Advances in lung cancer diagnosis and treatment - a review

Lung cancer is the second and third most common cancer in Iceland for females and males, respectively. Although the incidence is declining, lung cancer still has the highest mortality of all cancers in Iceland. Symptoms of lung cancer can be specific and localized to the lungs, but more commonly they are unspecific and result in significant diagnostic delay. Therefore, majority of lung cancer patients are diagnosed with non-localized disease. In recent years, major developments have been made in the diagnosis and treatment of lung cancer. Positive emission scanning (PET) and both transbroncial (EBUS) or transesophageal ultrasound (EUS) biopsy techniques have resulted in improved mediastinal staging of the disease and minimal invasive video-assisted thoracic surgery (VATS) has lowered postoperative complications and shortened hospital stay. Technical developments in radiotherapy have benefitted those patients who are not candidates for curative surgery. Finally, and most importantly, recent advances in targeted chemotherapeutics and development of immunomodulating agents have made individual tailoring of treatment possible. Recent screening-trials with low-dose computed tomography show promising results in lowering mortality. This evidence-based review focuses on the most important developments in the diagnosis and treatment of lung cancer, and includes Icelandic studies in the field.

Liposomal PHD2 Inhibitors and the Enhanced Efficacy in Stabilizing HIF-1α

Prolyl hydroxylase domain-containing protein 2 (PHD2) inhibition, which stabilizes hypoxia-inducible factor (HIF)-1α and thus triggers adaptation responses to hypoxia in cells, has become an important therapeutic target. Despite the proven high potency, small-molecule PHD2 inhibitors such as IOX2 may require a nanoformulation for favorable biodistribution to reduce off-target toxicity. A liposome formulation for improving the pharmacokinetics of an encapsulated drug while allowing a targeted delivery is a viable option. This study aimed to develop an efficient loading method that can encapsulate IOX2 and other PHD2 inhibitors with similar pharmacophore features in nanosized liposomes. Driven by a transmembrane calcium acetate gradient, a nearly 100% remote loading efficiency of IOX2 into liposomes was achieved with an optimized extraliposomal solution. The electron microscopy imaging revealed that IOX2 formed nanoprecipitates inside the liposome’s interior compartments after loading. For drug efficacy, liposomal IOX2 outperformed the free drug in inducing the HIF-1α levels in cell experiments, especially when using a targeting ligand. This method also enabled two clinically used inhibitors—vadadustat and roxadustat—to be loaded into liposomes with a high encapsulation efficiency, indicating its generality to load other heterocyclic glycinamide PHD2 inhibitors. We believe that the liposome formulation of PHD2 inhibitors, particularly in conjunction with active targeting, would have therapeutic potential for treating more specifically localized disease lesions.

Oral Colonization by Entamoeba gingivalis and Trichomonas tenax: A PCR-Based Study in Health, Gingivitis, and Periodontitis

BackgroundThe etiology of periodontitis remains unclear, as is the place of gingivitis in its pathophysiology. A few studies linked the colonization by oral parasites (Entamoeba gingivalis and Trichomonas tenax) to periodontal disease and its severity. The aim of the current study was to estimate the prevalence of these oral parasites among healthy individuals, and in patients with gingivitis and periodontitis in Jordan.MethodsThe study was conducted during July 2019–December 2019. Samples were composed of saliva and periodontal material including dental plaque sampled with probes. The detection of oral parasites was done using conventional polymerase chain reaction (PCR).ResultsThe total number of study participants was 237: healthy (n=94), gingivitis (n=53) and periodontitis (n=90). The prevalence of E. gingivalis was 88.9% among the periodontitis patients, 84.9% among the gingivitis patients and 47.9% in the healthy group. For T. tenax, the prevalence was 25.6% among the periodontitis patients, 5.7% among the gingivitis patients and 3.2% in the heathy group. Positivity for E. gingivalis was significantly correlated with the presence of periodontal disease compared to the healthy group with odds ratio (OR) of 6.6. Periodontal disease was also correlated with lower monthly income (OR=8.2), lack of dental care (OR=4.8), and history of diabetes mellitus (OR=4.5). Colonization by E. gingivalis was correlated with gingivitis (OR=6.1) compared to the healthy group. Colonization by E. gingivalis and T. tenax were significantly correlated with periodontitis (OR=6.4 for E. gingivalis, and OR=4.7, for T. tenax) compared to the healthy group. T. tenax was only detected among individuals with generalized periodontal disease compared to its total absence among those with localized disease (19.6% vs. 0.0%; p=0.039). The co-infection rate by the two oral parasites was 11.0%.ConclusionsThe higher prevalence of human oral parasites in periodontal disease compared to healthy individuals appears to be more than a mere marker for the disease and might also be associated with disease severity and potential for progression. Thus, the dogmatic view of E. gingivalis and T. tenax as commensals needs to be re-evaluated and their contribution to pathophysiology of periodontal diseases cannot be neglected.

