Advances in umbilical cord blood cell therapy: the present and the future

Introduction: Umbilical cord blood (UCB), previously seen as medical waste, is increasingly recognized as a valuable source of cells for therapeutic use. The best-known application is in hematopoietic stem cell transplantation (HSCT), where UCB has become an increasingly important graft source in the 28 years since the first umbilical cord blood transplantation (UCBT) was performed. Recently, UCB has been increasingly investigated as a putative source for adoptive cell therapy.

Areas covered: This review covers the advances in umbilical cord blood transplantation (UCBT) to overcome the limitation regarding cellular dose, immunological naivety and additional cell doses such as DLI. It also provides an overview regarding the progress in adoptive cellular therapy using UCB.

Expert opinion: UCB has been established as an important source of stem cells for HSCT. Successful strategies to overcome the limitations of UCBT, such as the limited cell numbers and naivety of the cells, are being developed, including novel methods to perform in vitro expansion of progenitor cells, and to improve their homing to the bone marrow. Promising early clinical trials of adoptive therapies with UCB cells, including non-immunological cells, are currently performed for viral infections, malignant diseases and in regenerative medicine.     

Prophylaxis for aspergillosis in patients with haematological malignancies: pros and cons

Introduction: Along with new diagnostic options, comes the recent development of novel antifungal agents that expanded the spectrum of activity over traditional treatments contributing to the successful management of fungal diseases. Nevertheless, invasive fungal infections (IFI) represent a major hindrance to the favorable outcome of patients with hematologic malignancies. According to these observations, an appropriate prevention of IFI occurring in hematologic patients should be considered of paramount importance. However, the wide use of antifungal agents may facilitate the emergence of resistance and may be associated to the occurrence of severe adverse events and eventually may significantly increase the cost of therapeutic procedures.

Areas covered: The aim of present review is to analyze advantages and disadvantages of primary antifungal prophylaxis (PAP) in hematologic patients.

Expert commentary: Patients with AML/MDS undergoing intensive chemotherapy and patients receiving stem cell transplantation are at high risk of IFI, and therefore may benefit form PAP, although several additional factors should be carefully evaluated in our decision-making approach, including the local epidemiology and the prompt availability of diagnostic facilities. The advent of new treatment options for hematologic patients such as target therapies might facilitate the rise of new risk categories so far underestimated.     

Anticancer cellular immunotherapies derived from umbilical cord blood

Introduction: The lack of highly effective drugs in many malignancies has prompted scientific interest in the development of alternative treatment strategies. Cellular immunotherapy involving the adoptive transfer of immune cells that potently recognize and eliminate malignantly transformed cells has become a promising new tool in the anticancer armory. Studies suggest that the unique biological properties of umbilical cord blood (UCB) cells could precipitate enhanced anticancer activity; hence, UCB could be an optimal source for immunotherapy with the potential to provide products with ‘off-the-shelf’ availability.

Areas covered: In this review, the authors summarize data on the transfer of naturally occurring or genetically modified UCB cells to treat cancer. The focus within is on the phenotypic and functional differences compared to other sources, the alloreactive and anticancer properties, and manufacturing of these products. Therapies utilizing cytokine-induced killer (CIK) cells, natural killer (NK) cells and chimeric antigen receptor (CAR) T-cells, are discussed.

Expert opinion: The cellular immunotherapy field has become a growing, exciting area that has generated much enthusiasm. There is evidence that anticancer immunotherapy with UCB-derived products is feasible and safe; however, considering the limited number of clinical trials using UCB-derived products, further studies are warranted to facilitate translation into clinical practice.     

Efficacy of antibody–drug conjugate brentuximab vedotin in treating Hodgkin’s lymphoma

Introduction: Hodgkin’s lymphoma (HL) patients refractory to first-line therapy or relapsed after autologous stem cell transplantation have a dismal prognosis, and their treatment represents an unmet medical need. Brentuximab vedotin (BV) is a second-generation antibody–drug conjugate (ADC) constituted by an anti-CD30 antibody linked to the cytotoxic drug monomethyl auristatin E. The first administration of BV in relapsed and refractory HL patients in a phase I study showed an impressive antilymphoma activity and prompted development of the drug.

