Radiation therapy is a highly effective local treatment for cancer. However, sporadic events of tumor regression in unirradiated fields, known as abscopal effect, have been observed for decades. This abscopal effect has more recently been postulated to be a result of antitumor immune response induced by radiation therapy. With the advent of modern immunotherapy, the potential for immune activation by radiation therapy defines a novel role for radiation therapy in systemic disease. In this context, we have searched documented cases abscopal effect of radiation therapy in literature. A total of 46 reported cases have been identified from 1969 to 2014 with median radiation dose of 31 Gy, median follow-up of 17.5 months, and median documented time to notice the abscopal effect was 2 months. This review systematically summarizes all clinical case reports of abscopal effect to gain insight into this uncommon but important phenomenon.
Abstract The immune checkpoint targeted agents, anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and anti-programed cell death-1 (PD-1)/anti-programmed death-ligand 1 (PD-L1) inhibitors are frequently associated with cutaneous side effects, which are often dose-limiting and can lead to discontinuation of therapy. Ipilimumab, a CTLA-4 inhibitor, is most commonly associated with a morbilliform eruption on the trunk and extremities and pruritus. More severe cutaneous toxicities reported include toxic epidermal necrolysis (TEN) and severe drug rash with eosinophila and systemic symptoms (DRESS). Recent case reports of Sweet’s syndrome and cutaneous sarcoidosis have also recently been described after treatment with ipilimumab. The cutaneous events usually occur early in the course of treatment and are dose dependent. PD-1 inhibitors, nivolumab and pembrolizumab, induce similar but less severe toxicities compared to the CTLA-4 inhibitors. The most common cutaneous adverse events include lichenoid reactions, eczema, vitiligo, and pruritus. Lichenoid oral mucosal lesions located on the tongue, buccal mucosa, lips, and/or gingivae have also recently been described. The time of onset of the cutaneous events with the PD-1 inhibitors occurs later than that seen with the CTLA-4 inhibitors. Anti-PD-L1 antibodies, such as Atezolizumab, have a similar side effect profiles compared to the PD-1 inhibitors. Combination of immune checkpoint inhibitors, ipilimumab and nivolumab, has recently been approved for the treatment of advanced melanoma. The combination therapy is associated with a more severe side effect profile compared to the agents used as monotherapy. We discuss the most frequently encountered cutaneous side effects of the immune checkpoint inhibitors and review the recommended management strategies.
Abstract ‘Precision′ trials, using rationally incorporated biomarker targets and molecularly selective anti-cancer agents, have become of great interest to both patients and their physicians. In the endeavor to test the cornerstone premise of precision oncotherapy, that is, determining if modulating a specific molecular aberration in a patient′s tumor with a correspondingly specific therapeutic agent improves clinical outcomes, the design of clinical trials with embedded genomic characterization platforms which guide therapy are an increasing challenge. The NCI Precision Medicine Initiative is an unprecedented large interdisciplinary collaborative effort to conceptualize and test the feasibility of trials incorporating sequencing platforms and large scale bioinformatics processing that are not currently uniformly available to patients. NCI-MPACT and NCI-MATCH are two genomic to phenotypic trials under this NCI initiative, where treatment is selected according to pre-determined genetic alterations detected using next generation sequencing technology across a broad range of tumor types. In this review we will discuss the objectives and trial designs that have enabled the public-private partnerships required to complete the scale of both trials, as well as interim trial updates and strategic considerations that have driven data analysis and targeted therapy assignment, with the intent of elucidating further the benefits of this treatment approach for patients.
Generally, the cause of lung cancer is attributed to tobacco smoking. But many of the new lung cancer cases have been reported in nonsmokers. Apart from smoking; air pollution, environmental exposure, mutations, and single-nucleotide polymorphisms are known to be associated with lung cancer. Improper diet, alcohol consumption, marijuana smoking, estrogen, infections with human papillomavirus (HPV), HIV, and Epstein-Barr virus are suggested to be linked with lung cancer but clear evidences to ascertain their relation is not available. This article provides a comprehensive review of various risk factors and the underlying molecular mechanisms responsible for increasing the incidence of lung cancer. The pathologic, histologic, and genetic differences exist with lung cancer among smokers and nonsmokers. A better understanding of the risk factors, differences in pathology and molecular features of lung cancer in smokers and nonsmokers and the mode of action of various carcinogens will facilitate the prevention and management of lung cancer.
