Real world data regarding the management of cancer-associated thrombosis.

PURPOSE OF REVIEW: Patients with cancer are at high risk for thrombotic events, mainly deep vein thrombosis and pulmonary embolism. Low-molecular-weight heparins (LMWHs) and direct oral anticoagulants (DOACs) are among the current treatment options for cancer-associated thrombosis (CAT). We assessed real world data (RWD) regarding treatment patterns of CAT from 1 September 2018 to 31 January 2020. RECENT FINDINGS: RWD showed that LMWHs were the most common initial anticoagulation treatment for CAT. Based on these data DOACs had a lower risk of recurrent venous thromboembolism compared with LMWHs and warfarin. However, the selection bias and the small number of patients in these studies might explain this difference and these limitations should be taken into consideration. Moreover, there was no statistical difference regarding adverse events during anticoagulant treatment between LMWHs and DOACs with the limitations of RWD. As far as the duration of the treatment is concerned, the adherence ranged from 100% to 67.3% at 6 months. SUMMARY: The current review of RWD illustrates that LMWHs and DOACs are used for the treatment of CAT. LMWHs are most commonly used for the initial management of CAT. Data regarding recurrence of CAT, adverse events, compliance and duration of anticoagulant treatment should be analyzed with caution as RWD are observational studies with many limitations. Further research is needed to elucidate the best algorithm for the management of CAT.

Impact of Radiation Therapy on Pain Relief of Cancer Patients Affected by on Malignant Psoas Syndrome: 26 Years of Experience.

AIM: The malignant psoas syndrome (MPS) is a rare and complex cancer-related clinical entity, with a significant impact on cancer patients' quality of life. The literature describing malignant infiltration of the psoas muscle as well as its management is limited. The primary endpoint of the study was the assessment of pain relief in symptomatic terminal-stage MPS patients. MATERIALS AND METHODS: Patients underwent hypofractionated (two- or three-dimensional conformal) radiotherapy as palliative treatment. A dose of 42.5 Gy in 17 daily fractions (2.5 Gy/fraction) was prescribed. Pain response was measured before 3 and 6 months after radiation delivery. RESULTS: Between May 1992 and April 2019, eight patients were treated. The median age was 75 years (range: 59-87 years). All patients had distant metastatic disease at the time of treatment. We found a significant pain relief (median duration of response of 105 days) and an improvement in health-related quality of life. CONCLUSIONS: Radiotherapy had a favorable outcome and can be considered an effective analgesic treatment in case of painful MPS.

Carcinoembryonic antigen and carbohydrate antigen 19-9 serum levels in non-small cell lung cancer.

PURPOSE: Τo investigate the potential diagnostic and prognostic role of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9) serum levels in non-small cell lung cancer (NSCLC). METHODS: One hundred consecutive patients with newly diagnosed primary NSCLC were included in this study (88 men and 12 women). Blood was drawn before any kind of treatment and the collected serum was processed using chemiluminescence in order CEA and CA 19-9 levels to be measured. RESULTS: No significant associations between CEA or CA 19-9 levels and any tested clinical and pathological parameter were detected. Moreover, CEA levels did not seem to affect survival. On the other hand, patients with high CA 19-9 values (≥37 IU/ml) (median survival: 8 months) had a shorter overall survival than patients with low CA 19-9 values (<37 IU/ml) (median survival: 13 months) (p=0.026). However, CA 19-9 levels did not remain an independent prognostic factor in the multivariate survival analysis (p=0.114). CONCLUSION: CEA and CA 19-9 serum levels do not seem to have any diagnostic role in NSCLC. With regard to their prognostic role, CEA values do not seem to affect the prognosis in NSCLC. However, high CA 19-9 values are associated with worse prognosis.

Pseudomyxoma Peritonei: A Challenging Clinical Diagnosis. Case Report and Review of the Literature.

