Abdulla


Phosphorylation of BRCA1‑Associated Protein 1 as an Important Mechanism in the Evasion of Tumorigenesis: A Perspective

Guru Prasad Sharma1, Anjali Geethadevi2, Jyotsna Mishra3, G. Anupa4, Kapilesh Jadhav5,
K. S. Vikramdeo6, Deepak Parashar2


Progress in Diagnosis and Treatment of Mixed Adenoneuroendocrine Carcinoma of Biliary‑Pancreatic System

Ge Zengzheng1, Huang-Sheng Ling2, Ming-Feng Li2, Xu Xiaoyan1, Yao Kai1, Xu Tongzhen3,
Ge Zengyu4, Li Zhou5


Surface-Enhanced Raman Spectroscopy to Study the Biological Activity of Anticancer Agent

Guoyu Qiu1, Xiaohui Xu1, Lupeng Ji2, Ruiping Ma3, Zilong Dang4, Huan Yang5


Alzheimer’s Disease Susceptibility Genes in Malignant Breast Tumors

Steven Lehrer1, Peter H. Rheinstein2


OSMCC: An Online Survival Analysis Tool for Merkel Cell Carcinoma

Umair Ali Khan Saddozai1, Qiang Wang1, Xiaoxiao Sun1, Yifang Dang1, JiaJia Lv1,2, Junfang Xin1, Wan Zhu3, Yongqiang Li1, Xinying Ji1, Xiangqian Guo1


Protective Activity of Selenium against 5‑Fluorouracil‑Induced Nephrotoxicity in Rats

Elias Adikwu, Nelson Clemente Ebinyo, Beauty Tokoni Amgbare


Advances on the Components of Fibrinolytic System in Malignant Tumors

Zengzheng Ge1, Xiaoyan Xu1, Zengyu Ge2, Shaopeng Zhou3, Xiulin Li1, Kai Yao1, Lan Deng4


A Patient with Persistent Foot Swelling after Ankle Sprain: B‑Cell Lymphoblastic Lymphoma Mimicking Soft‑tissue Sarcoma

Crystal R. Montgomery‑Goecker1, Andrew A. Martin2, Charles F. Timmons3, Dinesh Rakheja3, Veena Rajaram3, Hung S. Luu3


Coenzyme Q10 and Resveratrol Abrogate Paclitaxel‑Induced Hepatotoxicity in Rats

Elias Adikwu, Nelson Clemente Ebinyo, Loritta Wasini Harris


Progress in Clinical Follow‑up Study of Dendritic Cells Combined with Cytokine‑Induced Killer for Stomach Cancer

Ling Wang1,2, Run Wan1,2, Cong Chen1,2, Ruiliang Su1,2, Yumin Li1,2


Supraclavicular Lymphadenopathy as the Initial Manifestation in Carcinoma of Cervix

Priyanka Priyaarshini1, Tapan Kumar Sahoo2


ABO Typing Error Resolution and Transfusion Support in a Case of an Acute Leukemia Patient Showing Loss of Antigen Expression

Debasish Mishra1, Gopal Krushna Ray1, Smita Mahapatra2, Pankaj Parida2


Protein Disulfide Isomerase A3: A Potential Regulatory Factor of Colon Epithelial Cells

Yang Li1, Zhenfan Huang2, Haiping Jiang3


Clinicopathological Association of p16 and its Impact on Outcome of Chemoradiation in Head‑and‑Neck Squamous Cell Cancer Patients in North‑East India

Srigopal Mohanty1, Yumkhaibam Sobita Devi2, Nithin Raj Daniel3, Dulasi Raman Ponna4,
Ph. Madhubala Devi5, Laishram Jaichand Singh2


Potential Inhibitor for 2019‑Novel Coronaviruses in Drug Development

Xiaohui Xu1, Zilong Dang2, Lei Zhang3, Lingxue Zhuang4, Wutang Jing5, Lupeng Ji6, Guoyu Qiu1


Best‑Match Blood Transfusion in Pediatric Patients with Mixed Autoantibodies

Debasish Mishra1, Dibyajyoti Sahoo1, Smita Mahapatra2, Ashutosh Panigrahi3


Characteristics and Outcome of Patients with Pheochromocytoma

Nadeema Rafiq1, Tauseef Nabi2, Sajad Ahmad Dar3, Shahnawaz Rasool4


Comparison of Histopathological Grading and Staging of Breast Cancer with p53‑Positive and Transforming Growth Factor‑Beta Receptor 2‑Negative Immunohistochemical Marker Expression Cases

Palash Kumar Mandal1, Anindya Adhikari2, Subir Biswas3, Amita Giri4, Arnab Gupta5,
Arindam Bhattacharya6


Chemical Compositions and Antiproliferative Effect of Essential Oil of Asafoetida on MCF7 Human Breast Cancer Cell Line and Female Wistar Rats

Seyyed Majid Bagheri1,2, Davood Javidmehr3, Mohammad Ghaffari1, Ehsan Ghoderti‑Shatori4


Cyclooxygenase‑2 Contributes to Mutant Epidermal Growth Factor Receptor Lung Tumorigenesis by Promoting an Immunosuppressive Environment