Abstract Radiation therapy (RT) is a cornerstone in oncologic management and is employed in various curative and palliative scenarios for local-regional control. RT is thought to locally control tumor cells by direct physical DNA damage or indirect insults from reactive oxygen species. Therapeutic effects apart from those observed at the treatment target, that is, abscopal effect, have been observed for several decades, though the underlying mechanisms regulating this phenomenon have been unclear. Accumulating evidence now suggests that the immune system is a major determinant in regulating the abscopal effect. It is now evident that RT may also enhance immunologic responses to tumors by creating an in situ vaccine by eliciting antigen release from dying tumor cells. Harnessing the specificity and dynamic nature of the immune system to target tumors in conjunction with RT is an emerging field with much promise. To optimize this approach, it is important to systematically evaluate the intricacies of the host immune system, the new generation of immunotherapeutics and the RT approach. Here we will discuss the current biologic mechanisms thought to regulate the RT-induced abscopal effect and how these may be translated to the clinical setting.
Cervical cancer is the fourth most common cancer among women globally. The burden faced by low- and middle-income countries is significantly greater than high-income countries. The disparity is a direct result of the differences in resources. Developed nations have organized vaccination and screening programs that have decreased their cervical cancer incidence. More readily available personnel and technology exists to implement appropriate treatment modalities. However, for many underdeveloped nations, the scarcity of resources and infrastructure make such preventative and treatment programs limited or even nonexistent.
Several forms of genomic instability are known to drive the development of colorectal cancer (CRC). Chromosomal instability is the most common type found in 85% of the CRC, while 15% patients have microsatellite instability (MSI). MSI tumors are the subset of CRC that are characterized by dysfunction of mismatch repair genes (MMR) causing failure to repair errors in repetitive DNA sequences called microsatellites. Twelve percent of MSI tumors are acquired, caused by methylation-associated silencing of a gene that encodes a DNA MMR protein, while the remaining 3% have germline mutations in one of the MMR genes (Lynch syndrome). The identification of microsatellite stability status is clinically important as studies have revealed that MSI tumors have a better stage-adjusted survival compared with microsatellite stable tumors, and they respond differently to 5FU-based adjuvant chemotherapy depending on this status. There is recent success of immunotherapy (mainly anti-PD1 drugs) in metastatic CRC with MMR dysfunction that has led to the initiation of multiple trials based on immune checkpoint inhibitors. Additionally, it is important to identify patients with Lynch syndrome so that it can guide the frequency of surveillance of CRCs and recommendations of prophylactic surgery. Even though TNM staging remains a key determinant of patient prognosis and guides management in patients with CRC, molecular tumor heterogeneity contributes to significant variability in clinical outcomes despite the same disease stage; therefore, it is vital to know the type of genomic instability pathway that the tumor harbors. In this article, we discuss the unique genetic, pathologic, and clinical characteristics of microsatellite unstable (MSI) and stable CRC (MSS), their predictive value in directing the management with conventional chemotherapy or novel-targeted agents, and their prognostic significance in patient outcomes.
Infection of high-risk human papillomaviruses (HPVs) is a prerequisite for the development of cervical carcinoma. HPV infections are also implicated in the development of other types of carcinomas. Chronic or persistent infection of HPV is essential but HPV alone is inadequate, additional endogenous or exogenous cues are needed along with HPV to induce cervical carcinogenesis. The strategies that high-risk HPVs have developed in differentiating epithelial cells to reach a DNA-synthesis competent state leading to tumorigenic transformation are basically due to overexpression of the E6 and E7 oncoproteins and the activation of diverse cellular regulatory or signaling pathways that are targeted by them. Moreover, the Wnt/β-catenin/Notch and phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathways are deregulated in various cancers, and have also been implicated in HPV-induced cancers. These are basically related to the “cancer hallmarks,” and include sustaining proliferative signals, the evasion of growth suppression and immune destruction, replicative immortality, inflammation, invasion, metastasis and angiogenesis, as well as genome instability, resisting cell death, and deregulation of cellular energetics. These information could eventually aid in identifying or developing new diagnostic, prognostic biomarkers, and may contribute to design more effective targeted therapeutics and treatment strategies. Although surgery, chemotherapy and radiotherapy can cure more than 90% of women with early stage cervical cancer, the recurrent and metastatic disease remains a major cause of cancer mortality. Numerous efforts have been made to design new drugs and develop gene therapies to treat cervical cancer. In recent years, research on treatment strategies has proposed several options, including the role of HPV E5, E6, and E7 oncogenes, which are retained and overexpressed in most of the cervical cancers and whose respective oncoproteins are critical to the induction and maintenance of the malignant phenotype. Other efforts have been focused on antitumor immunotherapy strategies. It is known that during the development of cervical cancer, a cascade of abnormal events is induced, including disruption of cell cycle control, perturbation of antitumor immune response, alteration of gene expression, deregulation of microRNA and cancer stem cell and stemness related markers expression could serve as novel molecular targets for reliable diagnosis and treatment of HPV-positive cancers. However, the search for new proposals for disease control and prevention has brought new findings and approaches in the context of molecular biology indicating innovations and perspectives in the early detection and prevention of the disease. Thus, in this article, we discuss molecular signaling pathways activated by HPV and potential targets or biomarkers for early detection or prevention and the treatment of HPV-associated cancers.
