Aim: Circulating tumor cells (CTCs) are crucial to tumor metastasis and valuable for prediction of clinical outcome in patients with solid tumors. Here, the authors aimed to establish a method for enumeration and characterization of CTCs from liquid biopsies. Methods: Peripheral blood mononuclear cells (PBMCs) were separated from blood samples from patients with metastatic cancer using Ficoll-Hypaque gradients and cultured to isolate and enumerate CTCs. Cultured CTCs were morphologically characterized by light and phase contrast microscopy. The tumorigenicity of Ficoll-Hypaque-separated PBMCs was examined, in addition to their expression of mRNA metastasis markers. Results: CTCs were isolated in culture and enumerated by counting under phase contrast microscopy, demonstrating that 0.01-0.04% of total PBMCs were CTCs. CTCs were dormant, with large, oval-shaped, spiky morphology. PBMCs obtained from liquid biopsies exhibited anchorage-independent growth, forming numerous colonies in soft agar assays. Molecular profiling demonstrated expression of several metastatic genes, but not of cadherin 1 (encoding the adhesion protein), in all patients. Conclusion: The authors successfully isolated, enumerated, and characterized CTCs from liquid biopsies of metastatic cancer patients. This study has potential to facilitate the development of new diagnostic and therapeutic methods using liquid biopsies, for application in metastatic cancers.
Aim: A “seed” of lung cancer metastasis is circulating tumor cells (CTCs), which may be dislodged from a tumor during biopsy. This possibility was assessed among patients who underwent lung tumor biopsy using flexible fiber-topic bronchoscopy (FFB).
Methods: The study involved six patients with non-small cell lung cancer who underwent FFB biopsy to diagnose a lesion pathologically (5 males and 1 female, median age 63 years, 6 adenocarcinomas, of 4 clinical-stage IA, 1 stage IB, and 1 stage IIIA), CTCs were extracted from the peripheral vein blood at pre-FFB and at post-FFB using a size selection method.
Results: No tumor cell was detected at pre- and post-FFB was in three cases (50%); no tumor cells were detected pre-FFB while CTCs were detected at post-FFB in two cases (33.3%); and CTCs were detected at pre-FFB with numerous CTCs detected at post-FFB in one case (17.7%). In addition, similar tendencies were observed in each analysis of single-cell and clustered-cell categories.
Conclusion: These results suggest that a FFB biopsy of lung cancer may potentially dislodge CTCs from a tumor into the circulating peripheral blood.
Aim: To establish a standardized protocol for the isolation and enumeration of circulating tumor cells (CTCs) from peripheral blood of patients with metastatic breast cancer.
Methods: The protocol used tumor cells spiked in a lymphoid cell line with detection by flow cytometry and quantitative reverse transcription polymerase chain reaction (QRT-PCR). Cells of the human mammary cancer subtypes were spiked into Jurkat cells, which served as the lymphocyte designate in numbers from 10 to 500 per 105 Jurkat cells. This mixed population was probed for CD45, EpCAM, and pancytokeratin acquired from flow cytometry and characterized by microscopy. QRT-PCR was done for CK-19, MUC-1, EpCAM, and GAPDH. Validation was attained with blood samples from 22 patients with metastatic breast cancer and 20 healthy individuals.
Results: Flow cytometry could detect 1 breast cancer cell per 100,000 Jurkat cells, with similar detection levels in the breast cancer subtypes. Samples from patients with breast cancer showed a range of CTCs from 1-85 per 10 mL of blood. Quantitation of expression for EpCAM, CK-19, Muc-1, and Her2neu confirmed the presence of CTCs in 76% of samples.
Conclusion: Density gradient and immunomagnetic enrichment accomplished isolation of CTCs and quantitation was achieved using flow cytometry. Combined QRT-PCR and imaging further validated these findings, rendering a robust methodology.
Alkaline phosphatase (ALP) flare has been reported to occur during cancer treatment as a favorable event, particularly in the presence of bone metastasis. There have been only a few reports in lung cancer and associated radiographic findings have seldom been described. The authors observed ALP flare in a female patient with lung adenocarcinoma soon after the initiation of gefitinib. Moreover, on computed tomography, metastatic lesions of the rib and thoracic spine showed marked hyperostosis, with sizes larger than the original bone structure, suggesting efficacy of gefitinib. The significance of such hyperostosis should be elucidated.
Myelodysplastic syndromes (MDS) include a heterogeneous group of blood disorders generally afflicting older people. Several genetic factors have been reported from these patients that have an important role in the diagnosis, prognosis, and treatment of this disease. BCR-ABL1 is a genetic factor that has occasionally been reported in some studies. This review attempts to characterize MDS patients reported to harbor this fusion and to assess the diagnostic, therapeutic, and prognostic potential of BCR-ABL1 fusionin MDS patients. This review showed that BCR-ABL fusion has been reported in 22 MDS patients whose condition generally transformed to acute myeloblastic leukemia and was not responsive to conventional therapies. However, these patients showed a good response to treatment with tyrosine kinase inhibitors. Therefore, even though incidence of BCR-ABL fusion appears to be low in MDS patients, its detection is essential in assessing disease prognosis and choosing appropriate treatment.