The prostate tissue-based telomere biomarker as a prognostic tool for metastasis and death from prostate cancer after prostatectomy

ABSTRACTPurposeCurrent biomarkers are inadequate prognostic predictors in localized prostate cancer making treatment decision-making challenging. Previously, we observed that the combination of more variable telomere length among prostate cancer cells and shorter telomere length in prostate cancer-associated stromal cells – the telomere biomarker – is strongly associated with progression to metastasis and prostate cancer death after prostatectomy independent of currently used pathologic indicators.Experimental DesignWe optimized our method allowing for semi-automated telomere length determination in single cells in fixed tissue, and tested the telomere biomarker in tissue microarrays from five cohort studies of men surgically treated for clinically localized disease (N=2,255). We estimated the relative risk (RR) of progression to metastasis (N=311) and prostate cancer death (N=85) using models appropriate to each study’s design adjusting for age, prostatectomy stage, and tumor grade, which then we meta-analyzed using inverse variance weights.ResultsCompared with men who had less variable telomere length among prostate cancer cells and longer telomere length in prostate cancer-associated stromal cells, men with the combination of more variable and shorter telomere length, had 3.76-times the risk of prostate cancer death (95% CI 1.37-10.3; p=0.01) and had 2.23-times the risk of progression to metastasis (95% CI 0.99-5.02, P=0.05). The telomere biomarker was associated with prostate cancer death in men with intermediate risk disease (Grade Groups 2/3: RR=9.18, 95% CI 1.14- 74.0, p=0.037) and with PTEN intact tumors (RR=6.74, 95% CI 1.46-37.6, p=0.015).ConclusionsThe telomere biomarker is robust and associated with poor outcome independent of current pathologic indicators in surgically-treated men.Translational RelevanceCurrent prognostic biomarkers in localized prostate cancer are inadequate imperfect predictors; therefore, new biomarkers are needed to improve the prognostic classification and management of these patients. In a five-cohort study, we confirmed that the tissue-based telomere biomarker – the combination of more variable telomere length among prostate cancer cells and shorter telomere length in prostate cancer-associated stromal cells – was associated with progression to metastasis and prostate cancer death independent of currently used prognostic indicators after prostatectomy for clinically-localized disease. Importantly, the telomere biomarker was associated with poor outcome in men with intermediate risk disease, as well as in men with intact PTEN tumors. Thus, this tissue-based telomere biomarker has the translational potential to improve treatment and surveillance decision-making.

Real-world data analysis of patients with cancer of unknown primary

Cancer of unknown primary (CUP) is a heterogeneous malignancy in which the primary site of the tumor cannot be identified through standard work-up. The survival outcome of CUP is generally poor, and there is no consensus for treatment. Here, we comprehensively analyzed the real-world data of 218 patients with CUP (median age, 62 years [range, 19–91]; male, 62.3%). Next-generation sequencing was conducted in 22 (10%) patients, one of whom showed level 1 genetic alteration. Most (60.3%) patients were treated with empirical cytotoxic chemotherapy, and two patients received targeted therapy based on the NGS results. The median OS was 8.3 months (95% confidence interval [CI] 6.2–11.4), and the median progression-free survival of patients treated with chemotherapy was 4.4 months (95% CI 3.4–5.3). In multivariate Cox regression analysis, Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 and localized disease were significantly associated with favorable survival outcomes. Collectively, we found that CUP patients had a poor prognosis after standard treatment, and those with localized disease who received local treatment and those with better PS treated with multiple lines of chemotherapy had better survival outcomes. Targeted therapies based on NGS results are expected to improve survival outcomes.

Colon Cancer with Complete Pathological Response to Only 1 Cycle of Capecitabine: Treatment Modification in the Perspective of COVID-19 Pandemic

Incidence of colorectal cancer has surged in the past few decades, currently it accounts for approximately 10% cancer related mortality. Upfront curative surgery is the main stay of treatment for localized disease followed by adjuvant chemotherapy for high-risk disease; however, neo adjuvant chemoradiation followed by surgery and chemotherapy is a standard treatment for rectal cancer. Here, we present a case of a young male aged 33 years with eight months’ history of per rectal bleeding, associated with fever and weight loss who was later diagnosed as sigmoid colon adenocarcinoma. The patient managed to have only one cycle of neoadjuvant capecitabine, as his definitive surgery was delayed due to the rife in pandemic situation of Covid-19. Notably, follow up laparoscopic LAR specimen showed no residual disease, nevertheless, there was an eosinophilic abscess with a giant cell reaction and Ova of Ascaris lumbricoides, which seemingly contributed in achieving pathological complete response with minimal therapy.

