Usefulness of Photodynamic Therapy as a Possible Therapeutic Alternative in the Treatment of Basal Cell Carcinoma

Basal cell carcinoma (BCC) is the most common cancer in individuals with fair skin type (I–II) and steadily increasing in incidence (70% of skin malignancy). It is locally invasive but metastasis is usually very rare, with an estimated incidence of 0.0028%–0.55%. Conventional therapy is surgery, especially for the H region of the face and infiltrative lesions; in case of inoperable tumors, radiotherapy is a valid option. Recently, topical photodynamic therapy (PDT) has become an effective treatment in the management of superficial and small nodular BCC. PDT is a minimally invasive procedure that involves the administration of a photo-sensibilizing agent followed by irradiation at a pre-defined wavelength; this determines the creation of reactive oxygen species that specifically destroy target cells. The only major side effect is pain, reported by some patients during the irradiation. The high cure rate and excellent cosmetic outcome requires considering this possibility for the management of patients with both sporadic and hereditary BCC. In this article, an extensive review of the recent literature was made, in order to clarify the role of PDT as a possible alternative therapeutic option in the treatment of BCC.     

Increased Expression of Flightless I in Cutaneous Squamous Cell Carcinoma Affects Wnt/β-Catenin Signaling Pathway

Cutaneous squamous cell carcinoma (cSCC) accounts for 25% of cutaneous malignancies diagnosed in Caucasian populations. Surgical removal in combination with radiation and chemotherapy are effective treatments for cSCC. Nevertheless, the aggressive metastatic forms of cSCC still have a relatively poor patient outcome. Studies have linked actin cytoskeletal dynamics and the Wnt/β-catenin signaling pathway as important modulators of cSCC pathogenesis. Previous studies have also shown that the actin-remodeling protein Flightless (Flii) is a negative regulator of cSCC. The aim of this study was to investigate if the functional effects of Flii on cSCC involve the Wnt/β-catenin signaling pathway. Flii knockdown was performed using siRNA in a human late stage aggressive metastatic cSCC cell line (MET-1) alongside analysis of Flii genetic murine models of 3-methylcholanthrene induced cSCC. Flii was increased in a MET-1 cSCC cell line and reducing Flii expression led to fewer PCNA positive cells and a concomitant reduction in cellular proliferation and symmetrical division. Knockdown of Flii led to decreased β-catenin and a decrease in the expression of the downstream effector of β-catenin signaling protein SOX9. 3-Methylcholanthrene (MCA)-induced cSCC in Flii overexpressing mice showed increased markers of cancer metastasis including talin and keratin-14 and a significant increase in SOX9 alongside a reduction in Flii associated protein (Flap-1). Taken together, this study demonstrates a role for Flii in regulating proteins involved in cSCC proliferation and tumor progression and suggests a potential role for Flii in aggressive metastatic cSCC.     

Neutrophil Gelatinase-Associated Lipocalin as Potential Predictive Biomarker of Melanoma and Non-Melanoma Skin Cancers in Psoriatic Patients: A Pilot Study

Background: Studies have demonstrated a higher risk of nonmelanoma skin cancers (NMSC) and a modestly increased melanoma risk in patients with psoriasis. To date, no biomarkers predictive of evolution have been identified yet. Methods: The aim of this prospective case-control study was to investigate the potential role of neutrophil gelatinase-associated lipocalin (NGAL) as a predictive biomarker of skin cancers in psoriatic patients. Patients with a diagnosis of psoriasis were enrolled, as well as healthy subjects and patients with skin cancers as controls. Plasma protein expression of NGAL, metalloproteinases (MMP)-2, and MMP-9 was performed by an enzyme-linked immunosorbent assay (ELISA). In all the patients who developed skin cancer at follow-up, NGAL, MMP-2, and MMP-9 serum levels were dosed again. Results: Plasma NGAL levels were significantly higher in psoriatic patients with NMSC than without (182.3 ± 36.6 ng/mL vs. 139.9 ± 39.3 ng/mL) (p < 0.001). Plasma NGAL levels were significantly higher (p < 0.00001) in patients with psoriasis and NMSC than in patients with skin tumors without psoriasis (182.3 vs. 122.9). Patients with psoriasis who developed NMSC at follow-up showed increased plasma MMP-9 levels. Conclusion: NGAL seems to play a role in the pathogenesis of NMSC but not melanoma in patients with psoriasis.     