DNA damage is a vital challenge to cell homeostasis. Cellular responses to DNA damage (DDR) play essential roles in maintaining genomic stability and survival, whose failure could lead to detrimental consequences such as cancer development and aging. Nuclear factor-kappa B (NF-κB) is a family of transcription factors that plays critical roles in cellular stress response. Along with p53, NF-κB modulates transactivation of a large number of genes which participate in various cellular processes involved in DDR. Here the authors summarize the recent progress in understanding DNA damage response and NF-kB signaling pathways. This study particularly focuses on DNA damage-induced NF-κB signaling cascade and its physiological and pathological significance in B cell development and cancer therapeutic resistance. The authors also discuss promising strategies for selectively targeting this genotoxic NF-κB signaling aiming to antagonize acquired resistance and resensitize refractory cancer cells to cytotoxic treatments.
Aim: This study evaluates the efficacy and safety of percutaneous computed tomography (CT)-guided neurolysis using continuous radiofrequency for pain reduction in oncologic patients.
Methods: Over the course of 16 months, 22 patients underwent radiofrequency neurolysis as palliative therapy for pain reduction in celiac and splachnic plexus (n = 9), thoracic (n = 1), lumbar (n = 2) and superior hypogastric plexus (n = 5), as well as stellate ganglion (n = 5). Pain levels before treatment, one week after treatment, and at the last follow-up (average follow-up 6 months) were compared by means of a Numeric Visual Scale (NVS) questionnaire and a Brief Pain Inventory (Short Form) questionnaire.
Results: Median procedure time was 44 min. Median number of CT scans, performed to control correct positioning of the cannula and precise electrode placement, was 8. Pain scores of questionnaires prior to treatment (mean value 9.50 NVS units, range 8-10 NVS units) and post treatment (mean value 3.27 NVS units, range 2-6 NVS units) showed a mean decrease of 6.23 NVS units in terms of pain reduction and life quality improvement (P < 0.05). Overall mobility improved in 18/18 (100%) patients. No complication was observed.
Conclusion: This study concludes that CT-guided neurolysis by means of continuous radiofrequency ablation is a safe and efficient technique for pain palliation in oncologic patients.
Aim: To study the expression of PANDA, LincRNA-p21, and PUMA in lung tissue of patients with lung cancer from Xuanwei of Yunnan Province. Methods: Forty-five cases of lung cancer patients from Xuanwei and 42 lung cancer cases from non-Xuanwei were enrolled. Extraction of RNA was done using the Trizol kit. Real-time fluorescence quantitative PCR assay was done to obtain the relative expression. Results: Expressions of PANDA, LincRNA-p21, and PUMA in male and female patients or in squamous cell carcinoma and adenocarcinoma were not significantly different (P > 0.05). However, expression of LincRNA-p21 in Xuanwei patients was higher than non-Xuanwei patients (P < 0.05). Expression of PUMA in tumor tissue was lower than that in normal lung tissue (P < 0.05), and in Xuanwei patients was lower than non-Xuanwei patients (P < 0.05). In patients from non-Xuanwei regions, expression of LincRNA-p21 in patients with smoking index > 400 was higher than in those < 400 and non-smokers. Conclusion: Expressions of PANDA, LincRNA-p21, and PUMA in lung tissues have no gender differences or tissue specificity. High expression of LincRNA-p21 in Xuanwei patients may have relationship with cell damage caused by coal burning pollution in Xuanwei.
Metastases from head and neck cancers is rare occurrence. The common form of failure/recurrence in these cancers are local site recurrence or nodal metastases. Distant metastases are very rare and are most commonly seen in the lung, brain, liver and bones, and the latent period between the development of the primary and the distant metastases is usually long. There are very few cases reported of chest wall metastases from squamous cell carcinoma of head and neck. This article reports such a case of squamous cell carcinoma of buccal mucosa metastasizing to the chest wall four months after primary therapy. The metastasis was treated with local palliative radiotherapy to the chest wall. This case is special as the present knowledge on this type of presentation is limited in the medical literature.
Aim: Prostate cancer (PCa) is the second most prevalent male cancer worldwide and designated the sixth most frequent male cancer in Arab countries. Although prostate specific antigen (PSA) has become the best and most valuable biomarker for screening of PCa, elevated levels of PSA can reflect the presence of malignant cells but can overlap with benign prostatic diseases. There is a necessity to develop and improve current tools for early detection and diagnosis of PCa. This study was done to evaluate the validation of serum insulin-like growth factor-1 (IGF-1), IGF binding protein-3 (IGFBP-3), chromogranin A (CgA) and combination with PSA in treatment of benign prostatic hyperplasia (BPH) and PCa patients.