Areas covered: This article reviews pharmaceutical characteristics of ADC and specific chemical features of BV related to mechanism of action and mechanism of resistance. Administration recommendation and main toxicities will also be described. Antilymphoma efficacy of BV alone and in combination with conventional chemotherapy and new compounds in different settings of HL patients will be examined.

Expert opinion: BV seems to be an effective and safe option for treatment of HL patients. BV alone or in association with chemotherapy as salvage regimen or as bridge to autologous or allogeneic transplant showed encouraging results. Exploration of new drug combinations and new settings of treatment is warranted in order to reduce long-term therapy-related toxicities and ameliorate survival of poor prognosis patients.     

Voriconazole for prophylaxis of invasive fungal infections after allogeneic hematopoietic stem cell transplantation

Introduction: Invasive fungal infections (IFIs) following allogeneic hematopoietic stem cell transplantation (alloHSCT) are associated with a high mortality, and accordingly most alloHSCT recipients receive prophylaxis with antifungal agents. Despite some improvement in outcomes of IFIs over time, they continue to represent substantial clinical risk, mortality, and financial burden.

Areas covered: We review the main pathogens responsible for IFIs in recipients of alloHSCT, current treatment recommendations, and discuss clinical and economic considerations associated with voriconazole prophylaxis of IFIs in these patients.

Expert commentary: The clinical efficacy of voriconazole appears to be at least equivalent to other antifungal treatments, and generally well tolerated. Overall, benefit-risk balance is favorable, and findings from cost-effectiveness analyses support the use of voriconazole prophylaxis of IFIs in recipients of alloHSCT.     

T cell optimization for the treatment of pancreatic cancer

Introduction: Pancreatic cancer remains a deadly disease despite advances in surgery, chemotherapy, and radiation therapy. Treatment failure is likely due to intense chemoresistance and immunosuppression. Therefore, new treatment paradigms are urgently needed. Immunotherapy, particularly adoptive T cell transfer, is a highly-personalized therapy that involves the isolation and ex vivo expansion of tumor-specific T cells before administration to cancer-bearing hosts.

Areas covered: This review summarizes different strategies of adoptive T cell therapy and their application in pancreatic cancer treatment. It also highlights recent advances and gives discussion on the future directions in T cell-based immunotherapy for pancreatic cancer.

Expert opinion: Pancreatic ductal adenocarcinoma is extremely challenging to treat, in part, due to intense desmoplastic reaction and immunosuppression. The recent progress in cancer immunotherapy triggers a hope to use immunotherapeutic modality to treat pancreatic cancer. Immunotherapy is generally well tolerated, and has the potential to function as a monotherapy or in synergistic combination with conventional chemotherapy. We must make efforts to optimize the immunotherapeutic regimen and to select patients to treat based on their biological profile. To accomplish this goal, an intense collaboration is needed to bridge between bench and bedside.     

Safety profile of snake antivenom (use) in Hong Kong – a review of 191 cases from 2008 to 2015

Introduction: The mainstay of treatment for significant envenoming from snakebites is antivenom. However, there is insufficient data regarding the safety of antivenom used in Hong Kong. We describe the incidence of hypersensitivity reactions from antivenom use and review the frequency and reasons for intensive care unit (ICU) admission.

Methods: The Hong Kong Poisons Information Centre database was reviewed. All patients given snake antivenom between 2008 and 2015 were included. Patient demographics, species of snake involved, details of antivenom used, treatment location, use of pre-treatment, reasons for ICU admission (where applicable) and details of early and late antivenom reactions were extracted.

