Intralesional PV‐10 for the treatment of in‐transit melanoma metastases—Results of a prospective,non‐randomized,single center study

Background

Patients with in‐transit melanoma metastases frequently experience high rates of recurrence, limited overall survival and reduced quality of life. After promising results within a Phase II, multi‐center study, PV‐10 treatment was continued at our institution for patients with in‐transit disease.

Methodology

An open‐label, non‐randomized, prospective study was performed at the Princess Alexandra Hospital, Queensland, Australia. Patients were treated with PV‐10 in accordance with the treatment protocol established during a previous Phase II study. The primary outcome was the complete response of treated lesions.

Results

Forty‐five patients were enrolled over a total of 82 treatment episodes from July 2008 to December 2015. With sequential PV‐10 treatments the complete response rate was 42% and overall response rate 87% on an intention to treat analysis. The median follow‐up duration was 22 months and the median overall survival was 25 months from first PV‐10 treatment. Having fewer than 15 metastases at the time of treatment was associated with a complete response (P = 0.03).

Conclusions

Intralesional PV‐10 provided rapid lesion‐specific ablation of melanoma metastases with well‐tolerated local effects and minimal systemic adverse events. This therapy should be considered for patients with multiple accessible deposits within the spectrum of low to moderate disease volume.     

Quality‐of‐life and surgical treatments for rectal cancer—a longitudinal analysis using the California Cancer Registry

Background: Heterogeneous results for research investigating health‐related quality of life (HRQL) in patients undergoing sphincter‐ablating procedures for rectal cancer are likely due to single institution experiences and measurement of HRQL. To address this heterogeneity, we evaluated HRQL in patients with rectal cancer by type of surgery, location of tumor, and receipt of adjuvant therapy using an HRQL instrument that has not been used to address rectal cancer patients in a population‐based sample over time. Methods: The Functional Assessment of Cancer Therapy‐Colorectal instrument was administered at 9 and 19 months after diagnosis to a consecutive sample of 160 patients in Northern California identified by the California Cancer Registry. A broad multidimensional interpretation of HRQL was used to examine the impact of tumor location and treatment status, stage of disease, age, and gender. Results: In general, men had lower social well‐being scores, and younger patients had lower physical and emotional well‐being scores and colorectal concerns scores. We found no differences in HRQL by either tumor location or type of surgery, at either 9 or 19 months after diagnosis. Lower physical well‐being and greater adverse colorectal concerns were reported at 9 months among patients who received adjuvant therapy; however, only adverse colorectal concerns persisted over time. Conclusions: This study provides additional evidence that sphincter‐ablating procedures do not necessarily reduce quality of life in patients with rectal cancer. Distinctive features of this study include a broad multidimensional interpretation of HRQL, the 19 months of longitudinal follow‐up, and a prospective population‐based study design. Copyright © 2009 John Wiley & Sons, Ltd.     

Pan‐HER—An antibody mixture targeting EGFR,HER2 and HER3 abrogates preformed and ligand‐induced EGFR homo‐ and heterodimers

The human epidermal growth factor receptor (HER)‐family is involved in development of many epithelial cancers. Therefore, HER‐family members constitute important targets for anti‐cancer therapeutics such as monoclonal antibodies (mAbs). A limitation to the success of single HER‐targeting mAbs is development of acquired resistance through mechanisms such as alterted receptor dimerization patterns and dependencies. Pan‐HER is a mixture of six mAbs simultaneously targeting epidermal growth factor receptor (EGFR), HER2 and HER3 with two mAbs against each receptor. Pan‐HER has previously demonstrated broader efficacy than targeting single or dual receptor combinations also in resistant settings. In light of this broad efficacy, we decided to investigate the effect of Pan‐HER compared with single HER‐targeting with single and dual mAbs on HER‐family cross‐talk and dimerization focusing on EGFR. The effect of Pan‐HER on cell proliferation and HER‐family receptor degradation was superior to treatment with single mAbs targeting either single receptor, and similar to targeting a single receptor with two non‐overlapping antibodies. Furthermore, changes in EGFR‐dimerization patterns after treatment with Pan‐HER were investigated by in situ proximity ligation assay and co‐immunoprecipitation, demonstrating that Pan‐HER and the EGFR‐targeting mAb mixture efficiently down‐regulate basal EGFR homo‐ and heterodimerization in two tested cell lines, whereas single mAbs had limited effects. Pan‐HER and the EGFR‐targeting mAb mixture also blocked EGF‐binding and thereby ligand‐induced changes in EGFR‐dimerization levels. These results suggest that Pan‐HER reduces the cellular capability to switch HER‐dependency and dimerization pattern in response to treatment and thus hold promise for future clinical development of Pan‐HER in resistant settings.     