Methods: The study included 72 patients with PCa, 70 BPH patients and 56 healthy male subjects of matched age. Full history and clinical data were recorded for all subjects.
Results: Serum PSA attained sensitivity of 84% at 82% specificity with an accuracy of 83%, although IGF-1, IGFBP-3 and CgA did not recognize PCa patients.
Conclusion: Combinations of IGF-1 and IGFBP-3 biomarkers with PSA were effectively differentiated between PCa and control groups as well as improving the overall value of sensitivity, specificity and diagnostic accuracy of PCa to 85% and 86% for IGF-1/PSA and IGFP-3/PSA respectively.
Aim: Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) is still the “gold standard” for quantitative analysis of mRNA and the study of differentially expressed genes.
Methods: The authors describe a RT-qPCR array that exploits SYBR Green dye-based detection to perform reliable gene expression analysis on 41 genes involved in several pathways linked to DNA damage response, cell cycle progression, cellular senescence, and programmed cell death. To validate the RT-qPCR array, the authors investigated changes of the gene expression profile of HeLa cells treated with two well-characterized antiproliferative molecules such as cisplatin (CDDP) and sodium butyrate (NaBu).
Results: The results showed a gene expression profile compatible with both biological and gene expression data already reported in literature.
Conclusion: Importantly, the assay allowed the monitoring of additional and not reported gene regulations, indicating that this custom-made RT-qPCR array is a cheap, robust, and rapid tool for the study of drug-induced effects in human biological models.
Aim: Health care insurance improves access to care and thus outcome in patients with solid tumors. Little information on the impact of health care insurance on hematological malignancies including multiple myeloma exists. The authors aimed to analyze the effect of health care insurance on the survival of patients with multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) at Louisiana State University Health Sciences Center in Shreveport, LA.
Methods: Two hundred fifty seven patients were reviewed, of which 208 had MM and 49 had MGUS.
Results: One hundred and seventy seven patients (69%) were funded and 80 (31%) were non-funded. Funded patients with MM had an overall survival (OS) of 6.2 years compared to 3.8 years for non-funded patients (P < 0.001). Survivals were not significantly affected by race or gender. The analysis demonstrates that funded patients with MM and MGUS patients have statistically significant increased OS compared to patients with no insurance.
Conclusion: This study showed that patients with multiple myeloma and MGUS with health care insurance have longer overall survival when compared to non-funded patients.
Aim: Choroidal metastases are rare in the evolution of solid cancers and constitute exceptional metastatic sites involving functional visual prognosis. The authors conducted a retrospective study to determine the interest of external radiotherapy for the treatment of choroidal metastases.
Methods: The authors reviewed the records of 28 patients with choroidal metastases who had breast (n = 15), lung (n = 9), ovarian (n = 1), kidney (n = 1), prostate (n = 1) cancer or carcinoma with unknown primitive at the moment of the diagnosis (n = 1). The median age was 58 years (extremes: 34-71 years). Tumor stage before the discovery of metastatic choroidal metastasis was 50% of patients. Ocular involvement was unilateral (n = 22) or bilateral (n = 6). The delivered doses ranged from 20 to 50 Gy fractionated with 3-5 Gy in 2D technique (n = 5), conformational (n = 21), intensity modulation (n = 2). The most widely used prescription scheme delivered 30 Gy in 10 fractions (64%) using two 6 MV photons beams.
Results: At the end of irradiation, 13 patients (46%) showed an improvement of eye symptoms. For the others, a stabilization in symptoms was noted (n = 15). No patient had visual degradation. No acute or late grade 2-3 toxicities were objectified. The histological type did not influence the response (P = 0.5). There was no dose relationship-response in our series.
Conclusion: External radiation therapy is a useful technique in the palliative treatment of choroidal metastases. Acute and late toxicities are acceptable.
Primary sarcomas of kidney are exceptionally rare tumors, accounting for only 1-2% of all malignant tumors of kidney. Leiomyosarcoma (LMS) is the most common histological subtype among all renal sarcomas. The authors describe here a case of primary leiomyosarcoma of renal pelvis in a 50-year-old lady, presenting with flank pain. Based on triple phase cardio-electroencephalographic covariance tracing abdomen, presumptive diagnosis of renal cell carcinoma/renal sarcoma/neurogenic tumor was made and patient underwent radical nephrectomy. Microscopy reflected spindle cell tumor which showed strong positivity for desmin and smooth muscle actin with negative epithelial markers, thereby confirming the diagnosis of renal LMS. Owing to aggressive nature and low survival rates of LMS patient received adjuvant treatment in form of chemotherapy and radiotherapy. Patient is doing well 1 year post treatment.