Results: There were 191 patients who received snake antivenom. Most (93%) were treated with either the green pit viper antivenom from Thailand or the Agkistrodon halys antivenom from China. The incidences of early hypersensitivity reactions to green pit viper antivenom and Agkistrodon Halys antivenom were 4.7% and 1.4%, respectively. Most patients (69%) were managed in the ED observation ward or general ward. There were 59 patients managed in ICU, most (90%) of whom were admitted for close monitoring during antivenom administration. There were no cases of significant morbidity from antivenom administration. Eight patients (5.6%) had features suggestive of mild serum sickness.

Conclusions: The incidence of immediate hypersensitivity reaction to antivenom commonly used in Hong Kong is low. Majority of patients were managed safely in the emergency department observation ward or general ward. Serum sickness appears to be uncommon and possible cases presented with mild features.     

A double-blind placebo-controlled clinical investigation into pain reduction effect of placing the pain spot outside the intersection area of the two currents of interferential therapy compared to traditional method

Background: Interferential therapy (IFT) is applied to intersect in the painful area but no confirmed effect with this method. Experimentally, the highest voltage of IFT is induced outside the intersection of the two currents. Placing the painful area outside the intersection point (external application) would reveal a better effect.

Objectives: To examine the effect of external application in pain compared to traditional method.

Design: A double-blind placebo-controlled clinical investigation.

Setting: A public hospital.

Participants: 168 LBP subjects.

Interventions: Assignment: (1) external IFT, (2) placebo external IFT, (3) traditional IFT and (4) placebo traditional IFT. Groups 1 and 3 received 20 min of IFT at 100 Hz and groups 2 and 4 received sham IFT.

Main outcome measures: Before and after IFT session, pain severity (VAS), pressure threshold (PPT), pain distribution and ROM were assessed.

Results: IFT changed all outcomes similarly. VAS and ROM improved statistically, P < 0.03. A trend of better VAS reduced with active IFTs.

Conclusions: No therapeutic difference between the two methods.     

Managing the oncologic patient with suspected pneumonia in the intensive care unit

Introduction: Solid cancer patients are frequently admitted in intensive care units for critical events. Improving survival rates in this setting is considered an achievable goal today. Respiratory failure is the main reason for admission, representing a primary target for research.

Areas covered: This review presents a diagnostic and therapeutic algorithm for pneumonia and other severe respiratory events in the solid cancer population. It aims to increase awareness of the risk factors and the different etiologies in this changing scenario in which neutropenia no longer seems to be a decisive factor in poor outcome. Bacterial pneumonia is the leading cause, but opportunistic diseases and non-infectious etiologies, especially unexpected adverse effects of radiation, biological drugs and monoclonal antibodies, are becoming increasingly frequent. Options for respiratory support and diagnostics are discussed and indications for antibiotics in the management of pneumonia are detailed.

Expert commentary: Prompt initiation of critical care to facilitate optimal decision-making in the management of respiratory failure, early etiological assessment and appropriate antibiotic therapy are cornerstones in management of severe pneumonia in oncologic patients.     

Nucleos(t)ide analogues for preventing HBV reactivation in immunosuppressed patients with hematological malignancies: a network meta-analysis

Background: We aimed to evaluate the efficacy of five oral nucleos(t)ide analogues (NAs), including lamivudine, entecavir, adefovir, telbivudine and tenofovir, for the prevention of hepatitis B virus (HBV) reactivation and HBV-related complications in chronic hepatitis B virus (CHB) infected patients with hematological malignancies receiving chemotherapy or hematopoietic stem cell transplantation (HSCT) by network meta-analysis.

Methods: The search identified 28 articles involving 5 different prophylactic regimens covering 1478 participants.

Results: Among five prophylactic regimes, tenofovir (predicted probability, 90%), was the most effective intervention followed by entecavir (88%) in preventing HBV reactivation. There was no significant difference between tenofovir and entecavir for preventing HBV reactivation. With regards to other outcomes, tenofovir and telbivudine was not included to evaluate due to lack of relevant studies. Entecavir was the most effective intervention in reducing the risk of HBV related hepatitis (100%), HBV related death (61%) and all other causes of hepatitis (98%).