Background: Pseudomyxoma peritonei (PMP) is a clinical entity of subtle onset abdominal pain, ascites, and distention associated with characteristic imaging. In most cases, laparoscopic exploration will give the definitive diagnosis and histopathologic verification. However, usually there are difficulties in the diagnosis of this disease. Case Report: Herein, we present a case of a 51-year-old female who developed ascites over 5 months. An investigational laparotomy established the diagnosis of PMP, after the discovery of a mucinous, grey-brown tumor that was CK20 positive and CK7 negative. Subsequently, chemotherapy with oxaliplatin combined with 5-FU (FOLFOX4 regimen), was initiated and the patient survived for 30 months. We also present a comprehensive review of the English literature concerning the different symptoms and radiological findings of this rare entity. According to the literature review, 35 cases of PMP with different clinical and radiological findings have been described. In the majority of the cases, ultrasound, computed tomography or magnetic resonance imaging was orientating towards a proper diagnosis before a diagnostic laparotomy. Conclusion: The combination of a clinical picture with the characteristic imaging findings enables a prompt diagnosis of PMP, making prognosis more favorable.

ES-SCLC Patients with PD-L1+ CTCs and High Percentages of CD8+PD-1+T Cells in Circulation Benefit from Front-Line Immunotherapy Treatment.

SCLC is an aggressive cancer type with high metastatic potential and bad prognosis. CTCs are a valuable source of tumor cells in blood circulation and are among the major contributors to metastasis. In this study we evaluated the number of CTCs that express PD-L1 in treatment-naïve ES-SCLC patients receiving ICI in a front-line setting. Moreover, we explored the percentages of different immune T-cell subsets in circulation to assess their potential role in predicting responses. A total of 43 patients were enrolled-6 of them with LS-SCLC, and 37 with ES-SCLC disease. In addition, PBMCs from 10 healthy donors were used as a control group. Different T-cell subtypes were examined through multicolor FACS analysis and patients' CTCs were detected using immunofluorescence staining. SCLC patients had higher percentages of PD-1-expressing CD3+CD4+ and CD3+CD8+ T-cells, as well as elevated PD-1 protein expression compared to healthy individuals. Additionally, in ES-SCLC patients, a positive correlation between CD3+CD8+PD-1+ T-cells and PD-L1+ CTCs was detected. Importantly, patients harboring higher numbers of CD3+CD8+PD-1+ T-cells together with PD-L1+CTCs had a survival advantage when receiving front-line immunotherapy. Thus, this study proposes, for first time possible, immune cell-CTCs interaction, as well as a potential novel clinical biomarker for ICI responses in ES-SCLC patients.

Pre-Existing Immunity Predicts Response to First-Line Immunotherapy in Non-Small Cell Lung Cancer Patients.

T-cell-mediated anti-tumoral responses may have significant clinical relevance as a biomarker for response to immunotherapy. The value of peripheral blood pre-existing tumor antigen-specific T cells (PreI+) as a predictive immunotherapy biomarker in NSCLC patients was investigated, along with the frequency of various circulating immune cells. Fifty-two treatment-naïve, stage III/IV NSCLC patients, treated with front-line immune checkpoint inhibitors (ICI)-containing regimens were enrolled. PreI was calculated as the percentages of CD3+IFNγ+ cells after in vitro co-cultures of PBMCs with peptides against four different Tumor-Associated Antigens (TAA). Immunophenotyping of peripheral blood immune cells was performed using multicolor flow cytometry. PreI+ T cells were detected in 44% of patients. Median overall survival (OS) was significantly higher in PreI+ patients compared to PreI- patients (not reached vs. 321 days, respectively; p = 0.014). PreI+ patients had significantly higher numbers of possible exhausted CD3+CD8+PD-1+ cells and lower percentages of immunosuppressive Tregs compared to PreI- patients. Additionally, patients with PreI+ and low numbers of peripheral blood M-MDSCs had a significant survival advantage compared to the rest of the patients. Thus, combining pre-existing tumor antigen-specific immunity before initiation of ICI in NSCLC patients with selected immune-suppressive cells could identify patients who have a favorable clinical outcome when treated with ICI-containing regimens.

The Impact of Expert Pathology Review and Molecular Diagnostics on the Management of Sarcoma Patients: A Prospective Study of the Hellenic Group of Sarcomas and Rare Cancers.

