Latest Advances in Chemotherapeutic,Targeted, and Immune Approaches in the Treatment of Metastatic Melanoma

Melanoma is the most dangerous form of skin cancer owing to its metastatic potential and is an important public health concern. The melanoma incidence has been increasing worldwide. Although potentially curable when diagnosed early, metastatic melanoma carries a poor prognosis. Until recently, systemic therapy for metastatic melanoma was ineffective, but the recent successes in the development of new therapies for metastatic melanoma, such as mitogen-activated protein kinase (MAPK) pathway inhibitors, anti–cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4), and programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway blocking antibodies, as well as combination strategies of cytotoxic chemotherapy and inhibitors of angiogenesis, have all yielded promising results, changing the continually evolving landscape of therapeutic options for patients with this disease. The aim of this review was to summarize the evolution of and recent advances in the treatment of metastatic melanoma. Therefore, we conducted a comprehensive PubMed search between January 1, 1960, and February 1, 2014, using the search term melanoma or metastatic melanoma combined with terms such as chemotherapy, immunotherapy, CTLA-4, PD-1, PD-L1, adoptive T cell, targeted therapy, MAPK, molecular biology, and survival.     

Measuring differential treatment benefit across marker specific subgroups: The choice of outcome scale

Clinical and epidemiological studies of anticancer therapies increasingly seek to identify predictive biomarkers to obtain insights into variation in treatment benefit. For time to event endpoints, a predictive biomarker is typically assessed using the interaction between the biomarker and treatment in a proportional hazards model. Interactions are contrasts of summaries of outcomes and depend upon the choice of the outcome scale. In this paper, we investigate interaction contrasts under three scales — the natural logarithm of hazard ratio, the natural logarithm of survival probability, and survival probability at a pre-specified time. We illustrate that we can have a non-zero interaction on survival or logarithm of survival probability scales even when there is no interaction on the logarithm of hazard ratio scale. Since survival probabilities have clinically useful interpretation and are easier to convey to patients than hazard ratios, we recommend evaluating a predictive biomarker using survival probabilities. We provide empirical illustration of the three scales of interaction for evaluating a predictive biomarker using reconstructed data from a published melanoma study.     

The critical role of plasmapheresis in ABO-incompatible renal transplantation

BACKGROUND: Thousands of patients with chronic renal failure die yearly and are unable to have a kidney transplant due to the severe shortage of donors. Therapeutic plasma exchange (TPE) is performed to remove ABO antibodies and permit ABO‐incompatible (ABO‐I) kidney transplants, but there is only limited research within this area and a lack of standardized protocols for TPE. This article reviews the literature to provide a historical perspective of TPE for ABO‐I kidney transplantation and also provides the Johns Hopkins Hospital protocol with a focus on both titers and TPE. STUDY DESIGN AND METHODS: The TPE treatment plan is based on ABO titers with the goal of a titer of 16 or less at the anti‐human globulin (AHG) phase before surgery. Pretransplant therapy consists of every‐other‐day TPE followed immediately by cytomegalovirus hyperimmune globulin. ABO antibody titers are closely monitored before and after transplantation. After transplantation, TPE therapy is performed for all patients to prevent rebound of anti‐A and anti‐B titers until tolerance or accommodation occurs. TPE is discontinued and reinstituted based on the clinical criteria of creatinine levels, biopsy results, and ABO titer. RESULTS: Fifty‐three ABO‐I kidney transplants have been completed with no episodes of hyperacute antibody‐mediated rejection (AMR) and only three episodes of AMR. One‐year death‐censored graft survival is 100 percent and patient survival is 97.6 percent. CONCLUSIONS: While randomized clinical trials are needed to evaluate the optimal method and protocol to remove ABO antibodies, the current literature and our results indicate a critical role for TPE in ABO‐I renal transplantation.     

