Pembrolizumab-Induced Rupioid Psoriasis Treated by Apremilast Without Interrupting the Ongoing Antineoplastic Treatment.

We report the case of a 77-year-old man affected by a poorly differentiated metastatic pulmonary adenocarcinoma who, after the first course of therapy with cisplatin-pemetrexed-pembrolizumab treatment, developed rupioid psoriasis. We decided to discontinue pembrolizumab for four weeks until lesions improved and to start therapy with apremilast (an oral small molecule phosphodiesterase (PDE)4 inhibitor) in combination with systemic methylprednisolone 16 mg/day with consequent tapering until discontinuation in a few weeks. After accomplishing three months of treatment with apremilast, the patient gained complete remission of the rupioid lesions. Pembrolizumab therapy was reintroduced, and cycles were carried out without exacerbating the clinical picture. During the fourth month of therapy with apremilast, it was attempted to stop the treatment despite continuing the therapy with pembrolizumab. As a result, there was a relapse of the erythematous scaling plaques. After the subsequent reintroduction of apremilast, a new remission of the clinical picture occurred despite the absence of interruption of pembrolizumab. As far as we know, this is the second case of rupioid psoriasis induced by immunotherapy with pembrolizumab. Still, while the previous case was undergoing therapy with acitretin and methylprednisone, our patient is the first case treated with apremilast with excellent and rapid remission even after discontinuation and re-administration of pembrolizumab without exacerbation of dermatitis. In addition, the appearance of psoriasis during immunotherapy can be properly treated, which does not contraindicate the continuation of the antineoplastic treatment.

Tattoo-Associated Skin Reaction in a Melanoma Patient Receiving B-RAF and MEK Inhibitors: A Case Report with an Emphasis on Etiopathogenic and Histological Features.

Tattoo-associated cutaneous reactions have become quite frequent given the increasing percentage of tattooed subjects globally and also in Italy. On the other hand, the increasing use of target therapy is showing the ability of these drugs to affect the immune system and also cause adverse tattoo-related reactions. In this paper, we report a case of a 42-year-old patient with stage-IIID melanoma undergoing treatment with Dabrafenib and Trametinib. The patient reported erythema, oedema and scaling in areas of the body containing a black tattoo, and, conversely, no signs and/or symptoms in areas with tattoos of a different color. Histopathological and immunohistochemical features indicated a lympho-histiocytic reaction with a granulomatous morphology, mainly distributed around the vessels and hair adnexa. By discussing the cases reported in the literature prior to ours, we concluded and provided the possible indications of the pathogenesis.

Drug Survival of Upadacitinib and Predicting Factors of Discontinuation in Adult Patients Affected by Moderate-to-Severe Atopic Dermatitis: An Italian Multicenter Analysis.

Background: Limited real-world data are available on upadacitinib drug survival in patients with atopic dermatitis (AD). Objectives: To investigate upadacitinib drug survival, and the reasons and predictors of drug discontinuation in AD patients. Methods: All consecutive patients aged 18-75 years, affected by moderate-to-severe AD, and treated with upadacitinib for more than 1 month at dermatological clinics were included during November 2020-August 2023. Upadacitinib survival was investigated through Kaplan-Meier survival analysis and the predictors through multivariable logistic regression analysis. Results: Overall, 325 adult AD patients (mean (SD) age, 38.6(15.6) years) had a 1-year and 1.5-year upadacitinib drug survival of 91.5% and 80.2%, respectively. The main reasons for drug discontinuation (25/325, 7.7%) were adverse events (4.9%), including cutaneous or infectious diseases (1.5%), such as acne and herpes zoster; blood test changes (1.2%), including hypercholesterolemia, creatine phosphokinase or liver enzyme elevation, and lymphopenia; urinary or respiratory infections (0.9%); deep venous thrombosis (0.3%); malignancies (0.3%); loss of consciousness (0.3%); and arthralgias (0.3%); followed by ineffectiveness (0.6%). No specific characteristic was significantly associated with an increased risk of upadacitinib discontinuation. Conclusions: Our findings show that upadacitinib was effective in moderate-to-severe AD after more than 1 year of continuous treatment but point to the need for clinical and laboratory monitoring of patients.

Latent Mastocytosis Triggered by COVID-19 Vaccination: A Case Report.