Mun Kyoung Kim1, Aidin Iravani2, Matthew K. Topham2,3


Potential role of CircMET as A Novel Diagnostic Biomarker of Papillary Thyroid Cancer

Yan Liu1,2,3,4#, Chen Cui1,2,3,4#, Jidong Liu1,2,3,4, Peng Lin1,2,3,4,Kai Liang1,2,3,4, Peng Su5, Xinguo Hou1,2,3,4, Chuan Wang1,2,3,4, Jinbo Liu1,2,3,4, Bo Chen6, Hong Lai1,2,3,4, Yujing Sun1,2,3,4* and Li Chen 1,2,3,4*


Cuproptosis-related Genes in Glioblastoma as Potential Therapeutic Targets

Zhiyu Xia1,2, Haotian Tian1, Lei Shu1,2, Guozhang Tang3, Zhenyu Han4, Yangchun Hu1*, Xingliang Dai1*


Cancer Diagnosis and Treatments by Porous Inorganic Nanocarriers

Jianfeng Xu1,2, Hanwen Zhang1,2, Xiaohui Song1,2, Yangong Zheng3, Qingning Li1,2,4*


Delayed (20 Years) post-surgical Esophageal Metastasis of Breast Cancer - A Case Report

Bowen Hu1#, Lingyu Du2#, Hongya Xie1, Jun Ma1, Yong Yang1*, Jie Tan2*


Subtyping of Undifferentiated Pleomorphic Sarcoma and Its Clinical Meaning

Umair Ali Khan Saddozai, Zhendong Lu, Fengling Wang, Muhammad Usman Akbar, Saadullah Khattak, Muhammad Badar, Nazeer Hussain Khan, Longxiang Xie, Yongqiang Li, Xinying Ji, Xiangqian Guo


Construction of Glioma Prognosis Model and Exploration of Related Regulatory Mechanism of Model Gene

Suxia Hu, Abdusemer Reyimu, Wubi Zhou, Xiang Wang, Ying Zheng, Xia Chen, Weiqiang Li, Jingjing Dai


ESRP2 as a Non-independent Potential Biomarker-Current Progress in Tumors

Yuting Chen, Yuzhen Rao, Zhiyu Zeng, Jiajie Luo, Chengkuan Zhao, Shuyao Zhang


Resection of Bladder Tumors at the Ureteral Orifice Using a Hook Plasma Electrode: A Case Report

Jun Li, Ziyong Wang, Qilin Wang


Structural Characterization and Bioactivity for Lycium Barbarum Polysaccharides

Jinghua Qi1,2,  Hangping Chen3,Huaqing Lin2,4,Hongyuan Chen1,2,5* and Wen Rui2,3,5,6*


The Role of IL-22 in the Prevention of Inflammatory Bowel Disease and Liver Injury

Xingli Qi1,2, Huaqing Lin2,3, Wen Rui2,3,4,5 and Hongyuan Chen1,2,3


RBM15 and YTHDF3 as Positive Prognostic Predictors in ESCC: A Bioinformatic Analysis Based on The Cancer Genome Atlas (TCGA)

Yulou Luo1, Lan Chen2, Ximing Qu3, Na Yi3, Jihua Ran4, Yan Chen3,5*


Mining and Analysis of Adverse Drug Reaction Signals Induced by Anaplastic Lymphoma Kinase-Tyrosine Kinase Inhibitors Based on the FAERS Database

Xiumin Zhang1,2#, Xinyue Lin1,3#, Siman Su1,3#, Wei He3, Yuying Huang4, Chengkuan Zhao3, Xiaoshan Chen3, Jialin Zhong3, Chong Liu3, Wang Chen3, Chengcheng Xu3, Ping Yang5, Man Zhang5, Yanli Lei5*, Shuyao Zhang1,3*


Advancements in Immunotherapy for Advanced Gastric Cancer

Min Jiang1#, Rui Zheng1#, Ling Shao1, Ning Yao2, Zhengmao Lu1*


Tumor Regression after COVID-19 Infection in Metastatic Adrenocortical Carcinoma Treated with Immune Checkpoint Blockade: A Case Report

Qiaoxin Lin1, Bin Liang1, Yangyang Li2, Ling Tian3*, Dianna Gu1*


Mining and Analysis of Adverse Events of BRAF Inhibitors Based on FDA Reporting System

Silan Peng1,2#, Danling Zheng1,3#, Yanli Lei4#, Wang Chen3, Chengkuan Zhao3, Xinyue Lin1, Xiaoshan Chen3, Wei He3, Li Li3, Qiuzhen Zhang5*, Shuyao Zhang1,3*


Malignant Phyllodes Tumor with Fever, Anemia, Hypoproteinemia: A Rare and Strange Case Report and Literature Review

Zhenghang Li1, Yuxian Wei1*


Construction of Cuproptosis-Related LncRNA Signature as a Prognostic Model Associated with Immune Microenvironment for Clear-Cell Renal Cell Carcinoma

Jiyao Yu1#, Shukai Zhang2#, Qingwen Ran3, Xuemei Li4,5,6*


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