Antihepatitis B therapy: a review of current medications and novel small molecule inhibitors

There are approximately 350 million hepatitis B virus (HBV) carriers worldwide. Chronic HBV infection increases the risk of liver cirrhosis and hepatocellular carcinoma. To date, two classes of antiviral drugs have been approved by the Food and Drug Administration for the treatment of hepatitis B, immunomodulators (interferon [IFN]‐α and pegylated‐interferon [PEG‐IFN]‐α) and nucleos(t)ide analogs (lamivudine, telbivudine, adefovir, tenofovir [TDF], and entecavir [ETV]). Of these, ETV, TDF, and PEG‐IFN‐α are the most effective and are currently recommended for anti‐HBV therapy. However, these therapies are less than optimal because of their low rate of viral DNA and surface antigen clearance; thus, there exists a significant unmet medical need for safe and efficacious new anti‐HBV drugs. Covering diverse chemical structures and mechanisms of action, non‐nucleos(t)ide compounds offer great promise in the search for new anti‐HBV drugs. This review summarizes the currently approved anti‐HBV drugs and highlights advances in the identification and characterization of novel small molecule HBV inhibitors. We discuss the sources, structures, anti‐HBV effects, mechanisms of action, and potential toxicities of these novel inhibitors.     

A Blueprint for a Sepsis Protocol

Despite numerous advances in medicine, sepsis remains an unconquered challenge. Although outcomes have improved slightly over decades, the unacceptably high mortality rate of 30%–50% for severe sepsis and septic shock continues. However, after years of unsuccessful clinical trials, several investigations over the last few years have reported survival benefit in the treatment of sepsis. Physicians now have several proven therapies to treat sepsis, but have yet to implement them on a widespread, systematic basis. This led 11 international professional societies spanning multiple specialties and continents to come together to create the Surviving Sepsis Campaign. The product of their work is an international effort organized to improve care of patients with sepsis and includes consensus, evidence‐based guidelines for care that improves survival in septic patients, and an action plan for change. Given the clear role of early identification and treatment in stopping the sepsis cascade, therapy must start early in the emergency department (ED) and continue throughout the hospital course. The first of the recommendations by the Surviving Sepsis Campaign is the aggressive resuscitation strategy of early goal‐directed therapy (EGDT). EGDT is reported to reduce absolute mortality by a staggering 16%. The use of recombinant activated protein C was demonstrated to confer a 6% absolute survival benefit. Steroid supplementation in adrenal insufficiency produced a 10% benefit. Additionally, early and appropriate use of antibiotics remains a cornerstone of therapy. Although no randomized trial will be performed, the effects are undisputed. Finally, although predominantly intensive care unit therapies, tight glucose control and low‐tidal‐volume ventilation strategies have also led to improved survival. Armed with these new therapies, the medical community must rise to this call to action. Clinicians must change the approach to this disease, as well as the way the septic patient is viewed. Although complex and challenging, these therapies must be brought to the patient's bedside. We propose and describe the Multiple Urgent Sepsis Therapies (MUST) protocol as a practical way to implement a comprehensive treatment plan using available evidence‐based therapies.     

Current clinical overview of cutaneous melanoma

This article reviews current evidence on epidemiology, diagnosis and management of cutaneous melanoma. Incidence of cutaneous melanoma is rising in all Caucasian populations across the world; thus, melanoma represents a significant public health burden. Although, incidence of melanoma is in continuous increase, a decrease of mortality and improved survival has been observed in most western European populations. Clinical characteristics of four major types of melanoma (superficial spreading, nodular, lentigo maligna melanoma and acral lentiginous melanoma) have been described. Surgical removal of melanoma remains the standard care in all primary melanomas. Current evidence suggests use of 1 to 2 cm excision margins. Wider margins may be necessary in patients with thicker melanomas with higher risk for local recurrence. In the treatment of regional lymph nodes elective lymphadenectomy has been surpassed by the sentinel lymph node biopsy (SLNB). However, although prognostic value of SLNB has been confirmed, its therapeutical benefit still needs to be evaluated. Currently there is no standard adjuvant therapy for melanoma although interferon-alpha has been the most widely used treatment in the adjuvant setting. The role of metastasectomy (removal of distant metastases) is still controversial. Chemotherapeutic agents have a limited activity in patients with metastatic melanoma with response rates up to 25%. Although different vaccines have been tested in melanoma patients their role still remain to be established in phase III trials. Progresses in molecular biology and genetics of melanoma may lead to the development of novel melanoma therapies.     