Conclusion: Tenofovir and entecavir might be the most potent regimes in prevention of HBV reactivation for CHB infected patients with hematological malignancies undergoing chemotherapy or HSCT.     

Resolution of cannabis hyperemesis syndrome with topical capsaicin in the emergency department: a case series

Background: Cannabinoid hyperemesis syndrome (CHS) is characterized by symptoms of cyclic abdominal pain, nausea, and vomiting in the setting of prolonged cannabis use. The transient receptor potential vanilloid 1 (TRPV1) receptor may be involved in this syndrome. Topical capsaicin is a proposed treatment for CHS; it binds TRPV1 with high specificity, impairing substance P signaling in the area postrema and nucleus tractus solitarius via overstimulation of TRPV1. This may explain its apparent antiemetic effect in this syndrome.

Purpose: We describe a series of thirteen cases of suspected cannabis hyperemesis syndrome treated with capsaicin in the emergency departments of two academic medical centers.

Methods: A query of the electronic health record at both centers identified thirteen patients with documented daily cannabis use and symptoms consistent with CHS who were administered topical capsaicin cream for symptom management.

Results: All 13 patients experienced symptom relief after administration of capsaicin cream.

Conclusion: Topical capsaicin was associated with improvement in symptoms of CHS after other treatments failed.     

Patient trajectories in a Norwegian unit of municipal emergency beds

Objective: The Coordination reform was implemented in Norway from 2012, aiming at seamless patient trajectories. All municipalities are required to establish emergency care beds (MEBs) to avoid unnecessary hospital admissions. We aimed to examine occupancy rate, patient characteristics, diagnoses and discharge level of municipal care in a small MEB unit.

Design: Cross-sectional, observational study.

Setting: A two-bed emergency care unit.

Subjects: All patients admitted to the unit during one year.

Main outcome measures: Patients’ age and gender, comorbidity, main diagnoses and municipal care level on admission and discharge, diagnostic and therapeutic initiatives, occupancy rate.

Results: Sixty admissions were registered, with total bed occupancy 194 days, and an occupancy rate of 0.27. The patients (median age 83 years, 57% women) had mostly infections, musculoskeletal symptoms or undefined conditions. Some 48% of the stays exceeded three days and 43% of the patients were subsequently transferred to nursing homes or hospitals.

Conclusion: Occupancy rate was low. Patient selection was not according to national standards, and stays were longer. Many patients were transferred to nursing homes, indicating that the unit was an intermediate pathway or a short cut to institutional care. It is unclear whether the unit avoided hospital admissions.     

Molecular diagnosis and molecular profiling to detect treatment-resistant ovarian cancer

Introduction: Epithelial ovarian cancer remains the gynecologic tumor with the highest rate of recurrence after initial optimal cytoreductive surgery followed by adjuvant chemotherapy. Unfortunately, with the development of recurrent ovarian cancer often comes the discovery of chemo-resistant disease. The absence of improvement in long term survival, notwithstanding the use of newer agents as is seen in other cancers, emphasizes the need for improved understanding of the processes that lead to chemo-resistant disease.

Areas Covered: This review will cover the following topics: 1. Molecular and cellular mechanisms in platinum and paclitaxel resistance 2. Other molecular mediators of chemo-resistance 3. Expression of stem cell markers in ovarian cancer and relationship to chemo-resistance 4. MicroRNA and long non-coding RNA expression in chemo-resistant ovarian cancer 5. Determination of chromosomal aberrations as markers of chemo-resistance 6. Molecular profiling in chemo-resistant disease.

A standard MEDLINE search was performed using the key words; ovarian cancer, chemo-resistant disease, molecular profiling, cancer stem cells and chemotherapy.

Expert Commentary: Over the next few years the challenge remains to precisely determine the mechanisms responsible for the onset and maintenance of chemo-resistance and to effectively target these mechanisms.     