Aim: Intravesical Bacille Calmette-Guérin (BCG) is the mainstay adjuvant treatment of non-muscle-invasive bladder cancer. However, one third of the patients on BCG regimen relapse within the first year of treatment. This study aimed at identifying biomarkers to predict response to BCG treatment.
Methods: Gene expression was analyzed in blood cells of 58 patients treated with BCG through six consecutive weekly instillations and then at month 3, 6, 9, and 12. Cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-10, interferon (IFN)-γ, IL-1β, IL-2, IL-4, and IL-6; chemokines CCL2, CCL3, CCL8, CXCL9, and IP-10; and mediators of cytotoxicity CTLA4, Fas-L, Perf, GNLY, NOS2A, and HMOX-1 were analyzed before the 1st and the 6th week instillation and 24 h after to assess fast (within 24 h) and prolonged changes resulting from treatment.
Results: BCG instillation led to fast-increased expression of IL-1β, TNF-α, and IL-10 genes. When compared to relapsing patients, patients with no relapses within one year showed significantly lower expression of IL-1β at 1st week and less IFN-γ, HMOX-1, and GNLY at week 6. HMOX-1 and GNLY were independent predictive biomarkers, and values above the cut-off ≥ 110 and ≥ 13.0 ‰ mRNA, respectively, were considered prejudicial factors. Patients with two HMOX-1 and GNLY factors had highest (66.7%) relapsing risk.
Conclusion: Assessing immunomodulators’ expression in blood allows the establishment of predictive cut-off values and identification of probabilities for patients’ relapses after BCG treatment.
Adenosine receptors are a family of G-coupled receptors which mediate the anti-inflammatory and immune-suppressive effects of adenosine in a damaged tissue. A large number of evidence indicate that the accumulation of adenosine under hypoxic conditions favors tumor progression, helping cancer cells to evade immune responses. Tumor cells and/or lymphoid and myeloid cells can express the adenosine-generating enzyme CD73 and/or A2A receptor, which in turn strongly suppresses an effective T-cell-mediated response, while promotes the activity of suppressive cells such as Treg and myeloid-derived suppressor cells. CD73 inhibitors and A2A antagonists, either as single agents, or in combination with immune-checkpoints inhibitors such as anti PD-1 monoclonal antibodies, are currently in Phase I clinical trial in cancer patients. Recent studies show that A2B receptor plays an important role in mediating the pro-tumor effects of adenosine, since its selective blockade can inhibit tumor growth in some murine tumor models. Targeting A2B receptor reduces immunosuppression induced by myeloid cells and inhibits the stromal cells activity within the tumor microenvironment, limiting tumor angiogenesis and metastatic processes. Here, the authors review the current data on involvement of A2B receptor in regulating tumor progression and discuss the development of A2B receptor inhibitors as potential therapeutic agents in cancer treatment.
The primary mode of treatment for desmoid tumors is surgical excision. However, high recurrence rates (39-79%) have been reported when surgery is used alone. The role of adjuvant radiotherapy after surgical resection of primary disease is controversial and should be based on a balanced discussion of potential morbidity from radiotherapy and local recurrence. In this patient, the maximum dimension of tumor was 21 cm. This is a larger chest wall fibromatosis than has been reported thus far, to the best of our knowledge. In this case, post-operative margins were free, but in view of the large initial tumor size and potential morbidity in case of any future locoregional recurrence, post-operative adjuvant external beam radiation was delivered. An image guided intensity modulated radiotherapy technique was chosen to spare adjacent breast and lung parenchyma, and tolerance of these structures was well respected. This case provides insight into this treatment approach.
A 78-year-old female patient arrived at our practice complaining of progressive abdominal increase and presenting a clinical picture of intestinal obstruction. At physical examination, the abdomen appeared distended, moderately painful with the presence of a mass of hard consistency. Abdominal computed tomography scan showed a large hypodense pelvic mass that indicated a compression and lateral deviation of the uterus and bladder. Microscopically, the mass showed a uniform solid pattern, composed of medium and large-sized cells with hyperchromatic and pleomorphic nuclei demonstrating high mitotic activity and diffuse immunoreactivity for estrogen receptors and synaptophysin. A diagnosis of uterine poorly differentiated large cell neuroendocrine carcinoma, arising in the endometrium with an unusual colonic metastatic localization, was made.
Aim: Estrogen receptor-α (ER-α) activation drives the progression of luminal breast cancers. Signaling by transforming growth factor-β (TGF-β) typically opposes the actions of ER-α; it also induces epithelial-mesenchymal transition (EMT) programs that promote breast cancer dissemination, stemness and chemoresistance. The impact of EMT programs on nongenomic ER-α signaling remains unknown and was studied herein.