Reduced disease‐specific survival following a diagnosis of multiple primary cutaneous malignant melanomas—a nationwide,population‐based study

Outcome data comparing patients with multiple primary invasive cutaneous malignant melanomas (MPMs) to single primary invasive cutaneous malignant melanomas (SPMs) show conflicting results. We have analyzed differences in disease‐specific survival between these patients in a nationwide population‐based setting. From the Swedish Melanoma Register, 27,235 patients were identified with a first invasive cutaneous malignant melanoma (CMM) between 1990 and 2007, followed‐up through 2013. Of these, 700 patients developed MPMs. Cox proportional hazard regression was used for adjusted cause‐specific hazard ratios (HRs). An interval of ≤5 years between CMM diagnoses was significantly correlated to a decreased CMM‐specific survival in Stage I–II MPM‐ vs. SPM‐patients (HR 1.32; 95% CI 1.04–1.67; p = 0.02). MPM‐patients with longer time interval between diagnoses experienced similar risk of CMM‐death as SPM‐patients. The risk of CMM‐death increased by almost 50% above the expected outcome according to stage of the index CMM by the diagnosis of a second CMM (HR 1.48; 95% CI 1.19–1.85; p < 0.001). MPM vs. SPM‐patients had a worse outcome (HR 1.38; 95% CI 1.05–1.83; p = 0.001). This emphasizes the importance of prevention efforts in SPM‐patients to decrease the risk of subsequent CMMs and has implications for more vigilant follow‐up in MPM‐patients.     

Efficacy and safety of amphotericin B lipid‐based formulations—A systematic review and meta‐analysis

Invasive fungal infections, an important cause of mortality, are primarily treated using amphotericin B, which is available in different formulations, both conventional and lipid‐based (liposomal, lipid complex, colloidal dispersion and Intralipid^® infusion). The aim of our study was to determine the efficacy and safety of conventional amphotericin B vs its lipid‐based formulations. A systematic review followed by pairwise meta‐analysis was performed, including randomised controlled trials (RCTs) that evaluated the use of lipid‐based amphotericin B in patients with any degree of immunosuppression and susceptibility to invasive fungal infection. An electronic search was conducted using PubMed, Scopus, Web of Science and Scielo databases. Extracted outcomes were related to efficacy (cure) and safety (incidence of adverse events). Results were evaluated and meta‐analyses were performed. Twenty‐three RCTs were identified (n=2677 participants) for meta‐analysis. No significant differences between conventional amphotericin B and any of the five formulations evaluated were observed, with regard to the efficacy analysis. With respect to the adverse events of nephrotoxicity, fever, chills and vomiting, all lipid formulations presented better profiles than the conventional formulation. The present systematic review and meta‐analysis showed that conventional amphotericin B presents the same efficacy profile as lipid‐based formulations, although the latter were associated with a safer profile.     

Living with life‐prolonging chemotherapy—control and meaning‐making in the tension between life and death

Chemotherapy, radiotherapy, hormone therapy and immune therapy have made many cancers chronic, potential curable diseases rather than inevitably fatal, but the treatments are often both mentally and physically stressful even if the side effects varies. The right use of palliative chemotherapy is a complex issue and there are many aspects to take into consideration. The aim of the study was to gain insight into the illness narratives of cancer patients, from the day they suspected that something was wrong up to the present day where they are living with incurable cancer, undergoing life‐prolonging chemotherapy. Thirteen narrators were included. They were all cancer patients on chemotherapy with the intention of prolonging life (informed by their oncologist) in an outpatient's clinic in Norway. Narrative analyse of their illness stories was applied. The main findings showed that the narrators considered their lives worth living in spite of the treatment. They seemed to take control and build a new life on “what was left after the storm,” and described how they found meaning living in the tension between life and death.     