BACKGROUND: Hereby, we describe the first case of latent mastocytosis triggered by mRNA-based vaccine to prevent COVID-19 infection. CASE PRESENTATION: In a 42-year-old Arabian man affected by slight, undiagnosed mastocytosis, the second dose of the COVID-19 vaccine made more blatant his latent disease. The postvaccination diagnostic iter is illustrated and the potential reasons causing the onset of the cutaneous mastocytosis are discussed. CONCLUSION: In certain patients, clinicians should keep a longer follow-up of their patients, following the COVID-19 vaccination, not related to a few hours for the risk of immediate-type adverse events only.

Granulomatous Secondary Syphilis: A Case Report with a Brief Overview of the Diagnostic Role of Immunohistochemistry.

The diagnosis of syphilis can be challenging for dermatologists and dermatopathologists. In particular, secondary syphilis can have different clinical and histopathological presentations. A granulomatous tissue response is an unusual finding in secondary syphilis. We report the case of a 77-year-old man who presented with a 4-week history of non-pruritic generalised macules, papules, nodules and plaques. Histopathologically, there was a dense perivascular and periadnexal lympho-histiocytic dermal infiltrate with non-palisading and non-caseifying epithelioid granulomas and abundant plasma cells. The diagnosis of syphilis was confirmed by serology and immunohistochemical detection of Treponema pallidum in the biopsy specimen. A brief overview of the diagnostic role of immunohistochemistry is also provided, with particular emphasis on reported cases of granulomatous secondary syphilis.

Congenital Cutis Verticis Gyrata in a Newborn with Turner Syndrome: A Rare Clinical Manifestation of This Chromosomal Disease with Trichoscopic Evaluation.

Cutis verticis gyrata (CVG) is a rare disorder of the scalp that entails the development of ridges and furrows, which mimic the anatomical conformation of the brain. This skin condition has been classified in primary essential, primary non-essential, and secondary CVG, depending on the presence or absence of other associated disorders. We present the case report of a one-month-old female newborn affected by congenital CVG (CCVG), who also received a diagnosis of Turner syndrome (TS). Skin folding was present at birth and located at the left frontal region of the scalp in the sagittal plane. Our purpose was to make this pathology clinically and tricoscopically better known, since it can be related to different genetic, inflammatory, and neoplastic conditions, etc. Non-invasive investigations, such as ultrasonography (U/S) of the brain and scalp and trichoscopy, were also used to obtain the important clues necessary to help in the CVG classification. The clinical diagnosis and trichoscopical investigation of CVG may also be useful for those patients who may have a genetic disease that is not screened for during prenatal examinations.

Immunotherapy and the Combination with Targeted Therapies for Advanced Hepatocellular Carcinoma.

One of the most important abilities of a tumor is to establish a state of immunosuppression inside the tumor microenvironment. This is made possible through numerous mechanisms of tumor immune escape that have been identified in experimental studies during the last decades. In addition, the hepatic microenvironment is commonly oriented towards a state of immune tolerance because the liver receives blood from the hepatic arteries and portal veins containing a variety of endogenous antigens. Therefore, the hepatic microenvironment establishes an autoimmune tolerance, preventing an autoimmune reaction in the liver. On this basis, hepatic tumor cells may escape the immune system, avoiding being recognized and destroyed by immune cells. Moreover, since the etiology of Hepatocellular Carcinoma (HCC) is often related to cirrhosis, and hepatitis B or C, this tumor develops in the context of chronic inflammation. Thus, the HCC microenvironment is characterized by important immune cell infiltration. Given these data and the poor prognosis of advanced HCC, different immunotherapeutic strategies have been developed and evaluated for these patients. In this review, we describe all the clinical applications of immunotherapy for advanced HCC, from the drugs that have already been approved to the ongoing clinical trials.

Partially Dedifferentiated Primitive Malignant Melanoma with Pseudo-Angiomatous Features: A Case Report with Review of the Literature.