Abstract The last decade has witnessed rapid advances in the discovery and development of immune checkpoint inhibitors in cancer medicine, particularly drugs targeting programmed cell death 1 and programmed cell death ligand-1 in non-small cell lung cancer. The proven antitumor efficacy coupled with low rates of drug-related toxicities observed, albeit idiosyncratic, with these novel immunotherapeutics, have led to the registration of multiple programmed cell death 1 and programmed cell death ligand-1 inhibitors, such as nivolumab, pembrolizumab and atezolizumab, in second-line advanced non-small cell lung cancer, while durvalumab and avelumab are in late phase clinical testing. Moreover, pembrolizumab has shown a survival advantage in the first-line setting, however nivolumab failed to show a survival benefit possibly relating to patient selection on the basis of PD-L1 expression. Current patient selection is based on PD-L1 expression, using the relevant companion diagnostic test, where patients with strong PD-L1 expression being more likely to respond to these novel agents. Ongoing clinical research is now focused on the development of programmed cell death 1 and programmed cell death ligand-1 inhibitor monotherapy in neo-adjuvant and adjuvant non-small cell lung cancer. There is also much interest in using these drugs as a therapeutic backbone for rational combinations with other treatment modalities, including cytotoxic chemotherapies in the first line non-small cell lung cancer, other immunotherapies such as cytotoxic T-lymphocyte-associated protein-4 antagonists, molecularly targeted agents, including EGFR and ALK inhibitors, and radiotherapy. Concurrent treatment with radiotherapy is of particular interest due to the potential for the abscopal effect, whereby using radiotherapy to facilitate systemic treatment.
Although developments in the diagnosis and therapy of colorectal cancer (CRC) have been made in the last decade, much work remains to be done as it remains the second leading cause of cancer death. It is now well established that epigenetic events, together with genetic alterations, are key events in initiation and progression of CRC. Epigenetics refers to heritable alterations in gene expression that do not involve changes in the DNA sequence. These alterations include DNA methylation, histone alterations, chromatin remodelers, and noncoding RNAs. In CRC, aberrations in epigenome may also involve in the development of drug resistance to conventional drugs such as 5-fluorouracil, oxaliplatin, and irinotecan. Thus, it has been suggested that combined therapies with epigenetic agents may reverse drug resistance. In this regard, DNA methyltransferase inhibitors and histone deacetylase inhibitors have been extensively investigated in CRC. The aim of this review is to provide a brief overview of the preclinical data that represent a proof of principle for the employment of epigenetic agents in CRC with a focus on the advantages of combinatorial therapy over single-drug treatment. We will also critically discuss the results and limitations of initial clinical experiences of epigenetic-based therapy in CRC and summarize ongoing clinical trials. Nevertheless, since recent translational research suggest that epigenetic modulators play a key role in augmenting immunogenicity of the tumor microenvironment and in restoring immune recognition, we will also highlight the recent developments of combinations strategies of immunotherapies and epigenetic therapies in CRC, summarizing preclinical, and clinical data to signify this evolving and promising field for CRC treatment.