Effectiveness of telephone‐based interventions on health‐related quality of life and prognostic outcomes in breast cancer patients and survivors—A meta‐analysis

The aim of this meta‐analysis was to evaluate the effect of telephone‐based interventions on prognostic outcomes and health‐related quality of life (HRQoL) in breast cancer patients and survivors. A systematic search of the Cochrane Library, Web of science, Medline, EMBASE, CNKI and CBM database was carried out. Randomised, controlled trials (RCTs) examining the effects of telephone‐based intervention versus a control group receiving no telephone intervention, on prognostic outcomes and HRQoL with breast cancer were included. A meta‐analysis was conducted to quantify the effects of telephone‐based interventions on anxiety, depression, fatigue, self‐efficiency, physiological function, social‐domestic function and quality of life. In total, 14 studies involving 2002 participants were included. Due to the effect of telephone‐based interventions, statistically significant results were found on anxiety (standard mean difference [SMD] = ?0.16, 95% confidence intervals [CI] [0.01, 0.30], p = .04), self‐efficiency (SMD = 0.22, 95% CI [?0.34, ?0.10], p = .0004), social‐domestic function (SMD = 0.19, 95% CI [?0.35, ?0.03], p = .02) and quality of life (SMD = 0.54, 95% CI [?1.00, ?0.08], p = .02). Although the effects on depression, fatigue and physiological function were in the expected direction, these effects were not statistically significant (p > .05) based on the insufficient evidence.     

The changing trends and profile of pneumocystosis mortality in the United States, 1999‐2014

Pneumocystosis (PCP) mortality in the U.S. has received less attention in recent years. This study describes recent trends in mortality and the estimated burden of PCP in the U.S., using the national multiple cause of death data during 1999‐2014. PCP mortality rates were calculated for age, sex, race and year. Demographic differences were presented for decedents with and without a human immunodeficiency virus (HIV) co‐diagnosis. Matched odds ratios (MOR) were generated to describe associations between non‐HIV conditions and PCP mortality. In total, 11 512 PCP deaths occurred during 1999‐2014. Annual age‐adjusted PCP mortality decreased over this time period, from 0.479 to 0.154 per 100 000 population (1999 vs 2014 respectively). Over two‐thirds of decedents were male and Blacks had the highest mortality as compared to Whites. HIV co‐diagnosis accounted for 48% of all PCP deaths in 2014 vs 71% in 1999. Comorbid conditions such as connective tissue disorders (MOR=12.29; 95% confidence interval=[10.26, 14.71]) were associated with a PCP diagnosis. Productivity losses amounted to >$12 billion during the study period. Although widespread use of antiretroviral therapy and PCP prophylaxis for HIV infection likely contributed to the overall decline in PCP deaths during 1999‐2014, a continual need exists to prevent and treat this fungal disease in immune‐compromised populations that are not infected with HIV.     

Bevacizumab in Treatment of High‐Risk Ovarian Cancer—A Cost‐Effectiveness Analysis

Objective.

The objective of this study was to evaluate a cost-effectiveness strategy of bevacizumab in a subset of high-risk advanced ovarian cancer patients with survival benefit.

Methods.

A subset analysis of the International Collaboration on Ovarian Neoplasms 7 trial showed that additions of bevacizumab (B) and maintenance bevacizumab (mB) to paclitaxel (P) and carboplatin (C) improved the overall survival (OS) of high-risk advanced cancer patients. Actual and estimated costs of treatment were determined from Medicare payment. Incremental cost-effectiveness ratio per life-year saved was established.

Results.