Malignant melanoma (MM) is traditionally known as the "great mime" of human pathology, as it is potentially capable of imitating the most disparate neoplasms. It is known that in addition to the more classic histotypes of MM, there are also rare forms, including angiomatoid MM. Similarly, it has been amply demonstrated in the literature that MM is capable of dedifferentiating, losing melanocytic lineage markers, constituting a diagnostic challenge for the pathologist. Although 5 cases of primary angiomatoid MM have been described in the literature, to the best of our knowledge, no cases of dedifferentiated melanoma with pseudo-angiomatoid aspects have ever been described. In this paper, we present a very rare case of partially dedifferentiated MM in which the most dedifferentiated component lost melanocytic lineage immunohistochemical markers and assumed a pseudo-angiomatous morphology. Given the rarity of the case, we carried out a literature review of similar cases described, trying to draw new future perspectives not only about this particular variant of MM but also about the widest field of dedifferentiation/undifferentiation of MM.

Histopathological Patterns of Cutaneous Adverse Reaction to Anti-SARS-CoV-2 Vaccines: The Integrative Role of Skin Biopsy.

The advent of vaccines represented a milestone to allow the slowing down and then containing of the exponential increase in ongoing infections and deaths of COVID-19. Since the first months of the vaccination campaign in various continents, there has been a certain number of reports of adverse events, including skin reactions. We conducted a systematic review, searching on PubMed, Web of Science, Scopus, and Cochrane Library for the words: COVID vaccine, dermatopathology, skin, eruptions, rash, cutaneous, BNT162b2 (Pfizer-BioNTech), ChAdOX1 (AstraZeneca), and mRNA-1273 (Moderna). A total of 28 records were initially identified in the literature search of which two were duplicates. After screening for eligibility and inclusion criteria, 18 publications were ultimately included. Various clinical cutaneous manifestations and histopathological patterns following vaccination have been described in literature. The most frequent clinical-pathological presentations were erythematous maculo-papular eruptions in different way of distribution with histopathological pictures mostly represented by interface changes and mixed peri-vascular and peri-adnexal cell infiltrate. Other presentations included new onset of pemphigoid bullous disease (n = 15), delayed T-cell-mediated hypersensitivity reaction (injection site reactions) (n = 10), purpuric skin rash (n = 13), mostly localized on the legs bilaterally and symmetrically with histological pictures characterized by extravasation of erythrocytes in the superficial and middle dermis, and other types of reactions. New studies with large case series and further literature reviews are needed to improve the clinical management of patients and optimize the timeline for carrying out histological biopsy for confirmatory, supportive, and differential diagnosis purposes.

Keratosis Pilaris-like Eruption during Treatment of Chronic Myeloid Leukemia with Tyrosine Kinase Inhibitors: Literature Review and Report of a Case Related to Imatinib.

The advent of tyrosine kinase inhibitors (TKIs) blocking BCR-ABL activity has revolutionized the therapeutic management of patients with chronic myeloid leukemia (CML). Adverse cutaneous reactions (ACRs) are common nonhematologic adverse events associated with the use of BCR-ABL TKIs. A characteristic pattern of eruption resembling keratosis pilaris (KP) has been described in patients treated with these drugs, especially nilotinib and dasatinib. The pathogenesis of this ACR is still unknown. This type of reaction appears to be uncommon with imatinib. Here, we report the case of an elderly patient with an asymptomatic KP-like eruption, which appeared one month after starting treatment with imatinib for CML. The case presentation is accompanied by a review of similar reactions in patients with CML treated with BCR-ABL inhibitors, attempting to make an excursus on the molecular targets of such drugs and possible mechanisms underlying this ACR.

PRAME Immunoexpression in 275 Cutaneous Melanocytic Lesions: A Double Institutional Experience.