Methods: MCF-7 and BT474 cells were stimulated with TGF-β to induce EMT programs, at which point ER-α expression, localization, and nongenomic interactions with receptor tyrosine kinases and MAP kinases (MAPKs) were determined. Cell sensitivity to anti-estrogens both before and after traversing the EMT program was also investigated.
Results: TGF-β-stimulated MCF-7 and BT474 cells to acquire EMT phenotypes, which enhanced cytoplasmic accumulation of ER-α without altering its expression. Post-EMT cells exhibited: (1) elevated expression of EGFR and IGF1R, which together with Src formed cytoplasmic complexes with ER-α; (2) enhanced coupling of EGF, IGF-1 and estrogen to the activation of MAPKs; and (3) reduced sensitivity to tamoxifen, an event reversed by administration of small molecule inhibitors against the receptors for TGF-β, EGF, and IGF-1, as well as those against MAPKs.
Conclusion: EMT stimulated by TGF-β promotes anti-estrogen resistance by activating EGFR-, IGF1R-, and MAPK-dependent nongenomic ER-α signaling.
Aim: The study investigated the effect of papaya seeds on prostate cancer (PC) using PC-3 cell line because papaya seeds have effects on the male reproductive system notably decreasing sperm concentration, motility, and viability, leading to azoospermia after short-to-long-term treatment.
Methods: The black seeds from yellow (ripe) papaya and white seeds from green (unripe) papaya were harvested and then extracted in water, 80% methanol, and hexane. The cytotoxic effects of seeds extracts were determined using a WST-1 proliferation assay. The amount of total polyphenols was determined using Folin Ciocalteu reagent.
Results: The methanol extracts from black seeds significantly (P < 0.05) decreased cell proliferation of PC-3 cells whereas hexane- and water-extracts have no effect. However, the water-extract from white seeds stimulated PC cell proliferation. The black seeds contained significantly more polyphenols than that of white seeds. The data suggest that black seeds from papaya have anticancer effects on PCs whereas white seeds stimulated prostate cancer proliferation. The anticancer effect of black seeds may be because of their high concentration of polyphenols.
Conclusion: The black seeds from papaya may have a potential to reduce growth of prostate cells; however, consumption of white seeds should be avoided as they may stimulate pre-existing prostate cancer.
Aim: To study the impact of Helicobacter pylori (H. pylori) and lipid metabolic disorder on the expression of Th17-related cytokines in gastric cancer (GC). Methods: GC specimens were randomly collected from 42 patients, of whom 15 had H. pylori infection and 27 were without. Tumor RNA was extracted for reverse transcription quantitative polymerase chain reaction quantification of gene expression. Results: The mRNA levels of interleukin (IL)-6 and leptin, which are known to regulate Th17 differentiation, were upregulated by 20 and 6 folds, respectively, in H. pylori-infected compared to uninfected patients. IL-17A and granulocyte-macrophage colony-stimulating factor, two cytokines produced by Th17 cells, were 5- and 6-fold higher in tumors with H. pylori infection, respectively. Consistently, RORγt, a transcription factor regulating Th17 differentiation, was increased 6-fold in H. pylori-positive vs. negative tumors. Further elevation of RORγt was seen in advanced H. pylori-associated tumors. In addition, H. pylori infection was also associated with enhanced expression of CXCL1 (5 folds), chemotactic factor capable of driving bone marrow-derived immature myeloid cells. Interestingly, we observed that H. pylori-associated increase of IL-17A was enhanced in the group with higher plasma triglycerides. Conclusion: The findings demonstrate a cross-talk and synergistic role of H. pylori infection and abnormal lipid metabolism in GC development, at least partly via cooperative induction of Th17 differentiation and activation.