Immunotherapy for the Treatment of Squamous Cell Carcinoma: Potential Benefits and Challenges

Melanoma and nonmelanoma skin cancers (NMSCs) are recognized as among the most common neoplasms, mostly in white people, with an increasing incidence rate. Among the NMSCs, squamous cell carcinoma (SCC) is the most prevalent malignancy known to affect people with a fair complexion who are exposed to extreme ultraviolet radiation (UVR), have a hereditary predisposition, or are immunosuppressed. There are several extrinsic and intrinsic determinants that contribute to the pathophysiology of the SCC. The therapeutic modalities depend on the SCC stages, from actinic keratosis to late-stage multiple metastases. Standard treatments include surgical excision, radiotherapy, and chemotherapy. As SCC represents a favorable tumor microenvironment with high tumor mutational burden, infiltration of immune cells, and expression of immune checkpoints, the SCC tumors are highly responsive to immunotherapies. Until now, there are three checkpoint inhibitors, cemiplimab, pembrolizumab, and nivolumab, that are approved for the treatment of advanced, recurrent, or metastatic SCC patients in the United States. Immunotherapy possesses significant therapeutic benefits for patients with metastatic or locally advanced tumors not eligible for surgery or radiotherapy to avoid the potential toxicity caused by the chemotherapies. Despite the high tolerability and efficiency, the existence of some challenges has been revealed such as, resistance to immunotherapy, less availability of the biomarkers, and difficulty in appropriate patient selection. This review aims to accumulate evidence regarding the genetic alterations related to SCC, the factors that contribute to the potential benefits of immunotherapy, and the challenges to follow this treatment regime.     

Spreading of Isolated Ptch Mutant Basal Cell Carcinoma Precursors Is Physiologically Suppressed and Counteracts Tumor Formation in Mice

Basal cell carcinoma (BCC) originate from Hedgehog/Patched signaling-activated epidermal stem cells. However, the chemically induced tumorigenesis of mice with a CD4Cre-mediated biallelic loss of the Hedgehog signaling repressor Patched also induces BCC formation. Here, we identified the cellular origin of CD4Cre-targeted BCC progenitors as rare Keratin 5⁺ epidermal cells and show that wildtype Patched offspring of these cells spread over the hair follicle/skin complex with increasing mouse age. Intriguingly, Patched mutant counterparts are undetectable in age-matched untreated skin but are getting traceable upon applying the chemical tumorigenesis protocol. Together, our data show that biallelic Patched depletion in rare Keratin 5⁺ epidermal cells is not sufficient to drive BCC development, because the spread of these cells is physiologically suppressed. However, bypassing the repression of Patched mutant cells, e.g., by exogenous stimuli, leads to an accumulation of BCC precursor cells and, finally, to tumor development.     

Treatment Strategies and Metabolic Pathway Regulation in Urothelial Cell Carcinoma: A Comprehensive Review

For a long time, cisplatin-based chemotherapy had been viewed as first-line chemotherapy for advanced and metastatic urothelial carcinoma (UC). However, many patients with UC had been classified as cisplatin-ineligible who can only receive alternative chemotherapy with poor treatment response, and the vast majority of the cisplatin-eligible patients eventually progressed, even those with objective response with cisplatin-based chemotherapy initially. By understanding tumor immunology in UC, immune checkpoint inhibitors, targeting on programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) pathways, had been proven as first-line treatment for cisplatin-ineligible metastatic UC and as second-line treatment for patients with platinum-refractory metastatic UC by the U.S Food and Drug Administration (FDA). In 2020, JAVEIN bladder 100 further reported that PD-L1 inhibitors showed benefits on prolonged survival and progression-free survival as maintenance therapy. Besides targeting on immune checkpoint, manipulation of the tumor microenvironment by metabolic pathways intervention, including inhibition on tumor glycolysis, lactate accumulation and exogenous glutamine uptake, had been investigated in the past few years. In this comprehensive review, we start by introducing traditional chemotherapy of UC, and then we summarize current evidences supporting the use of immune checkpoint inhibitors and highlight ongoing clinical trials. Lastly, we reviewed the tumor metabolic characteristic and the anti-tumor treatments targeting on metabolic pathways.     