In recent years, the preferentially expressed antigen in melanoma (PRAME) has also been used in the histopathological diagnosis of melanocytic lesions, in order to understand if it could constitute a valid, inexpensive, and useful resource in dermatopathological fields. We performed a double-center study to evaluate whether the data on the usefulness and possible limitations of PRAME could also be confirmed by our group. From 1 December 2021 to 29 March 2022, we collected 275 cases of melanocytic lesions that were immunostained with PRAME (Ab219650) and rabbit monoclonal antibody (Abcam). To better correlate the PRAME expression with its nature (benign, uncertain potential for malignancy, or malignant), we categorized PRAME tumor cells' percentage positivity and intensity of immunostaining in a cumulative score obtained by adding the quartile of positive tumor cells (0, 1+, 2+, 3+, 4+) to the PRAME expression intensity in tumor cells (0, 1+, 2+, 3+). Of these 275 lesions, 136 were benign, 12 were of uncertain potential for malignancy (MELTUMP or SAMPUS or SPARK nevus), and 127 were malignant. The immunoexpression of PRAME was completely negative in 125/136 benign lesions (91.9%), with only a few positive melanocytes (1+) and intensity 1+ in the remaining 11 cases (8.1%). Of the 127 cases of melanoma (superficial spreading, lentigo maligna, and pagetoid histotypes), PRAME was strongly positive in 104/127 cases (81.8%) with intensity 4+ and 3+. In 17 cases (13.3%; melanoma spindle and nevoid cell histotypes), PRAME was positive in percentage 2+ and with intensity ranging from 2+ to 3+. In 7 cases (5.5%) of desmoplastic melanoma, PRAME was 1+ positive and/or completely negative. Of the 12 cases of lesions with uncertain potential for malignancy, the immunoexpression of PRAME was much more heterogeneous and irregularly distributed throughout the lesion. These data are perfectly in agreement with the current literature, and they demonstrate that the reliability of PRAME is quite high, but its use cannot cause physicians to disregard the morphological information and the execution of other ancillary immunohistochemical stains such as Melan-A, HMB-45, MiTF, and SOX-10.

SARS-CoV-2 and Skin: New Insights and Perspectives.

The SARS-CoV-2 pandemic has disrupted global health systems and brought the entire globe to its knees. Although born as a disease of the respiratory system, COVID-19 can affect different parts of the body, including the skin. Reports of ongoing skin manifestations of COVID-19 have gradually multiplied, pushing researchers to investigate the etiopathogenic mechanisms underlying these phenomena in more depth. In an attempt to investigate the possible association between SARS-CoV-2, ACE2, TMPRSS2 and skin manifestations, we performed immunohistochemical investigations of the ACE2 receptor and TMPRSS2 in nine skin samples from SARS-CoV-2-positive patients compared to a cohort of healthy controls. Furthermore, after consulting public databases regarding ACE2 mRNA expression in various cell populations resident in the skin, we conducted a literature review aimed at outlining the current state of this topic. We did not find statistically different immuno-expression of ACE2 and TMPRSS2 between the group of SARS-CoV-2-positive patients (nine skin biopsies) and the control group. Regarding ACE2, major immunolabeling was present in the epidermal keratinocytes and, rarely, in the fibroblasts and in the adenomeres of the eccrine sweat glands. Regarding the immune expression of TMPRSS2, we found no significant differences between the two groups, with a weak immune staining only in some skin cytotypes. From the review of the literature, we isolated 35 relevant articles according to the inclusion criteria adopted. ACE2 appears to be a target of SARS-CoV-2, although, other receptor molecules may potentially be implicated, such as TMPRSS2. Future studies with large cases and different molecular investigative methods are needed to further elucidate the mechanisms underlying the skin manifestations of SARS-CoV-2.

Targeted Therapy for Hepatocellular Carcinoma: Old and New Opportunities.

Hepatocellular carcinoma (HCC) is the most frequent primitive cancer of the liver, accounting for 90% of all recorded cases. HCC is the third most common cause of cancer-related death, with a 5-year survival rate of just 3%. In the advanced stages, systemic treatments allow doctors to obtain clinical benefits, although the prognosis remains very poor. In the past few decades, new molecular targeted therapies against receptor tyrosine kinases have been developed and clinically evaluated. Sorafenib was the first oral tyrosine kinase inhibitor (TKI) approved for the treatment of advanced HCC in 2007. Subsequently, other TKIs, including Cabozantinib, Regorafenib, Lenvatinib, and vascular endothelial growth factor receptor (VEGFR) inhibitors such as Ramucirumab and VEGF inhibitors such as Bevacizumab have been approved as first- or second-line treatments. More recently, the combination of immune checkpoint inhibitors and VEGF inhibitors (Atezolizumab plus Bevacizumab) have been analyzed and approved for the treatment of advanced HCC. On the basis of the poor prognoses and the meager benefits deriving from the available systemic therapies, research into new treatments is extremely necessary. In this review, we focus on the available systemic therapies for advanced HCC, with a look toward the future.

Spreading Allergic Contact Dermatitis to Tea Tree Oil in an Over-the-Counter Product Applied on a Wart.