The effect on the patient flow in a local health care after implementing reverse triage in a primary care emergency department: a longitudinal follow-up study

Objective: Reverse triage means that patients who are not considered to be in need of medical services are not placed on the doctor’s list in an emergency department (ED) but are sent, after face-to-face evaluation by a triage nurse, to a more appropriate health care unit. It is not known how an abrupt application of such reverse triage in a combined primary care ED alters the demand for doctors’ services in collaborative parts of the health care system.

Design: An observational study.

Setting: Register-based retrospective quasi-experimental longitudinal follow-up study based on a before–after setting in a Finnish city.

Subjects: Patients who consulted different doctors in a local health care unit.

Main outcome measures: Numbers of monthly visits to different doctor groups in public and private primary care, and numbers of monthly referrals to secondary care ED from different sources of primary care were recorded before and after abrupt implementation of the reverse triage.

Results: The beginning of reverse triage decreased the number of patient visits to a primary ED doctor without increasing mortality. Simultaneously, there was an increase in doctor visits in the adjacent secondary care ED and local private sector. The number of patients who came to secondary care ED without a referral or with a referral from the private sector increased.

Conclusions: The data suggested that the reverse triage causes redistribution of the use of doctors’ services rather than a true decrease in the use of these services.     

A European survey of perendoscopic treatment of biliary complications in patients with alveolar echinococcosis

Background: Biliary complications represent a turning point in the course of Alveolar Echinococcosis (AE). We conducted a European survey to collect data on the current usage and results of perendoscopic interventions (PEIs) for their treatment.

Methods: Patient’s characteristics and follow-up until January 31st, 2015 were recorded using an online questionnaire.

Results: From 18 centers 129 PEIs were analyzed in 38 patients; 139 plastic stents were inserted during 85 PEIs; median time between stent placements was significantly longer when 3 stents or more were placed. Initial symptoms disappeared in 95% and long-term bile duct patency was obtained in 73% of cases. Cholangitis was a more frequent complication of the PEIs (10%) than in other indications; intensive lavage of the bile ducts may prevent this complication.

Conclusion: European centers use perendoscopic biliary drainage as an efficient and safe alternative to surgery to treat AE biliary complications. Insertion of multiple plastic stents delays stent occlusion and leads to effective and prolonged bile duct patency.     

Contemporary molecular tests for prognosis and treatment guidance for castration-resistant prostate cancer

Introduction: Currently, clinical factors related to the malignancy and patient-related factors such as performance status and comorbidities are employed to select agents to treat metastatic castration resistant prostate cancer (mCRPC).

Areas covered: This paper covers emerging molecular panels that may be used in the clinic as prognostic or predictive biomarkers to treat mCRPC.

Expert commentary: The expression of androgen receptor variant (AR-V)-7 in circulating tumor cells appears especially promising to select patients for taxane chemotherapy versus androgen inhibitors, abiraterone and enzalutamide. Additionally, the presence of DNA repair alterations such as BRCA alterations are rapidly emerging as a predictive biomarker to develop precision medicine using PARP inhibitors for these patients.     

A systematic review to determine the optimal type and dosage of land-based exercises for treating knee osteoarthritis

Background: Exercise has been acknowledged as an effective non-pharmacological intervention for osteoarthritis. Consensus regarding the type of exercise i.e., aerobic or resistance, weight bearing or non-weight bearing, and dosage i.e., frequency, loading, duration, or intensity, is yet to be reached.

Objective: The purpose of this review was to address two questions: (1) is there a difference in clinical outcomes between different exercise programmes; and (2) what is the optimal dosage of exercises for people with knee osteoarthritis.

Methods: A systematic review was conducted. A study of published (AMED, CINAHL, MEDLINE, EMBASE, PubMed, and the Cochrane Library) and unpublished literature (WHO International Clinical Trials Registry Platform, current controlled trials and the United States National Institute of Health Trials Registry, and Open Grey) was undertaken in January 2013. Studies assessing the clinical outcomes of different types and dosages of exercise for people with osteoarthritis of the knee were included. Methodological quality was assessed using the critical appraisal skills programme (CASP) randomized controlled trial (RCT) appraisal tool.