Carcinoembryonic antigen (CEA), carbohydrate antigen (CA)-125, CA19-9, and CA72-4 are often found modulated parameters in gastric cancer. Our present study is focused to evaluate the synchronization of these biomarkers in response to palliative chemotherapy. A retrospective study was conducted on 216 gastric cancer patients undergoing first-line cisplatin chemotherapy along with antiangiogenic regimen. Blood samples were taken and analyzed biochemically and statistically. Progression occurred in 78 of 216 patients and the median progression-free survival (PFS) was 5 months. For serum CEA, the median PFS was 4 versus 7 months for elevated and normal groups respectively ( = 0.01). The median PFS for normal and elevated CA19-9 and CA72-4 was 6 vs 4 months respectively ( = 0.001). In the multivariate Cox regression model, elevated pretreatment level of CEA, CA19-9, and distant metastases were independent factors associated with increased risk of progression ( = 0.021, = 0.000, = 0.006, respectively). Conclusively, elevated pretreatment level of CEA and CA19-9 is correlated with high risk of progression and worse prognosis. Moreover, an additional antiangiogenic therapy is more effective in decreasing cancer biomarker level after palliative chemotherapy that may be correlated with therapeutic triumph.
Uterine corpus endometrial carcinoma (UCEC) is one of the most common female gynecological malignant tumors that threaten women health seriously. MicroRNAs (miRNAs) has been proved to play critical roles in tumor pathogenesis and malignant progression. In this study, we aimed to explore a novel signature of microRNA expression for predicting the overall survival (OS) of patients with UCEC. The genome-wide miRNA expression profiles and relevant clinical characteristics of 348 patients with UCEC were downloaded from the Cancer Genome Atlas (TCGA) data portal and analyzed comprehensively. A total of 144 miRNAs were confirmed to be expressed differentially in tumor tissues. Among them, 6 miRNAs (hsa-mir-15a.MIMAT0000068, hsa-mir-142.MIMAT0000433, hsa-mir-142.MIMAT0000434, hsa-mir-3170.MIMAT0015045, hsa-mir-1976.MIMAT0009451, and hsa-mir-146a.MIMAT0000449) were validated to be significantly correlated with the OS of patients with UCEC. The risk indictor established by the 6-microRNA signature was proved be an independent prognostic factor (Hazard ratio = 0.391; 95% CI: 0.195-0.783; = 0.008). In conclusion, we identified miRNAs that were correlated with the occurrence and progression of UCEC and established a 6-microRNA expression signature as a predictor for the OS of patients with UCEC.
Abstract Immune checkpoint inhibitors have been approved for a variety of cancer species. Renal complications in use of these agents are not very common compared with other immune related adverse events (irAE). However, it is crucial for physicians to recognize and manage renal manifestations of irAE. In this review, we will summarize the up-to-date knowledge of the clinical presentation, pathological features and management of renal irAE. In addition, we will discuss the safety of immune checkpoint inhibitors in patients with chronic kidney disease as well as in kidney transplant recipients.
Immune checkpoint inhibitors are novel agents approved for the treatment of late-stage malignancies. Despite its important clinical benefits, checkpoint inhibition is associated with a unique spectrum of side effects known as immune-related adverse events. Skin toxicities are the most frequent immune-related adverse events during anti-PD1 blockade therapies. Among them, rare cases of psoriasis exacerbation have been reported. We present the clinical characteristics of exacerbated psoriasis in 5 patients under anti-PD1/PDL1 therapy. A total of 5 patients were overall included (4 males, 1 female mean age 65.8 years). Among them, 3 were diagnosed with nonsmall cell lung cancer, 1 with papillary urothelial carcinoma, and 1 with squamous cell carcinoma of the tonsil. Of all, 3 patients were treated with anti-PD1 (1 with pembrolizumab, 2 with nivolumab), whereas the remaining 2 with anti-PDL1 (durvalumab). Only 1 out of 5 patients had active psoriatic lesions at the time of treatment initiation, 2 shared a past history of psoriasis, and 1 reported a strong related family history (3/5 siblings). Four out of 5 patients experienced guttate lesions, though the most severe exacerbation was noted in the durvalumab group. Four out of 5 patients managed to continue treatment after close dermatologic monitoring, whereas 1 patient under durvalumab was forced to treatment delays owing to the severity of the skin reactions. Skin rashes appeared in all patients after the fourth cycle of immunotherapy. Both anti-PD1 and anti-PDL1 therapies can lead to psoriasis exacerbation although more severe flares were noted in patients treated with durvalumab. Not only personal but also related family history of psoriasis are significant risk factors and need to be outlined before treatment initiation. If such related history exists, strict skin surveillance can lead to the early diagnosis and treatment of any psoriatic exacerbations that could otherwise severely affect quality of life or even compromise therapeutic protocols and final prognosis.