Tea tree oil is an essential oil obtained by distillation from the leaves and terminal branchlets of Melaleuca alternifolia and is now present in numerous products for body care and self-medication. We report a case of allergic contact dermatitis to tea tree oil in a young man who was applying a lotion containing tea tree oil on a wart localized on the plantar aspect of the right big toe, which had previously been treated with cryotherapy. He developed a severe eczematous eruption on the right foot and the right leg, with subsequent id reactions affecting the right thigh, the contralateral lower limb, the trunk and the upper limbs. The lotion was discontinued, and the dermatitis resolved after topical corticosteroid therapy. Patch testing with the aforementioned lotion 10% pet. and oxidized tea tree oil 5% pet. identified tea tree oil as the culprit agent of the dermatitis. This case report confirms that products made of natural ingredients, often perceived to be harmless, can cause allergic reactions.

Balloon Cell Melanoma: Presentation of Four Cases with a Comprehensive Review of the Literature.

BACKGROUND: balloon cell melanoma represents less than 1% of all histological forms of malignant melanoma and represents a diagnostic challenge for the dermatopathologist. METHODS: in this paper we present our cases of BCM found in our daily practice from 1 January 2008 to 31 December 2021, and we conduct a review of the literature relating to this entity in the period from the first description, 1970, to early 2022. RESULTS: four cases of melanoma balloon cell have been extrapolated from our electronic database, while in the review of the literature we have identified 115 cases of patients with primary and/or metastatic BCM. CONCLUSIONS: we believe that future studies with numerous case series are essential not only to increase the knowledge of the pathophysiology of this neoplasm but also to correctly evaluate the response of BCM patients to new oncological therapies.

Lack of reactivation of tuberculosis in patients with psoriasis treated with secukinumab in a real-world setting of latent tuberculosis infection.

BACKGROUND: Some biologics for psoriasis, especially anti-tumor necrosis factor (TNF)-α therapies, may re-activate latent tuberculosis (TBC) infection with consequent morbidity and mortality. However, there is a low reported incidence of conversion to positive TBC status among patients with psoriasis treated with second-generation biologic therapies, particularly anti-interleukin (IL)-17 therapies such as secukinumab. OBJECTIVES: To evaluate the safety profile of secukinumab in psoriasis patients with latent TBC infection. METHODS: Real-life data were collected by retrospective chart review on patients with moderate-to-severe psoriasis who showed positivity for TBC screening at baseline and underwent secukinumab treatment for psoriasis at six Italian centers. Patients received secukinumab 300 mg at week 0/1/2/3/4, then every 4 weeks. RESULTS: Fifty-nine patients were enrolled; 30.5% also had psoriatic arthritis and other comorbidities were common. At baseline, the mean psoriasis duration was 14.5 years. Ten (17%) patients did not undergo prophylaxis before starting secukinumab. Conversely, isoniazid ± rifampicin or rifampicin alone prophylaxis was administered in 49/59 (83.1%) patients. After a mean treatment duration of 84 weeks, there were no cases of TBC reactivation and no unexpected safety signals. CONCLUSIONS: Secukinumab use over an extended period was safe in psoriasis patients with latent TBC, even in patients who did not receive chemoprophylaxis.

Italian adaptation of EuroGuiDerm guideline on the systemic treatment of chronic plaque psoriasis.

SIDeMaST (Società Italiana di Dermatologia Medica, Chirurgica, Estetica e delle Malattie Sessualmente Trasmesse) contributed to the development of the present guideline on the systemic treatment of chronic plaque psoriasis. With the permission of EuroGuiDerm, SIDeMaST adapted the guideline to the Italian healthcare context to supply a reliable and affordable tool to Italian physicians who take care of patients affected by moderate to severe plaque psoriasis. The content of the guideline includes general information on the scope and purpose, health questions covered, target users and strength/limitations of the guideline, suggestions for disease severity grading and treatment goals. It presents the general treatment recommendations as well as detailed management and monitoring recommendations for the individual drugs including acitretin, cyclosporine, fumarates, methotrexate, adalimumab, apremilast, brodalumab, certolizumab pegol, etanercept, guselkumab, infliximab, ixekizumab, risankizumab, secukinumab, tildrakizumab and ustekinumab. Moreover, the guideline provides guidance for specific clinical situations such as patient with concomitant psoriatic arthritis, inflammatory bowel disease, a history of malignancies, a history of depression, diabetes, viral hepatitis, disease affecting the heart or the kidneys as well as concomitant neurological disease. Advice on how to screen for tuberculosis and recommendations on how to manage patients with a positive tuberculosis test result are given. It further covers treatment for pregnant women or those with childbearing potential. Information on vaccination, immunogenicity and systemic treatment during the COVID-19 pandemic is also provided.