A γ-Secretase Inhibitor Attenuates Cell Cycle Progression and Invasion in Human Oral Squamous Cell Carcinoma: An In Vitro Study

Notch signaling is associated with many human malignancies, including oral squamous cell carcinoma (OSCC). However, the exact function of Notch signaling in OSCC remains unclear. Here, we investigated the effect of Notch signaling inhibition using a γ-secretase inhibitor (DAPT) on OSCC behaviours in vitro. Bioinformatic analysis of public-available gene expression profiles revealed the dysregulation of the Notch signaling pathway in OSCC compared with normal tissues, indicating the role of Notch signaling in OSCC regulation. RNA sequencing analysis of DAPT-treated human OSCC cells revealed the dysregulation of genes related to cell cycle-related pathways. Blocking Notch signaling significantly inhibited cell proliferation. DAPT-induced G0/G1 cell cycle arrest induced cell apoptosis. Furthermore, cell migration and invasion were also reduced in DAPT-treated cells. These findings indicate that Notch signaling activation participates in OSCC regulation by promoting cell growth, cell cycle progression, cell migration, and invasion. These mechanisms could facilitate OSCC progression. These results imply the potential use of Notch signaling inhibitors as a candidate adjuvant treatment in OSCC patients.     

Effect of Oral Taurine on Morbidity and Mortality in Elderly Hip Fracture Patients: A Randomized Trial

Hip fracture patients represent a large part of the elderly surgical population and face severe postoperative morbidity and excessive mortality compared to adult surgical hip fracture patients. Low antioxidant status and taurine deficiency is common in the elderly, and may negatively affect postoperative outcome. We hypothesized that taurine, an antioxidant, could improve clinical outcome in the elderly hip fracture patient. A double blind randomized, placebo controlled, clinical trial was conducted on elderly hip fracture patients. Supplementation started after admission and before surgery up to the sixth postoperative day. Markers of oxidative status were measured during hospitalization, and postoperative outcome was monitored for one year after surgery. Taurine supplementation did not improve in-hospital morbidity, medical comorbidities during the first year, or mortality during the first year. Taurine supplementation lowered postoperative oxidative stress, as shown by lower urinary 8-hydroxy-2-deoxyguanosine levels (Generalized estimating equations (GEE) analysis average difference over time; regression coefficient (Beta): −0.54; 95% CI: −1.08–−0.01; p = 0.04), blunted plasma malondialdehyde response (Beta: 1.58; 95% CI: 0.00–3.15; p = 0.05) and a trend towards lower lactate to pyruvate ratio (Beta: −1.10; 95% CI: −2.33–0.12; p = 0.08). We concluded that peri-operative taurine supplementation attenuated postoperative oxidative stress in elderly hip fracture patients, but did not improve postoperative morbidity and mortality.     

Immunology and Immunotherapeutic Approaches for Advanced Renal Cell Carcinoma: A Comprehensive Review

Renal cell carcinoma (RCC) is a malignant tumor associated with various tumor microenvironments (TMEs). The immune system is activated by the development of cancer and drives T cell anti-tumor response. CD8 T cells are known to improve clinical outcomes and sensitivity to immunotherapy, and play a crucial role against tumors. In contrast, tumor-associated macrophages (TAMs) suppress immunity against malignancy and lead to tumor progression. TAMs are promoted from damaged TMEs and mount proinflammatory responses to pathogens. Initial immunotherapy consists of interferon-α and interleukin-2. However, response to such therapy is unclear in most patients, and it is associated with high levels of toxicity. Immune checkpoint inhibitors (ICIs), which up-regulate immune responses by blocking the programed cell death protein 1 (PD-1) receptor, the ligand of PD-1, or cytotoxic T-lymphocyte-associated protein 4 T cells, have led to a new era of immunotherapy. Furthermore, combination strategies with ICIs have proven effective through several randomized controlled trials. We expect the next generation of immunotherapy to lead to better outcomes based on ongoing trials and inspire new therapeutic strategies.     