To compare surgical outcomes and adverse events between patients received microsurgical resection of high-grade gliomas with or without fluorescein sodium-guidance. A retrospective study was conducted in our hospital between June 2016 and January 2017. Patients were divided into 2 groups: Fluorescein Group (42 patients) and Nonfluorescein Group (40 patients). Intraoperative (hemorrhage value and operation time) and postoperative (consistency between fluorescence-stained tissue and histopathological results, rate of resection) measurements were documented. Postoperative adverse events were recorded. Patients were followed up for 6 months to evaluate postsurgery glioma recurrence. Intraoperatively, hemorrhage value, and operation time were significantly less in Fluorescencein than in Nonfluorescencein group. The rate of glioma complete resection was significantly higher in Fluorescencein than in Nonfluorescencein group (85.7%vs 62.5%, = 0.02). The rate of glioma recurrence was significantly lower in Fluorescencein than in Nonfluorescencein group (11.9%vs 25.0%, = 0.01), and no significant differences on adverse events were observed. Intraoperative fluorescein sodium-guidance could facilitate the complete resection and significantly decrease the postoperative recurrence in patients with high-grade gliomas.
Globally, human papillomavirus (HPV) infection is one of the most common sexually transmitted infection. HPV is linked to at least five malignancies including vulvar, vaginal, anal penile, oropharyngeal, and cervical cancer. Three HPV vaccines are currently available: bivalent (HPV 16,18), quadrivalent (HPV 6,11,16,18), and nonavalent (6,11,16,18,31,33,45,52,58) targeting between 2 and 7 oncogenic HPV serotypes. This review highlights the currently epidemiologic burden of HPV-related cancers, efficacy of current HPV vaccines, and speculates about the benefits of widespread HPV vaccination. At present, all three vaccines are effective in reducing cervical disease and anogenital dysplasia in industry sponsored clinical trials and in limited study of clinical effectiveness. Models predict elimination of HPV infection with global vaccination rates of 80% and benefits in reducing malignancy at 20% global coverage. Large population-based clinical efficacy studies of these vaccines will be necessary to assess the true impact of vaccination. HPV vaccines provide a promising primary approach to preventing malignancy and barriers to vaccine access must be addressed to meet vaccination goals.
Cancer and stroke are the second and third causes of death worldwide; brain metastases (BM) occur in one third of patients with cancer, any neurologic deficit in these population always prompts the clinician to discard metastases for their presence carries a bad outcome. Both might share clinical presentation and differences in their outcome are not entirely known. The aim was to compare risk factors, clinical presentation, and outcome of cancer patients with BM vs stroke. A descriptive study with prospectively acquired data from a cancer referral center included patients seen at the neuro-oncologic unit from March 2011 to February 2018 with confirmed cancer who had BM or stroke. Six hundred and thirteen BM patients were compared with 268 with stroke and cancer. Demographic factors, cancer type, risk factors, clinical presentation, and outcome are presented. Median overall survival in months for those with any stroke was 15 (95%confidence interval [CI] 8.6-21.4)—5 (95%CI 0.12.4) for hemorrhagic stroke and 22 (95%CI 13.4-30.6) in the ischemic group—and for those with BM 12 (95%CI 10.4-13.6). Hemorrhagic stroke commonly found in stroke patients as well as focal motor weakness, aphasia, and altered mental status. BM was more common in breast and lung cancer with headache, visual complaint, and/or vertigo. Survival in cancer patients with BM is not that different than those with stroke, but clinical presentation and risk factors were found different.
: Primary squamous cell carcinoma (SCC) of the breast is a metaplastic carcinoma subtype which includes fibromatosis-like and sarcomatoid features. This is a very aggressive tumor with poor prognosis. Other sites of primary SCC should be ruled out first to classify these tumors as primary SCC of the breast. Here we present a case of locally advanced primary SCC of the breast. : A 72 years old woman presented with a right axillary lump. Trucut biopsy was performed, it showed squamous cell carcinoma. Estrogen receptor had poor immunoreactivity, negative for both progesteron receptor and HER 2 in immunohistochemistry staining. PETCT imaging were conducted to showing only 6 × 6.5 cm mass in right breast adjacent to axilla, multiple lymphadenomegaly in right axillary. We planned neoadjuvant chemotherapy consisting of weekly paclitaxel followed by epirubicin and cyclophosphamide combination. Postoperative pathology revealed wide necrosis, no viable tumor cell. We started adjuvant anastrozole treatment of 1 mg/day. No evidence of disease was detected after 1 year follow up. : Primary squamous cell carcinoma of the breast is a very rare disease with no standard treatment approach. Our case achieved pathologic complete response after neoadjuvant chemotherapy.