Results: Ten studies assessing 958 knees from 916 participants were included. Exercise significantly improved pain and function for people with knee osteoarthritis. There was no significant difference in outcomes for different types of exercise i.e., aerobic versus resistance, weight bearing versus non-weight bearing. There was no significant difference in respect to the intensity of exercise i.e., high- versus lower-intensity resistance or aerobic exercises. The quality of the literature was moderate to high.

Conclusions: While exercise appears to improve symptoms and optimize function for people with knee osteoarthritis, the optimal form and dosage of exercise remains unknown.

Funding: None.

PROSPERO Registration Number: CRD42012002811.     

Pain pattern classification and directional preference for patients with neck pain

Objectives:

Pain Pattern Classification (PPC) and Directional Preference (DP) have been shown to be predictive of health care outcomes and serve to guide orthopedic clinical decision making. We conducted a prospective, observational cohort study to verify the association between PPC, DP, and clinical outcomes.

Methods:

Clinical outcome measures including pain intensity and disability were completed at first examination and follow-up by 335 patients. A Pearson’s chi-squared test was used to determine differences in prevalence rates for the categorical variables, and two-sample t-tests were used to determine differences in rates for the continuous variables. A Tukey’s range test was used to determine differences in follow-up pain intensity and disability for neck pain dual-classification schemes.

Results:

The prevalence of DP was 82.4%. The prevalence of CEN, Non-CEN, and Non-Classifiable (NC) was 15.2%, 42.1%, and 25.1%, respectively. The prevalence of DP was lowest for patients with sub-acute symptoms and who were <45 years old. Patients classified as DP CEN had, on average 2.62 NDI units less than patients classified as Non-DP. Patients classified as DP CEN had, on average, 0.90 pain intensity units less than patients classified as Non-DP at follow-up. Patients who demonstrated DP CEN did not have clinically significant lower pain intensity or disability at follow-up than patients who demonstrated Non-DP.

Discussion:

The results of this investigation need to be interpreted with caution with respect to the study design and it’s subsequent strengths and limitations.

Level of Evidence:

1b.     

Serum osmolal gap in clinical practice: usefulness and limitations

Background: Although serum osmolal gap can be a useful diagnostic tool, clinicians are not familiar with its use in clinical practice.

Objectives: The review presents in a series of questions-answers and under a clinical point of view the current data regarding the use of osmolal gap.

Discussion: The definition and the best formula used for the calculation of osmolal gap, the main causes of increased osmolal gap with or without increased anion gap metabolic acidosis, as well as the role of concurrent lactic acidosis or ketoacidosis are presented under a clinical point of view.

Conclusions: The calculation of osmolal gap is crucial in the differential diagnosis of many patients presenting in emergency departments with possible drug or substance overdose as well as in comatose hospitalized patients.     

Promising immunotherapies for esophageal cancer

Introduction: Esophageal cancer (EC) is the eighth most common cancer in the world, and the prognosis of EC is still poor. Although immunotherapy has been developed in melanoma and lung cancer, it is also expected to show efficacy in EC. Currently, several clinical trials are ongoing to evaluate the safety and efficacy of immunotherapies, immune checkpoint inhibitors, adoptive T cell transfer, and therapeutic cancer vaccines in EC.

Areas covered: This review provides an overview and the status of immunotherapy in EC. Clinical significance of molecules related immune checkpoints, especially PD-1 and PD-L1 is presented and the designs, results and future directions of clinical trials using immunotherapy in EC are provided.

Expert opinion: To bring immunotherapy to the forefront of treatment for EC, it is necessary to select patients who can obtain a high efficacy of immunotherapy and to also elucidate the correct timing for administration. Moreover, combination therapies of immunotherapy with existing chemotherapy or radiation or other immunotherapy with different mechanisms of action must be evaluated to achieve excellent outcomes in patients with EC.