DOG1 as an Immunohistochemical Marker of Acinic Cell Carcinoma: A Systematic Review and Meta-Analysis

DOG1 is a transmembrane protein originally discovered on gastrointestinal stromal tumors and works as a calcium-activated chloride channel protein. There are a limited number of articles on the potential utility of this antibody in the diagnosis of salivary gland tumors in routine practice. In this study, we aimed to investigate the role of DOG1 as an immunohistochemical marker in patients with salivary acinic cell carcinoma (ACC) through meta-analysis. A literature search was performed of the PubMed, Scopus, and Web of Science databases for English-language studies published from January 2010 to September 2021. The literature search revealed 148 articles, of which 20 were included in the study. The overall rate of DOG1 expression in salivary acinic cell carcinoma was 55% (95% CI = 0.43–0.58). Although ACC is a challenging diagnosis, paying careful attention to the cytomorphological features in conjunction with DOG1 immunostaining can help to reach an accurate diagnosis.     

Varicella Skin Complications in Childhood: A Case Series and a Systematic Review of the Literature

Even if varicella is generally considered a harmless disease in childhood, severe complications may occur. We examined varicella skin complications (VSCs) in hospitalized immunologically healthy children, over a nine-year period. We also systematically analyzed previous reports to calculate the rate of VSCs in the literature. VSCs occurred in 16.4% of children hospitalized for varicella. This figure is in accordance with the literature, as the range of VSCs was 2.6%–41.2%. Skin complications may represent determinants of hospitalization and of other indirect costs in young children.     

Temporal Bone Squamous Cell Carcinoma: Molecular Markers Involved in Carcinogenesis,Behavior, and Prognosis: A Systematic Review

Temporal bone squamous cell carcinoma (TBSCC) is an uncommon malignancy with a poor prognosis in advanced cases. The dismal outcome of advanced TBSSC cases is largely due to the cancer’s local aggressiveness and the complex anatomy of this region, as well as to persistent pitfalls in diagnosis and treatment. Molecular changes occur in malignancies before any morphological changes become visible, and are responsible for the disease’s clinical behavior. The main purpose of this critical systematic review is to assess the level of knowledge on the molecular markers involved in the biology, behavior, and prognosis of TBSCC. A search (updated to March 2022) was run in PubMed, Scopus, and Web of Science electronic databases without publication date limits for studies investigating molecular markers in cohorts of patients with primary TBSCC. The search terms used were: “temporal bone” OR “external auditory canal” OR “ear”, AND “cancer” OR “carcinoma” OR “malignancy”. We preliminarily decided not to consider series with less than five cases. Twenty-four case series of TBSCC were found in which different analytical techniques had been used to study the role of several biomarkers. In conclusion, only very limited information on the prognostic role of molecular markers in TBSCC are currently available; prospective, multi-institutional, international prognostic studies should be planned to identify the molecular markers involved in the clinical behavior and prognosis of TBSCC. A further, more ambitious goal would be to find targets for therapeutic agents able to improve disease-specific survival in patients with advanced TBSCC.     

Pathogenesis of Penile Squamous Cell Carcinoma: Molecular Update and Systematic Review

Penile squamous cell carcinoma (PSCC) is a rare but aggressive neoplasm with dual pathogenesis (human papillomavirus (HPV)-associated and HPV-independent). The development of targeted treatment is hindered by poor knowledge of the molecular landscape of PSCC. We performed a thorough review of genetic alterations of PSCC focused on somatic mutations and/or copy number alterations. A total of seven articles have been identified which, overall, include 268 PSCC. However, the series are heterogeneous regarding methodologies employed for DNA sequencing and HPV detection together with HPV prevalence, and include, in general, a limited number of cases, which results in markedly different findings. Reported top-ranked mutations involve TP53, CDKN2A, FAT1, NOTCH-1 and PIK3CA. Numerical alterations involve gains in MYC and EGFR, as well as amplifications in HPV integration loci. A few genes including TP53, CDKN2A, PIK3CA and CCND1 harbor both somatic mutations and copy number alterations. Notch, RTK-RAS and Hippo pathways are frequently deregulated. Nevertheless, the relevance of the identified alterations, their role in signaling pathways or their association with HPV status remain elusive. Combined targeting of different pathways might represent a valid therapeutic approach in PSCC. This work calls for large-scale sequencing studies with robust HPV testing to improve the genomic understanding of PSCC.     