Communication between cells: exosomes as a delivery system in prostate cancer

Despite the considerable efforts in screening and diagnostic protocols, prostate cancer still represents the second leading cause of cancer-related death in men. Many patients with localized disease and low risk of recurrence have a favourable outcome. In a substantial proportion of patients, however, the disease progresses and becomes aggressive. The mechanisms that promote prostate cancer progression remain still debated. Many findings point to the role of cross-communication between prostate tumor cells and their surrounding microenvironment during the disease progression. Such a connection fosters survival, proliferation, angiogenesis, metastatic spreading and drug-resistance of prostate cancer. Recent years have seen a profound interest in understanding the way by which prostate cancer cells communicate with the surrounding cells in the microenvironment. In this regard, direct cell-to-cell contacts and soluble factors have been identified. Increasing evidence indicates that PC cells communicate with the surrounding cells through the release of extracellular vesicles, mainly the exosomes. By directly acting in stromal or prostate cancer epithelial cells, exosomes represent a critical intercellular communication system. By querying the public database (https://pubmed.ncbi.nlm.nih.gov) for the past 10 years, we have found more than four hundred papers. Among them, we have extrapolated the most relevant about the role of exosomes in prostate cancer malignancy and progression. Emerging data concerning the use of these vesicles in diagnostic management and therapeutic guidance of PC patients are also presented. Graphical Abstract

Quality of Life After Definitive Linear Accelerator-based Stereotactic Radiotherapy for Prostate Cancer: a Longitudinal Study

Background: Prostate cancer is the second most common malignancy worldwide, and the majority of patients are diagnosed with localized disease. We examined patients’ quality of life after stereotactic body radiation therapy (SBRT) for prostate cancer. Method: We included patients who were treated between 2016 and 2020. Inclusion criteria were adenocarcinoma of the prostate; class risk of low, intermediate, and high; and a World Health Organization performance status of 0–2. Quality of life was measured using the Functional Assessment of Cancer Therapy-Prostate (FACT-P). Results: A total of 439 patients were treated with SBRT, with a median age of 73 years old. The median follow-up period was 34 months. FACT-P Trial Outcome Index (p < 0.0001), FACT-General (p = 0.0003), and FACT-P-Total (p < 0.0001) scores declined at 1 month post-SBRT, then recovered and returned to the same level as before treatment at 3–4 months post-SBRT. The decrease in quality of life in the first month was particularly remarkable in patients who received long-term hormone injections (36%). One month after the end of SBRT, about 22% of patients experienced "quite a bit” or more troubling side effects. Conclusions: This study showed longitudinal changes in quality of life by FACT-P after SBRT for prostate cancer. Overall, prostate SBRT was well tolerated.

Long-Term Outcome of Conjunctival Extranodal Marginal Zone Lymphoma: A Large Single-Institution Analysis