Treatment of AL Amyloidosis: Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) Consensus Statement 2020 Update

Immunoglobulin light chain (AL) amyloidosis is a clonal plasma cell disorder leading to progressive and life-threatening organ failure. The heart and the kidneys are the most commonly involved organs, but almost any organ can be involved. Because of the nonspecific presentation, diagnosis delay is common, and many patients are diagnosed with advanced organ failure. In the era of effective therapies and improved outcomes for patients with AL amyloidosis, the importance of early recognition is further enhanced as the ability to reverse organ dysfunction is limited in those with a profound organ failure. As AL amyloidosis is an uncommon disorder and given patients’ frailty and high early death rate, management of this complex condition is challenging. The treatment of AL amyloidosis is based on various anti–plasma cell therapies. These therapies are borrowed and customized from the treatment of multiple myeloma, a more common disorder. However, a growing number of phase 2/3 studies dedicated to the AL amyloidosis population are being performed, making treatment decisions more evidence-based. Supportive care is an integral part of management of AL amyloidosis because of the inherent organ dysfunction, limiting the delivery of effective therapy. This extensive review brings an updated summary on the management of AL amyloidosis, sectioned into the 3 pillars for survival improvement: early disease recognition, anti–plasma cell therapy, and supportive care.     

Targeting the ERK signaling pathway in cancer therapy

The extracellular signal‐regulated kinase (ERK) signaling pathway is a major determinant in the control of diverse cellular processes such as proliferation, survival, differentiation and motility. This pathway is often up‐regulated in human tumors and as such represents an attractive target for the development of anticancer drugs. Because of its multiple roles in the acquisition of a complex malignant phenotype, specific blockade of the ERK pathway is expected to result in not only an anti‐proliferative effect but also in anti‐metastatic and anti‐angiogenic effects in tumor cells. Recently potent small‐molecule inhibitors targeting the components of the ERK pathway have been developed. Among them, BAY 43‐9006 (Raf inhibitor), and PD184352, PD0325901 and ARRY‐142886 (MEK1/2 inhibitors) have reached the clinical trial stage. We briefly discuss the possibility that combination of ERK pathway inhibitors (cytostatic agents) and conventional anticancer drugs (cytotoxic agents) provides an excellent basis for the development of new chemotherapeutic strategies against cancer.     

Primary cutaneous malignant melanoma: recognition, properties, and management.

The fact that malignant melanoma occurs on a readily observable organ, the skin, and behaves in a predictable biological pattern in many cases suggests that its rate of cure should be high. Yet, despite advances in recognition and management, a significant percentage of patients still succumb to their disease. More sensitive methods of early detection and more effective therapies are required to improve survival.     

Melanoma vaccines as a therapeutic option.

BACKGROUND: In 1998, 41,600 new cases of melanoma with 7,300 deaths were expected. Worldwide, the incidence has risen 5% a year against a backdrop of generally decreasing cancer trends. Later stages of melanoma carry a severe prognosis. The need for newer, more effective therapeutic strategies for cancer is obvious. For melanoma, early diagnosis and surgical treatment are the only options that are currently curative. Chemotherapy and radiation therapy are of limited efficacy. METHODS: We reviewed the various forms of immunotherapy, concentrating on vaccine therapy. We then reviewed the history of our own vaccine in the context of the field of immunotherapy, and compared efficacy, immune response, production methods, and survival. RESULTS: Survival is improved among recipients of melanoma vaccine when compared with patients receiving conventional therapy. CONCLUSIONS: Imnmunotherapy in the form of melanoma vaccines is better than conventional therapy and is trending toward purer antigenic preparations.     

Surgical management of heart failure

This article introduces the mechanisms and theories behind the surgical treatments for heart failure; however, heart failure is a complex problem and requires multiple solutions. Surgery offers treatment strategies that target underlying physiologic changes and may provide both quality of life and survival benefit to patients who have specific clinical characteristics consistent with the aims of the procedure. Nurses must include surgical treatment early in their hierarchy of treatment plans, especially when coronary artery occlusion, hibernating myocardium, or mitral valve regurgitation is the cause of heart failure. In addition, newer investigational surgical therapies must also be considered for patients with advanced heart failure who have already been optimized on medical and cardiac resynchronization therapies and who require a novel approach to potentially improve individual outcomes.     