Immune Disregulation in Cutaneous Squamous Cell Carcinoma of Patients with Recessive Dystrophic Epidermolysis Bullosa: A Single Pilot Study.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is one of the most devastating complications of recessive dystrophic epidermolysis bullosa (RDEB). We recently demonstrated a reduction in immune cell peritumoral infiltration in RDEB patients with cSCC, together with a reduction in CD3+, CD4+, CD68+ and CD20 lymphocytes as compared to primary and secondary cSCC in patients without RDEB. Recently, new molecules, such as high mobility group box 1 (HMGB1), T cell immunoglobulin, mucin domain 3 (TIM-3) and Heme oxygenase-1 (HO-1), have been shown to play a role in antitumoral immunity. OBJECTIVE: Patients with RDEB are known to be at increased risk of developing skin cancers, including the dreaded squamous cell carcinoma of the. Tendentially, cSCCs that arise in the context of EBDR are more aggressive and lead to statistically significant bad outcomes compared to cSCCs developed on the skin of patients without EBDR. In an attempt to study the microenvironment of these lesions, we conducted an immunohistochemical analysis study of proteins that could be actively involved in the genesis of this type of malignant neoplasms. METHODS: In this retrospective study, the OH1-HMGB1-TIM3 activation axis, as correlated to the T lymphocytes cell count, was assessed in biopsy samples from 31 consecutive cases consisting of 12 RDEB patients with cSCC, 12 patients with primary cSCC and 7 RDEB patients with pseudoepitheliomatous cutaneous hyperplasia. Parametric Student's t-test was applied for normally distributed values, such as CD4+ and CD8+, and non-parametric Mann-Whitney test for non-normally distributed values, such as HMGB-1, TIM-3 and HO-1. RESULTS: In RDEB patients with cSCC and with pseudoepitheliomatous hyperplasia, the expression of CD4 T helper lymphocytes was lower than in the peritumoral infiltrate found in primary cSCC. CD8 cytotoxic T lymphocytes were increased in primary cSCC compared to the other two groups. An increased HMGB1 expression was evident in both primary and RDEB cSCC. TIM3 expression was higher in RDEB patients with cSCC compared to the other two groups. A significantly reduced immunohistochemical expression of HO-1 was evident in the tumoral microenvironment of cSCC-RDEB as compared to primary cSCC. CONCLUSIONS: These data suggest that a reduced immune cell peritumoral infiltration in RDEB patients could be responsible, in the complexity of the mechanisms of carcinogenesis and host response, of the particular aggressiveness of the cSCC of RDEB patients, creating a substrate for greater local immunosuppression, which, potentially, can "open the doors" to development and eventual metastasis by this malignant neoplasm.

Intra-Arterial Infusion Chemotherapy in Advanced Pancreatic Cancer: A Comprehensive Review.

Advanced pancreatic cancer (PC) has a very poor prognosis due to its chemoresistant nature. Nowadays, only a few therapeutic options are available for PC, and the most effective ones are characterized by low response rates (RRs), short progression-free survival and overall survival, and severe toxicity. To improve clinical results, small series studies have evaluated loco-regional chemotherapy as a treatment option for PC, demonstrating its dose-dependent sensitivity towards the tumor. In fact, pancreatic arterial infusion (PAI) chemotherapy allows higher local concentrations of chemotherapeutic agents, sparing healthy tissues with a lower rate of adverse events compared to systemic chemotherapy. This therapeutic approach has already been evaluated in different types of tumors, especially in primary and metastatic liver cancers, with favourable results. With regard to advanced PC, a few clinical studies have investigated the safety and efficacy of PAI with promising results, especially in terms of RRs compared to systemic chemotherapy. However, clear evidence about its efficacy has not been established yet nor have the underlying mechanisms leading to its success. In this review, we aim to summarize the literature data on the clinical approaches to pancreatic arterial drug administration in terms of techniques, drug pharmacokinetics, and clinical outcomes for advanced PC.