Aim: Overtreatment of early-stage low-risk prostate cancer patients represents a significant problem in disease management and has significant socio-economic implications. Changes in prostate cancer screening and treatment practices in the United States have been associated with the recent decline in overall incidence and concomitant significant increase of the annual incidence of metastatic prostate cancer has been documented. Therefore, development of genetic and molecular markers of clinically significant disease in patients diagnosed with low grade localized prostate cancer would have a major impact in disease management. Methods: Identification of gene expression signatures (GES) associated with lethal prostate cancer has been performed using microarray analyses of biopsy specimens obtained at the time of diagnosis from 281 patients with Gleason 6 (G6) and G7 tumors in a Swedish watchful waiting cohort with up to 30 years follow-up. The performance of GES has been validated in independent cohort of 568 prostate cancer patients of the Cancer Genome Anatomy Project Prostate Cancer database. Results: GES comprising 98 genes identified 89% and 100% of all death events 4 years after diagnosis in G7 and G6 patients, respectively. At 6 years follow-up, 83% and 100% of all deaths events were captured in G7 and G6 patients, respectively. Remarkably, the 98-gene signature appears to perform successfully in patients stratification with as little as 2% of cancer cells in a specimen, strongly indicating that it captures a malignant field effect in human prostates harboring cancer cells of different degrees of aggressiveness. In G6 and G7 tumors from prostate cancer patients of age 65 or younger, GES identified 86% of all death events during the entire follow-up period. In G6 and G7 tumors from prostate cancer patients of age 70 or younger, GES identified 90% of all death events 6 years after diagnosis. Conclusion: Classification performance of the reported in this study 98-genes GES of lethal prostate cancer appeared suitable to meet design and feasibility requirements of a prospective 4 to 6 years clinical trial, which is essential for regulatory approval of diagnostic and prognostic tests in clinical setting. Prospectively validated GES of lethal PC in biopsy specimens of G6 and G7 tumors will help physicians to identify, at the time of diagnosis, patients who should be considered for exclusion from active surveillance programs and who would most likely benefit from immediate curative interventions.
The field of circulating tumor cell (CTC) enrichment has seen many emerging technologies in recent years, which have resulted in the identification and monitoring of clinically relevant, CTC-based biomarkers that can be analyzed routinely without invasive procedures. Several molecular platforms have been used to investigate the molecular profile of the disease, from high throughput gene expression analyses down to single cell biological dissection. The established presence of CTC heterogeneity nevertheless constitutes a challenge for cell isolation as the several subpopulations can potentially display different molecular characteristics; in this scenario, careful consideration must be given to the isolation approach, whereas methods that discriminate against certain subpopulations may result in the exclusion of CTCs that carry biological relevance. In the context of prostate cancer, CTC molecular interrogation can enable longitudinal monitoring of key biological features during treatment with substantial clinical impact, as several biomarkers could predict tumor response to AR signaling inhibitors (abiraterone, enzalutamide) or standard chemotherapy (taxanes). Thus, CTCs represent a valuable opportunity to personalize medicine in current clinical practice.
Aim: The objective of this study was to examine the health-related quality of life (HRQOL), and its correlates among rectal cancer survivors. Methods: This cross-sectional study was conducted in the northwest of Iran. Rectal cancer survivors were selected from teaching hospitals. HRQOL was estimated using the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire C30. Information about socio-demographic, lifestyle and clinical features of disease was obtained by trained interviewers. Results: A total of 96 patients were included in this study with mean age of 57.31 ± 14.15 years, 54% were male and 59% over 55 years of age. Women performed poorer than men in many dimensions of HRQOL (P < 0.05). Total score of symptoms was higher in those who had a higher stage of the disease. Participants with insufficient physical activity had a lower score in physical and role dimensions and a higher score of pain and fatigue (P < 0.05). In multiple regression models, treatment, stage of disease, and physical activity were important predictive factors of HRQOL. Conclusion: Some clinico-epidemiological factors were associated with a reduced score of HRQOL and its dimensions in this study. Overall, better performance in the presence of a modifiable factor; physical activity, is an opportunity for interventional strategies to improve the HRQOL.
Hyperthermia is a type of medical modality for cancer treatment using the biological effect of artificially induced heat. Even though the intrinsic effects of elevated body temperature in cancer tissues are poorly understood, increasing the temperature of the body has been recognized as a popular therapeutic method for tumorous lesions as well as infectious diseases since ancient times. Recently accumulated evidence has shown that hyperthermia amplifies immune responses in the body against cancer while decreasing the immune suppression and immune escape of cancer. It also shows that hyperthermia inhibits the repair of damaged cancer cells after chemotherapy or radiotherapy. These perceptions indicate that hyperthermia has potential for cancer therapy in conjunction with immunotherapy, chemotherapy, radiotherapy, and surgery. Paradoxically, the anticancer effect of hyperthermia alone has not yet been adequately exploited because deep heating techniques and devices to aggregate heat effects only in cancer tissues are difficult in practical terms. This review article focuses on the current understanding concerning cancer immunity and involvement of hyperthermia and the innate and adoptive immune system. The potential for combination therapy with hyperthermia and chemotherapy, radiotherapy, and surgery is also discussed.
Uveal (eye) melanoma is the most common primary eye malignancy in adults. Despite optimal treatments for primary uveal melanoma, up to 50% of patients subsequently develop systemic metastasis, often in the liver. Once hepatic metastasis develops, the survival of patients is generally short and currently available treatments fail to show meaningful improvement of survival. Recent development of immune checkpoint blockades revolutionized immunotherapy for metastatic cutaneous (skin) melanoma. Unfortunately, metastatic uveal melanoma is unresponsive to this approach, thus there is an unmet need to improve the treatment of metastatic uveal melanoma. One unique characteristic of uveal melanoma is that the majority of metastases first develop in the liver. The liver is highly specialized in development of immune tolerance to food-derived antigens and consequently serves a unique function in the immune system. Understanding the mechanisms by which the liver orchestrates immune-related responses is important to the development of an effective immunotherapy for hepatic metastases such as metastatic uveal melanoma. In this review article, the authors overview the immunological aspects of the liver and discuss approaches to improve immunotherapy for metastatic uveal melanoma.
Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Most of the time, these tumors are diagnosed at late stages. Because no effective treatments exist for patients with advanced stage HCC, there is an urgent need for novel, effective treatments. Cancer cells originate as a consequence of abnormal expression of oncogenes or loss of tumor suppressor genes. Often, neoplastic transformation results in a hyper-mutated cellular genome, which in turn produces neo-antigens from mutated genes. These tumor-specific or tumor-associated antigens can be recognized by antigen-presenting cells and trigger T-lymphocytes to elicit anticancer immunity. Immune responses to cancers are often rendered ineffective by tumor immune-editing and immune-suppressive mechanisms. Yet, therapeutic strategies to stimulate anti-cancer immunity have had remarkable success in several solid and hematological malignancies. Among the various strategies for cancer immunotherapy, cell-mediated immunotherapy holds considerable promise to overcome anergy and systemic immune suppression. This brief review will focus on cell-mediated immunotherapy for HCC.
The knowledge that the body possesses natural defenses to combat cancer existed long before the modern period, with multiple anecdotal reports of tumors miraculously disappearing, sometimes spontaneously or after a febrile or infectious episode. Spontaneous tumor regression of untreated malignant tumors is currently a well-accepted albeit rare phenomenon, and it is recognized that immunosuppression is associated with a higher cancer risk. The treatment of bladder carcinoma by intravesical administration of live attenuated Bacillus Calmette-Guérin bacteria was shown to be very effective in 1976 and is now standard treatment. Effective immunity against cancer involves complex interactions between the tumor, the host, and the environment. Cancer immunotherapy uses various strategies to augment tumor immunity and represents a paradigm shift in treating cancer, since attention has become more focused on the “biologic passport” of the individual tumor rather than the site of origin of the tumor. The different types of cancer immunotherapies discussed here include biologic modifiers, such as cytokines and vaccines, adoptive cell therapies, oncolytic viruses, and antibodies against immune checkpoint inhibitors, such as the co-inhibitory T-cell receptor PD-1 and one of its ligands, programmed death-ligand 1.
For scientists pursuing drug development for prostate cancer, it is critical that an appropriate ex vivo or in vitro model system is available for study. Cancer research has generally consisted of: (1) finding the means to arrest fast growing cancer cells; or (2) (as a compromise) to slow down the excessive rate of cell growth; or in the best case (3) to kill the cancer cells whilst sparing the surrounding normal tissues. As the knowledge of the biological nature of the cancer cell improves, it has become increasingly apparent that such a simplistic attitude to cancer therapy development or indeed diagnosis is rapidly outdated, and a closer liaison between the clinic and the laboratory studies is more important than ever as the author seeks to target specific gene expression pathways, specific signaling pathways, cancer specific mutations and indeed the interactions between cancer cells and their micro-environment, all of which provide a tremendous potential for novel therapeutic development.
If the treatment landscape for prostate cancer is to be transformed, clinicians and scientists must work together ever more closely. Prostate cancer defeats physicians when patients are not accurately stratified according to patients’ risk of dying of disease, when the effects of tumor heterogeneity are insufficiently understood, and when attempts at therapy by clinicians spur further disease evolution and the emergence of new resistance mechanisms. At the same time, clinicians’ over-treat men who in reality do not need it, and some of those men needlessly suffer long term side effects as a result. This commentary is aimed at stimulating debate about how we as clinicians and scientists can assist one another and improve our knowledge to the benefit of patients dying from metastatic disease.
It is now well established that the tumor microenvironment plays an essential role in the survival, growth, invasion, and spread of cancer through the regulation of angiogenesis and localized immune responses. This review examines the role of the HOX genes, which encode a family of homeodomain-containing transcription factors, in the interaction between prostate tumors and their microenvironment. Previous studies have established that HOX genes have an important function in prostate cancer cell survival in vitro and in vivo, but there is also evidence that HOX proteins regulate the expression of genes in the cancer cell that influence the tumor microenvironment, and that cells in the microenvironment likewise express HOX genes that confer a tumor-supportive function. Here we provide an overview of these studies that, taken together, indicate that the HOX genes help mediate cross talk between prostate tumors and their microenvironment.