Anti‐MDA‐5 antibody‐positive clinically amyopathic dermatomyositis with rapidly progressive interstitial lung disease treated with therapeutic plasma exchange: A case series

We present six cases of antimelanoma differentiation‐associated gene 5 antibody (anti‐MDA5‐Ab)‐positive clinically amyopathic dermatomyositis (CADM) with rapidly progressive interstitial lung disease (RP‐ILD), which is known to have a poor prognosis. The outcomes of these cases are described after treatment with therapeutic plasma exchange (TPE). Clinical and therapeutic data for patients with CADM with RP‐ILD were collected retrospectively from medical records. All six patients received early intensive care including high‐dose corticosteroids, intravenous cyclophosphamide, and a calcineurin inhibitor, but lung disease and hypoxia became more severe. TPE was performed over a median of 9.5 sessions (range 3‐14) per patient, and the median duration from admission to TPE was 23 days. Three patients received combined direct hemoperfusion using a polymyxin B‐immobilized fiber column (PMX‐DHP) therapy on successive days to manage acute respiratory failure. Four patients survived and two died due to respiratory failure. In the survival cases, ferritin decreased, and ferritin and KL‐6 were lower at diagnosis. The patients who died had a higher alveolar‐arterial oxygen difference and more severe lung lesions at the time of initiation of TPE. These findings indicate that a combination of conventional therapy and TPE may be useful for improvement of the prognosis of CADM with RP‐ILD at the early stage of onset.     

Assessment of melanoma extent and melanoma metastases invasion using electron paramagnetic resonance and bioluminescence imaging

The clinical outcome of melanoma depends on the local and distant spread of the disease at the time of diagnosis, as the estimated 5‐year survival rate is about 100% for superficial melanoma diagnosed early, but less than 10% for melanoma that has disseminated to major organs such as lungs. There is a crucial need for new effective methods for the detection and the characterization of melanomas. In the pre‐clinical setting, this will help to understand the factors that contribute to the malignancy while the transfer into the clinic will contribute to an early effective treatment of patients. Melanoma lesions can be detected by electron paramagnetic resonance (EPR) using paramagnetic properties of melanin pigments. As part of the development of EPR imaging to characterize melanomas, we evaluated in the present study the usefulness of EPR to report on the extension of lung metastases by comparing the method with bioluminescence imaging using B16 melanoma cells expressing luciferase. B16 melanoma cells were injected subcutaneously or intravenously in C57/BL6 mice. The primary tumors or the lung colonization by melanoma cells was measured after several delay periods to obtain several degrees of invasiveness. The animals were measured in‐vivo with bioluminescence after i.v. injection of luciferin. The primary tumors or lungs were then excised. After freeze‐drying, the content of melanin in lungs was measured and imaged by EPR at 9 GHz. We observed a direct relationship between the EPR intensity and the bioluminescence intensity. Another tumor model (KHT sarcoma), non‐pigmented but expressing luciferase, was used to confirm that the EPR signal was directly linked to the melanin pigment present in the tumors. Copyright © 2011 John Wiley & Sons, Ltd.     

B Lymphocytes in Rheumatoid Arthritis and the Effects of Anti–TNF-α Agents on B Lymphocytes: A Review of the Literature

Purpose

The aim of this article was to review published research related to B lymphocytes in rheumatoid arthritis, their role in the pathogenesis of the disease, the effects of tumor necrosis factor (TNF)-α inhibitors on B lymphocytes, the risk for infection, and responses to vaccines.