Background The most common subtype of B-cell lymphomas presenting in the conjunctiva is extranodal marginal zone lymphoma (EMZL), accounting for ~80% of cases. Most patients (pts) present with localized disease, and radiation therapy (RT) is the preferred treatment strategy. We aimed to retrospectively analyze our single-institution experience to provide further insight into the characteristics and long-term outcomes of conjunctival EMZL. Methods We evaluated 72 pts diagnosed with conjunctival EMZL between 01/1995 and 12/2020 at the University of Miami. Pts' characteristics included age, sex, TNM-AJCC ocular lymphoma and Ann Arbor staging systems, MALT-IPI score, treatment (RT, chemotherapy, rituximab), and treatment response (complete response (CR), partial response, stable disease, progression of disease). Primary endpoints were progression-free survival (PFS) and overall survival (OS), estimated using the Kaplan-Meier method, and compared using the log rank test and the univariable Cox regression analysis. We also performed a competing risk univariable analysis (UVA) assessing predictors of cumulative incidence of relapse/progression, with death without relapse as a competing risk, using the Fine and Gray regression analysis. Results Among all 72 pts, mean age was 59.9 yrs (7-93) with 38 (52.8%) being &gt;60 yrs old, 46 (63.9%) were female, 56 (77.8%) had unilateral conjunctival disease, localized disease (T1N0M0 and Ann Arbor stage I) was present in 63 (87.5%), 6 (8.3%) had disseminated disease with more than 1 extranodal site involved, and 29 (40.3%) had a MALT-IPI of 1 or 2. After biopsy and surgical removal, 65 (90.2%) received additional treatment, while 6 (8.3%) were followed only, and in one case therapy information was not available . RT was the most common treatment (53 pts [73.6%], with 46 [86.8%] of those treated with ≥ 30 Gy). In two of these patients RT was combined with chemotherapy. Other treated pts received immunochemotherapy (12 [16.7%], including rituximab in 8). Five pts with stage II-IV disease received systemic therapy. CR was achieved in 63 (87.5%) after first line treatment, and no high-grade lymphoma transformation was seen. With a median follow up of 6.67 yrs (0.56-24.13), there were 14 relapses (19.4%). Among 53 pts treated with RT there were 8 relapses (15.1%), only one (1.9%) within the RT field. There were 23 progression events (31.9%, 14 relapses and 9 deaths without documented relapse), and a total of 14 deaths (19.4%). Mean PFS and OS were 6.69 yrs (0.49-20.37, SD 4.95) and 7.81 yrs (0.56-24.13, SD 5.40), respectively. The 10-yr PFS and OS were 68.4% (95%CI 52.8, 79.8%) and 89.4% (95%CI 77.4, 95.2%), respectively. Variables associated with shorter PFS in UVA Cox model were age &gt; 60 yrs (HR=2.93, 95%CI 1.08, 7.95; p=0.035), high MALT-IPI (1-2) (HR=2.42, 95%CI 1.01, 5.78; p=0.048), and use of chemotherapy only (HR=2.73, 95%CI 1.13, 6.56; p=0.025). Variables associated with shorter OS included age &gt;60 yrs (HR=9.07, 95%CI 1.17, 70.26; p=0.035) and high MALT-IPI (HR=6.19, 95%CI 1.35, 28.33; p=0.019). CR after frontline therapy was associated with longer PFS (HR=0.13, 95%CI 0.04, 0.45; p=0.001) but not OS. PFS of MALT-IPI 0 vs 1-2 was significantly longer (p=0.042), with 10-yr PFS 80.9% (95%CI 63.4%, 90.6%) vs 55.6% (95%CI 32.1%, 73.8%). Similarly, longer OS was observed in MALT-IPI 0 pts (p=0.0077; 10-yr OS 95.2% [95%CI 82.2%, 98.8%] vs 80.6% [95%CI 55.6%, 92.4%]) (Figure). A subset UVA Cox analysis of patients with Ann Arbor stage I showed longer PFS associated with CR after frontline therapy (HR 0.15, 95%CI 0.04, 0.58; p=0.006) with no significant association with age &gt;60 yrs, high MALT-IPI or use of chemotherapy. Variables associated with shorter OS were age &gt;60 yrs (HR 8.01, 95%CI 1.00, 63.98; p=0.05) and high MALT-IPI (HR 13.41, 95%CI 1.67, 107.99; p=0.015), similarly to the primary analysis. On univariable Fine and Gray regression models with death without relapse/progression as a competing risk, RT (SHR=0.33, 95%CI 0.12, 0.96; p=0.041) and CR-post frontline therapy (SHR=0.11, 95%CI 0.03, 0.36; p&lt;0.001) were associated with lower risk of relapse. Conversely, chemotherapy (SHR=3.47, 95%CI 1.20, 10.0; p=0.022) was associated with higher risk of relapse. Conclusion Patients with conjunctival EMZL exhibit excellent long-term survival, and RT remains the most effective frontline therapy. MALT-IPI appropriately identifies patients at risk for treatment failure. Figure 1 Figure 1. Disclosures Alderuccio: ADC Therapeutics: Consultancy, Research Funding; Oncinfo / OncLive: Honoraria; Puma Biotechnology: Other: Family member; Inovio Pharmaceuticals: Other: Family member; Agios Pharmaceuticals: Other: Family member; Forma Therapeutics: Other: Family member. Lossos: Lymphoma Research Foundation: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy; NCI: Research Funding; Stanford University: Patents & Royalties; Verastem: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; NIH grants: Research Funding; University of Miami: Current Employment.

Somatic driver mutation prevalence in 1844 prostate cancers identifies ZNRF3 loss as a predictor of metastatic relapse

Driver gene mutations that are more prevalent in metastatic, castration-resistant prostate cancer (mCRPC) than localized disease represent candidate prognostic biomarkers. We analyze 1,844 localized (1,289) or mCRPC (555) tumors and quantify the prevalence of 113 somatic driver single nucleotide variants (SNVs), copy number aberrations (CNAs), and structural variants (SVs) in each state. One-third are significantly more prevalent in mCRPC than expected while a quarter are less prevalent. Mutations in AR and its enhancer are more prevalent in mCRPC, as are those in TP53, MYC, ZNRF3 and PRKDC. ZNRF3 loss is associated with decreased ZNRF3 mRNA abundance, WNT, cell cycle & PRC1/2 activity, and genomic instability. ZNRF3 loss, RNA downregulation and hypermethylation are prognostic of metastasis and overall survival, independent of clinical and pathologic indices. These data demonstrate a strategy for identifying biomarkers of localized cancer aggression, with ZNRF3 loss as a predictor of metastasis in prostate cancer.