The estimated cost of PC is $535 per cycle; PCB + mB (7.5 mg/kg) is $3,760 per cycle for the first 6 cycles and then $3,225 per cycle for 12 mB cycles. Of 465 high-risk stage IIIC (>1 cm residual) or stage IV patients, the previously reported OS after PC was 28.8 months versus 36.6 months in those who underwent PCB + mB. With an estimated 8-month improvement in OS, the incremental cost-effectiveness ratio of B was $167,771 per life-year saved.

Conclusion.

In this clinically relevant subset of women with high-risk advanced ovarian cancer with overall survival benefit after bevacizumab, our economic model suggests that the incremental cost of bevacizumab was approximately $170,000.     

Socioeconomic conditions among long‐term gynaecological cancer survivors—a population‐based case–control study

Background: The population of gynaecological cancer survivors is growing, yet little is known about the effects of cancer and treatment on socioeconomic conditions well beyond the completion of therapy. The aim of this study was to investigate the socioeconomic conditions in long‐term survivors of gynaecological cancer compared with a representative group of women from the general population. Material and methods: The study comprises women aged 32–75 residing in central part of Norway and who were treated as primary cases of gynaecological cancer at the University Hospital in Trondheim, Norway (n=160), and a control group from the general population (n=493). All analyses were done by χ² test and logistic regression. Results: Gynaecological cancer survivors scored lower on a Socioeconomic Condition Index than the control group. They had on the average a complete remission period of 12 years. Compared with the control group, they were more often disabled (p<0.01) and had lower annual household income (p<0.01). No difference was detected between the groups in ability to pay bills. More cases than controls had experienced problems assigning personal insurance (p<0.03). Conclusion: Long‐term gynaecological cancer survivors lived under poorer socioeconomic conditions, were more often disabled and had lower annual household income than the women in the control group, whereas no difference in ability to pay bills were found between the groups. In spite of poorer socioeconomic conditions, the gynaecological cancer survivors seem to adapt well to their financial situation. Copyright © 2009 John Wiley & Sons, Ltd.     

The effects of Candida proteinases on human proMMP‐9, TIMP‐1 and TIMP‐2

Matrix metalloproteinase (MMP)‐9 activity is controlled by the balance between MMP‐9 and its major tissue inhibitor of metalloproteinases (TIMPs). We hypothesised whether Candida proteinases may affect local tissue inflammatory processes by modifying these molecules. The effects of sonicated cells and concentrated growth media of six Candida species on MMP‐9, TIMP‐1 and TIMP‐2 were tested. Incubated samples were analysed by Western blot and detected by enhanced chemoluminescence techniques. The residual activity of degraded TIMP‐1 was evaluated by a casein degradation assay. The proteinase activity of the microbial strains was also assessed by a fluorimetric assay, and the action of inhibitors on MMP‐14 and Candida parapsilosis Cp2 was demonstrated. Cell fractions of both strains of C. parapsilosis exerted a weak ability to convert 92‐kDa proMMP‐9 to 86‐kDa active form. Cell fractions of both strains of Candida albicans, C. parapsilosis Cp2, Candida glabrata reference strain, and both strains of Candida krusei fragmented TIMP‐1 (28 kDa) to a 24‐kDa species, which associated with reduced inhibitory activity on MMP‐9 caseinolysis. Our findings indicate that Candida can participate in tissue inflammation by modifying the host’s MMP‐9 and their inhibitors. A rapid fluorimetric assay can be adapted for Candida proteinases.     

Deep facial mycosis due to Trichophyton verrucosum—molecular genetic identification of the dermatophyte in paraffin‐embedded tissue—case report and review of the literature