Precise classification of sarcomas is crucial to optimal clinical management. In this prospective, multicenter, observational study within the Hellenic Group of Sarcoma and Rare Cancers (HGSRC), we assessed the effect of expert pathology review, coupled with the application of molecular diagnostics, on the diagnosis and management of sarcoma patients. Newly diagnosed sarcoma patients were addressed by their physicians to one of the two sarcoma pathologists of HGSRC for histopathological diagnostic assessment. RNA next-generation sequencing was performed on all samples using a platform targeting 86 sarcoma gene fusions. Additional molecular methods were performed in the opinion of the expert pathologist. Therefore, the expert pathologist provided a final diagnosis based on the histopathological findings and, when necessary, molecular tests. In total, 128 specimens from 122 patients were assessed. Among the 119 cases in which there was a preliminary diagnosis by a non-sarcoma pathologist, there were 37 modifications in diagnosis (31.1%) by the sarcoma pathologist, resulting in 17 (14.2%) modifications in management. Among the 110 cases in which molecular tests were performed, there were 29 modifications in diagnosis (26.4%) through the genomic results, resulting in 12 (10.9%) modifications in management. Our study confirms that expert pathology review is of utmost importance for optimal sarcoma diagnosis and management and should be assisted by molecular methods in selected cases.

Metachronous Single Pulmonary Metastasis of Prostate Cancer: Report of a Rare Case and Literature Review.

BACKGROUND: Prostate cancer recurrence after definitive local therapy usually involves the bone and regional lymph nodes. CASE REPORT: We present the case of a 72-year-old male patient with an isolated lung nodule, seven years after radical prostatectomy for prostate cancer, pT2bN0 and Gleason score 7(4+3), and prostatic-specific antigen (PSA) levels within normal limits. The nodule was considered as a primary lung cancer and the patient was subjected to lobectomy. The immunohistochemical staining showed that the tumor was PSA(+) and NKX3.1 (+), revealing that it was metastasis from prostatic cancer and that wedge resectomy was the proper procedure. Three years later the patient is disease-free, suggesting the importance of aggressive treatment of oligometastatic disease. CONCLUSION: Metastasis to the lung is present in more than 40% of men with metastatic prostate cancer; however, lung metastases without any bone or lymph node involvement are extremely rare and only a handful of cases are reported in the literature. Surgical excision of the metastatic lung site is the most common therapeutic approach associated with a good prognosis.

Bortezomib reverses the proliferative and antiapoptotic effect of neuropeptides on prostate cancer cells.

OBJECTIVES: Neuropeptides are important signal initiators in advanced prostate cancer, partially acting through activation of nuclear factor kappa B. Central to nuclear factor kappa B regulation is the ubiquitin-proteasome system, pharmacological inhibition of which has been proposed as an anticancer strategy. We investigated the putative role of the proteasome inhibitor bortezomib in neuropeptides signaling effects on prostate cancer cells. METHODS: Human prostate cancer cell lines, LNCaP and PC-3, were used to examine cell proliferation, levels of proapoptotic (caspase-3, Bad) and cell cycle regulatory proteins (p53, p27, p21), as well as total and phosphorylated Akt and p44/42 mitogen-activated protein kinase proteins. Furthermore, 20S proteasome activity, subcellular localization of nuclear factor kappa B and transcription of nuclear factor kappa B target genes, interleukin-8 and vascular endothelial growth factor, were assessed. RESULTS: Neuropeptides (endothelin-1, bombesin) increased cell proliferation, whereas bortezomib decreased proliferation and induced apoptosis, an effect maintained after cotreatment with neuropeptides. Bad, p53, p21 and p27 were downregulated by neuropeptides in PC-3, and these effects were reversed with the addition of bortezomib. Neuropeptides increased proteasomal activity and nuclear factor kappa B levels in PC-3, and these effects were prevented by bortezomib. Interleukin-8 and vascular endothelial growth factor transcripts were induced after neuropeptides treatment, but downregulated by bortezomib. These results coincided with the ability of bortezomib to reduce mitogen-activated protein kinase signaling in both cell lines. CONCLUSIONS: These findings are consistent with bortezomib-mediated abrogation of neuropeptides-induced proliferative and antiapoptotic signaling. Thus, the effect of the drug on the neuropeptides axis needs to be further investigated, as neuropeptide action in prostate cancer might entail involvement of the proteasome.

Metastatic rectal cancer in the ampulla of Vater: A unique case.