Researchers are currently trying to understand why some men with prostate cancer go on to develop aggressive disease whilst others maintain slow growing tumors. Although endogenous genetic anomalies within the tumor cell are important, the prevailing view is that the tissue microenvironment as a whole is the determinant factor. Many studies have focussed on the role of soluble factors in modulating the nature of the tumor microenvironment. There is however a growing interest in the role of extracellular vesicles, including exosomes, as regulators of disease progression. A variety of resident cells, as well as infiltrating cells, all contribute to a heterogeneous population of exosomes within the tumor microenvironment. Studies focussing on the role of exosomes in prostate cancer are however relatively rare. In this review, evidence from various cancers, including prostate, is used to present numerous potential roles of exosomes in prostate cancer. Whilst further validation of some functions may remain necessary it is clear that exosomes play a major role in intercellular communication between various cell types within the tumor microenvironment and are necessary for driving disease progression.
Aim: To develop new therapies for prostate cancer, disease heterogeneity must be addressed. This includes patient variation, multi-focal disease, cellular heterogeneity, genomic changes and epigenetic modification. This requires more representative models to be used in more innovative ways.
Methods: This study used a panel of cell lines and primary prostate epithelial cell cultures derived from patient tissue. Several assays were used; alamar blue, colony forming assays, γH2AX and Ki67 immunofluorescence and comet assays. Ptychographic quantitative phase imaging (QPI), a label-free imaging technique, combined with Cell Analysis Toolbox software, was implemented to carry out real-time analysis of cells and to retrieve morphological, kinetic and population data.
Results: A combination of radiation and Vorinostat may be more effective than radiation alone. Primary prostate cancer stem-like cells are more resistant to etoposide than more differentiated cells. Analysis of QPI images showed that cell lines and primary cells differ in their size, motility and proliferation rate. A QPI signature was developed in order to identify two subpopulations of cells within a heterogeneous primary culture.
Conclusion: Use of primary prostate epithelial cultures allows assessment of therapies whilst taking into account cellular heterogeneity. Analysis of rare cell populations and embracing novel techniques may ultimately lead to identifying and overcoming treatment resistance.
The membrane-type matrix metalloproteinases (MT-MMPs), an important subgroup of the wider MMP family, demonstrate widespread expression in multiple tumor types, and play key roles in cancer growth, migration, invasion and metastasis. Despite a large body of published research, relatively little information exists regarding evidence for MT-MMP expression and function in metastatic prostate cancer. This review provides an appraisal of the literature describing gene and protein expression in prostate cancer cells and clinical tissue, summarises the evidence for roles in prostate cancer progression, and examines the data relating to MT-MMP function in the development of bone metastases. Finally, the therapeutic potential of targeting MT-MMPs is considered. While MT-MMP inhibition presents a significant challenge, utilisation of MT-MMP expression and proteolytic capacity in prostate tumors is an attractive drug development opportunity.
Androgens play an important role in prostate cancer (PCa) development and progression. Although androgen deprivation therapy remains the front-line treatment for advanced prostate cancer, patients eventually relapse with the lethal form of the disease. The prostate tumor microenvironment is characterised by elevated tissue androgens that are capable of activating the androgen receptor (AR). Inhibiting the steroidogenic enzymes that play vital roles in the biosynthesis of testosterone (T) and dihydrotestosterone (DHT) seems to be an attractive strategy for PCa therapies. Emerging data suggest a role for the enzymes mediating pre-receptor control of T and DHT biosynthesis by alternative pathways in controlling intratumoral androgen levels, and thereby influencing PCa progression. This supports the idea for the development of multi-targeting strategies, involving both dual and multiple inhibitors of androgen-metabolising enzymes that are able to affect androgen synthesis and signalling at different points in the biosynthesis. In this review, we will focus on CYP17A1, AKR1C3, HSD17B3 and SRD5A, as these enzymes play essential roles in all the three androgenic pathways. We will review also the AR as an additional target for the design of bifunctional drugs. Targeting intracrine androgens and AKR1C3 have potential to overcome enzalutamide and abiraterone resistance and improve survival of advanced prostate cancer patients.
Cytoreductive surgery (CS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have gained increasing consensus in treatment of peritoneal carcinomatosis from colorectal cancer. The presence of liver metastases is generally considered a contraindication for CS + HIPEC, as hepatic involvement no longer represents a loco-regional aspect of disease. Despite this, liver resection (LR) has been tested in selected cases in combination with CS + HIPEC for treatment of peritoneal carcinomatosis with liver metastasis. Relevant studies on this topic were identified through a search in the electronic PubMed database, using the appropriate keywords. CS + HIPEC + LR allows similar outcomes in terms of survival and morbidity with respect to CS + HIPEC, especially in patients with low tumor load. CS + HIPEC + LR represents a reasonable approach for patients with peritoneal carcinomatosis and liver metastases from colorectal cancer. Patients should be selected in high volume tertiary centres, preferably in the context of a prospective trial.