休克指数及CRAMS创伤评分法在腹部闭合伤早期抗休克治疗中的效果研究

目的 验证休克指数及CRAMS创伤评分法的应用在腹部闭合伤患者早期抗休克治疗中效果的研究。方法 (1) 将45例腹部闭合伤患者按随机数字表法分为干预组和对照组,两组均接受腹部闭合伤抗休克常规治疗,干预组按照干预策略既定的方案进行抗休克指数的监测及CRAMS创伤评分法查看两组之间的存活率是否存在统计学差异。（2）回顾45例腹部闭合伤病例,将其分为腹腔出血组和腹腔无出血组,探讨休克指数,CRAMS创伤评分法诊断出血的灵敏度。 结果 (1) 干预组与对照组相比,在腹腔脏器闭合性损伤时把休克指数与CRAMS创伤评分法相结合,与单纯的依靠收缩压和心率相比,在统计学上无明显差异。（2）通过对45例病例2个指标的灵敏度分析,监测休克指数与CRAMS创伤评分法对于判断腹腔内出血的灵敏度高于监测心率和收缩压。 结论 据试验结果我们可以推断：结合休克指数与CRAMS创伤评分法在腹部闭合伤患者抗休克的治疗中较单纯依靠心率和收缩压更具有临床意义。在急诊科,我们可以增加对于腹部闭合伤患者抗休克治疗时的休克指数与CRAMS创伤评分法的监测,可提高对于腹部闭合伤患者的病情判断、指导抢救及预后。     

Long-term survival of a patient with pancreatic cancer and lung metastasis: A case report and review of literature

BACKGROUNDPancreatic cancer (PC) is a leading cause of cancer-related death, given its poor prognosis and the limited benefits of traditional therapies. As tumors become more genetically disorganized as they progress, genetic mutations might become new markers for us to predict their behavior. Nowadays, many inhibitors can selectively target gene products as a form of targeted therapy, with some showing promise as treatment for various types of cancer.CASE SUMMARYWe describe a rare case of a PC patient with long-term survival of more than 8 yr. The patient was diagnosed with pancreatic ductal adenocarcinoma (PDAC) with BAP1 and PIK3CA gene mutations and Raf1 fusion and achieved partial response twice after treatment with apatinib in combination with chemotherapy.CONCLUSION BAP1, PIK3CA mutations, and Raf1 fusion are rare in PDAC. Patients with these three gene alterations of PDAC may achieve long-term survival with apatinib. Further research in other contexts is needed to determine whether apatinib has ideal efficacy for PC treatment.     

Ipilimumab in the treatment of melanoma

INTRODUCTION: Recent advances in the understanding of the complex cellular mechanisms regulating cancer immunity have led to new strategies in the development of cancer immunotherapy. Targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), a key negative regulator of immune activity, with the monoclonal antibody ipilimumab has shown promising clinical benefit in patients with advanced or metastatic melanoma. AREAS COVERED: This review illustrates the pharmacology of ipilimumab and highlights the clinical evidence regarding its efficacy and safety in patients with advanced or metastatic melanoma. The unique clinical response pattern and class-specific immune-related toxicity profile associated with this biologic agent are also characterized. A literature search using PubMed database was undertaken using search words ipilimumab, anti-cytotoxic T-lymphocyte-associated antigen 4, melanoma and tumor immunity barrier. EXPERT OPINION: Ipilimumab, approved by the FDA for patients with advanced or metastatic melanoma based on the overall survival benefit when compared with a peptide vaccine, is a major breakthrough in the treatment of melanoma. While clinicians are embracing this innovative biologic agent, special attentions in patient selection, class-specific immune-related toxicities and their management as well as treatment response evaluation are needed.     

Coles and Woolworths have installed public access defibrillators in all their stores: It is time other Australian businesses followed their lead

We welcome the recent announcement by Coles and Woolworths that public access defibrillators (PADs) are now available in their stores, as early defibrillation with PADs is associated with significantly increased survival from out‐of‐hospital cardiac arrests (OHCAs). From 2008 to 2018 there were 120 OHCAs in Victorian supermarkets, overall 26.6% survived; however, when defibrillated by a PAD 66.6% survived. For all OHCA in Victoria, survival for defibrillation by a PAD was also higher at 55.5%, compared to 28.8% for paramedic defibrillation. Using this state‐wide PAD survival rate, we estimate an additional 12 patients could have survived had PADs been available in all supermarkets. In Victoria last year there were 421 potentially viable OHCAs in public locations, of these 132 patients survived; however, had PADs been available an additional 101 patients could have survived. We therefore strongly encourage local businesses to install PADs, to safeguard the well‐being of their employees, customers and local communities.