Malignant Transformation of Giant Cell Tumour of Bone: A Review of Literature and the Experience of a Referral Centre

Giant cell tumour of bone (GCTB) is a benign, locally aggressive primary bone neoplasm that represents 5% of all bone tumours. The principal treatment approach is surgery. Although generally GCTB is considered only a locally aggressive disease, it can metastasise, and lung metastases occur in 1–9% of patients. To date, only the use of denosumab has been approved as medical treatment for GCTB. Even more rarely, GCTB undergoes sarcomatous transformation into a malignant tumour (4% of all GCTB), but history of this malignant transformation is unclear and unpredictable. Considering the rarity of the event, the data in the literature are few. In this review, we summarise published data of GCTB malignant transformation and we analyse three cases of malignant transformation of GCTB, evaluating histopathology, genetics, and radiological aspects. Despite the rarity of this event, we conclude that a strict follow up is recommended to detect early malignant transformation.     

An Easy‐to‐Fabricate Hydrogel Platform with Tunable Stiffness and Cell Anchorage: Validation of Its Feasibility in Modulating Sonic Hedgehog Signaling Pathway Physically

The biophysical factors of microenvironments have increasingly been recognized as playing key roles in driving cell functions along with biochemical cues. However, current synthetic extracellular matrix materials with tunable biophysical properties are both costly and technically complicated to prepare, therefore limiting their application in the molecular biology field. Herein, an interpenetration hydrogel group with gradient stiffness and cell anchor points is developed, and the matrix stiffness and adhesion property functions as key regulators to determine the final output of Sonic Hedgehog (Shh) signaling is reported. Specifically, it is shown that the spreading areas of mouse embryonic fibroblasts are mainly regulated by stiffness of the matrix. The Shh‐induced Gli1 expression also increases with the cell spreading area. Finally, this work shows that b1‐integrin and focal adhesion kinase, respectively, act as sensors of matrix stiffness and adhesion properties, demonstrating the significance of the precise regulation of Shh signaling by cellular microenvironments. These results demonstrate the feasibility of using this hydrogel platform to study the impact of biophysical changes of the microenvironment on particular cellular signal pathways, and can potentially be applied in low‐cost, high throughput screening of signal pathways which are responsive to the biophysical changes of microenvironments.     

High Expression of LAMP3 Is a Novel Biomarker of Poor Prognosis in Patients with Esophageal Squamous Cell Carcinoma

Lysosomal-associated membrane protein 3 (LAMP3), identified as a molecular marker of mature dendritic cells, is one of the LAMP family members. Its expression was induced by hypoxia, and was associated with hypoxia mediated metastasis in breast and cervical cancers. However, epithelial expression of LAMP3 and its prognostic value in esophageal squamous cell carcinoma (ESCC) is still unknown. In the current study, mRNA expression of LAMP3 in 157 ESCC tissues and 50 adjacent normal tissues was detected by quantitative real-time PCR (qRT-PCR). LAMP3 protein expression in 46 paired cancerous and normal tissues was detected by immunohistochemistry (IHC). Then, DNA copy number was examined to observe its potential correlation with mRNA expression. The results showed that both mRNA and protein expression level of LAMP3 was significantly higher in cancerous tissues compared with normal controls (p < 0.001). LAMP3 DNA copy number was amplified in 70% of ESCC tissues and positive correlated with mRNA expression (p = 0.037). Furthermore, patients with higher LAMP3 expression had worse overall survival (HR = 1.90, 95% CI = 1.17–3.09, p = 0.010) and disease-free survival (HR = 1.80, 95% CI = 1.18–2.74, p = 0.006). In conclusion, our results suggest that epithelial LAMP3 expression is an independent prognostic biomarker for ESCC.     