Deep trichophytosis is relatively uncommon. The infection of the bearded area is also known as sycosis barbae or tinea barbae and can be caused by various fungal species, most often zoophilic fungi. We report on an 80‐year‐old male patient with severe sycosis barbae who had no animal contact and was treated with systemic antibiosis without improvement. Microbial and mycological investigations using swabs from oozing lesions revealed Staphylococcus haemolyticus and Candida parapsilosis. Histology demonstrated fungal elements in hair follicles. Paraffin‐embedded material was subjected to further mycological analysis. For molecular diagnostics DNA was prepared from paraffin sections for real‐time polymerase chain reaction (RT‐PCR). For sequencing, DNA was isolated from paraffin‐embedded skin tissue and the ITS region of the rDNA was selected. Sequencing of the ITS2 region of rRNA revealed a 100% accordance with Trichophyton (T.) verrucosum. Treatment with oral terbinafine achieved a complete remission. Sycosis barbae is an important differential diagnosis for infections of the bearded area. Nucleic acid amplification techniques (NAAT) are more and more used for direct examination of dermatophytes in clinical samples, eg T. verrucosum. NAAT are also used as culture confirmation tests for identification of rare dermatophytes like T. verrucosum. Today, singleplex and multiplex quantitative real‐time PCR (qRT‐PCR) assays for the detection of the most common dermatophytes including T. verrucosum in clinical specimens are available. Recently, an ITS2 PCR assay has been successfully used for direct detection of T. verrucosum in paraffin‐embedded formalin‐fixed skin tissue. The PCR is fast and highly specific. The sensitivity of direct molecular detection of the dermatophytes both in native clinical material, and in paraffin‐embedded skin tissue can been increased.     

Vascular cell adhesion molecule‐1 (VCAM‐1)—An increasing insight into its role in tumorigenicity and metastasis

Vascular cell adhesion molecule‐1 (VCAM‐1) first attracted attention more than two decades ago as endothelial adhesion receptor with key function for leukocyte recruitment in term of cellular immune response. The early finding of VCAM‐1 binding to melanoma cells, and thus a suggested mechanistic contribution to metastatic spread, was the first and for a long time the only link of VCAM‐1 to cancer sciences. In the last few years, hallmarked by a growing insight into the molecular understanding of tumorigenicity and metastasis, an impressive variety of VCAM‐1 functionalities in cancer have been elucidated. The present review aims to provide a current overview of VCAM‐1 relevance for tumor growth, metastasis, angiogenesis, and related processes. By illustrating the intriguing role of VCAM‐1 in cancer disease, VCAM‐1 is suggested as a new and up to now underestimated target in cancer treatment and in clinical diagnosis of malignancies.     

Immune response in human chromoblastomycosis and eumycetoma – focusing on human interleukin‐17A,interferon‐gamma,tumour necrosis factor‐alpha,interleukin‐1 beta and human beta‐defensin‐2

Knowledge regarding host immune response to chromoblastomycosis and eumycetoma is limited, particularly concerning cytokines and antimicrobial peptides production. This was a retrospective study of 12 paraffin‐embedded tissue samples from patients diagnosed with chromoblastomycosis or eumycetoma from histological findings and tissue culture. DNA extraction and polymerase chain reaction (PCR) from tissues were done to evaluate human interleukin‐17A (IL‐17A), interferon‐gamma (IFN‐γ), tumour necrosis factor‐alpha (TNF‐α), interleukin‐1 beta (IL‐1β) and human beta‐defensin‐2 (HBD‐2) expressions. Human beta‐actin primer was used for confirming DNA detection, and DNA extracted from psoriasis lesional skin samples was used as positive controls. The twelve paraffin‐embedded sections used in this study consisted of five chromoblastomycosis and seven eumycetoma tissues. All PCR reactions showed beta‐actin band at 51 bp in all clinical specimens, confirming adequate DNA levels in each reaction. As positive control, the psoriasis skin samples revealed bands for IL‐17A at 174 bp, IFN‐γ at 273 bp, TNF‐α at 360 bp, IL‐1β at 276 bp and HBD‐2 at 255 bp. For the chromoblastomycosis and eumycetoma tissues, PCR analyses showed IL‐17A band at 174 bp in two eumycetoma tissues and HBD‐2 band at 255 bp in a chromoblastomycosis tissue. This study demonstrated IL‐17A expression in human eumycetoma and HBD‐2 expression in human chromoblastomycosis for the first time. However, their role in immune response remains to be elucidated.