Bilateral Meningioma: A Case Report and Review of the Literature

Here, we present a rarely seen example of bilateral meningiomas exhibiting different malignancy grades, I (meningothelial) and II (atypical), recorded in a 72-year-old patient. The presence of two separated lesions of different grades in a single patient can elucidate meningioma progression. To this end, the involvement of specific protein markers of epithelial to mesenchymal transition (EMT), the process responsible for progression, was tested in both tumors. Protein expression status of specific epithelial (E-cadherin) and mesenchymal markers (N-cadherin, SNAIL&SLUG and TWIST1) was investigated. Furthermore, markers that are connected to Wnt signaling pathway–beta-catenin, GSK3beta and DVL1—were also analyzed. For signs of neurofibromatosis and schwanomatosis genetic testing was performed. Immunohistochemistry evaluated by immunoreactivity score (IRS) was used to determine the signal strengths and proteins’ location. Our results indicated that, in comparison to the grade I tumor, mesenchymal markers SNAIL and SLUG were upregulated in the atypical meningioma. TWIST1, beta-catenin and GSK3beta were upregulated in both grades, while E-cadherin was partially lost. A pronounced cadherin switch could not be established; however, N-cadherin showed widespread tissue presence. Genetic testing did not detect changes of NF2 or SMARCB1 genes denying germline origin of the lesions. The rare presence of two different grades in one patient elucidate previously unknown molecules involved in meningioma progression.     

Role of miRNAs in Human T Cell Leukemia Virus Type 1 Induced T Cell Leukemia: A Literature Review and Bioinformatics Approach

Human T cell leukemia virus type 1 (HTLV-1) was identified as the first pathogenic human retrovirus and is estimated to infect 5 to 10 million individuals worldwide. Unlike other retroviruses, there is no effective therapy to prevent the onset of the most alarming diseases caused by HTLV-1, and the more severe cases manifest as the malignant phenotype of adult T cell leukemia (ATL). MicroRNA (miRNA) dysfunction is a common feature of leukemogenesis, and it is no different in ATL cases. Therefore, we sought to analyze studies that reported deregulated miRNA expression in HTLV-1 infected cells and patients’ samples to understand how this deregulation could induce malignancy. Through in silico analysis, we identified 12 miRNAs that stood out in the prediction of targets, and we performed functional annotation of the genes linked to these 12 miRNAs that appeared to have a major biological interaction. A total of 90 genes were enriched in 14 KEGG pathways with significant values, including TP53, WNT, MAPK, TGF-β, and Ras signaling pathways. These miRNAs and gene interactions are discussed in further detail for elucidation of how they may act as probable drivers for ATL onset, and while our data provide solid starting points for comprehension of miRNAs’ roles in HTLV-1 infection, continuous effort in oncologic research is still needed to improve our understanding of HTLV-1 induced leukemia.     

Tumor Immune Microenvironment and Immunosuppressive Therapy in Hepatocellular Carcinoma: A Review

Liver cancer has the fourth highest mortality rate of all cancers worldwide, with hepatocellular carcinoma (HCC) being the most prevalent subtype. Despite great advances in systemic therapy, such as molecular-targeted agents, HCC has one of the worst prognoses due to drug resistance and frequent recurrence and metastasis. Recently, new therapeutic strategies such as cancer immunosuppressive therapy have prolonged patients’ lives, and the combination of an immune checkpoint inhibitor (ICI) and VEGF inhibitor is now positioned as the first-line therapy for advanced HCC. Since the efficacy of ICIs depends on the tumor immune microenvironment, it is necessary to elucidate the immune environment of HCC to select appropriate ICIs. In this review, we summarize the findings on the immune microenvironment and immunosuppressive approaches focused on monoclonal antibodies against cytotoxic T lymphocyte-associated protein 4 and programmed cell death protein 1 for HCC. We also describe ongoing treatment modalities, including adoptive cell transfer-based therapies and future areas of exploration based on recent literature. The results of pre-clinical studies using immunological classification and animal models will contribute to the development of biomarkers that predict the efficacy of immunosuppressive therapy and aid in the selection of appropriate strategies for HCC treatment.