BACKGROUND: A metastatic lesion located in the ampulla of Vater is considered extremely rare, with only 32 cases reported globally. CASE: A 65-year-old patient was primarily diagnosed with a rectal adenocarcinoma. Twenty-four months later as part of the oncological follow-up, the patient was diagnosed with a single secondary tumor in the ampulla of Vater. After undergoing a pancreaticoduodenectomy (Whipple procedure), the patient experienced an uneventful recovery and received adjuvant chemotherapy. Sixteen months later the patient remained disease-free. CONCLUSION: To the best of our knowledge, the present case represents the first reported metastatic tumor in the ampulla of Vater, originating from a rectal adenocarcinoma. This case underlines the critical role of immunohistochemistry in arriving at a correct diagnosis in order to guide clinical decision-making.

Radiotherapy and Breast Reconstruction: What Is the Ideal Timing? A Narrative Review.

INTRODUCTION: Women undergoing mastectomy choose to pursue breast reconstruction (BR) in order to reduce their body image distress.Adjuvant chest wall irradiation is associated with a negative cosmetic outcome. The aim of our review was to identify the optimal timing of BR relating to radiotherapy delivery. MATERIALS AND METHODS: Using Cochrane Library, Embase, PubMed, Springer, Wanfang and CNKI, we performed a non-systematic review of articles published up to August 2021. RESULTS: There is no hard evidence in favor of immediate, delayed or 2-stage BR when post-mastectomy radiation is indicated. Immediate and 2-stage BR seem to be valid alternatives to delayed BR. CONCLUSIONS: Further research is essential in order to assess clinician and patient reported aesthetic outcomes and determine the optimal timing of BR in view of post-mastectomy radiotherapy, in breast cancer survivors.

New prophylaxis strategies to reduce the risk of thromboembolism in cancer.

Introduction: Patients with cancer are at risk of thrombotic events, mainly deep vein thrombosis and/or pulmonary embolism. The thrombosis risk is generally 4-6 times higher than in a healthy population and depends on factors related to patient characteristics, tumor factors, and treatment-related factors. The decision-making for prophylactic anticoagulation is individualized according to the relative risks and benefits. The VTE risk has been quantified using different assessment scores.Areas covered: This article reviews current data and ongoing research on predictive factors involved in cancer-related thrombosis and highlights the currently suggested strategies for prophylaxis. Several trials that compared the two treatment options, direct factor Xa inhibitor or LMWH, with placebo and not each other are discussed. This article analyzed the safety and efficacy features that led several international organizations such as ASCO, NCCN, and others, to issue guidelines for the prophylaxis and treatment of patients at high risk of thrombosis by using LMWH, fondaparinux, and DOACs.Expert opinion: ASCO, NCCN, and other international organizations recommend thromboprophylaxis in high-risk patients. However, further investigation is needed to define better biomarkers for more accurate identification of cancer patients that will benefit from anticoagulant treatment.

Additive inhibition of colorectal cancer cell lines by aspirin and bortezomib.

PURPOSE: To investigate the effect of cyclooxygenase-2 (Cox-2) inhibitor aspirin (acetylsalicylic acid, ASA) and proteasome inhibitor bortezomib in the proliferation and apoptosis of colorectal cancer cell lines. METHODS: MTT assay, trypan blue exclusion and DNA fragmentation have been used to investigate cell proliferation and apoptosis in the presence of drugs. For the determination of Cox activity a colorimetric method was used. Western blotting was used for the measurement of the effect of the drugs in different proteins expression. RESULTS: Bortezomib together with aspirin inhibit the growth of colorectal cancer cell lines HCT116, HT-29, and CaCo2 more than each drug alone. In the first two cell lines ASA inhibitory effects are Cox-2 independent because HCT116 cells do not express the enzyme while in HT-29 cells, Cox-2 has no activity as shown by a Cox activity assay. In CaCo2 cells that express enzymatically active Cox-2 this activity is inhibited by ASA. ASA is also able to suppress the increase in Cox-2 activity induced by bortezomib in these cells. Cell cycle inhibitors p21 and p27 are induced in the three cell lines by bortezomib and the combination treatment. Akt1 kinase is down-regulated in all three lines by the same treatments. Transcription factor NF-kappaB is retained in the cytoplasm by drug treatment in cell lines HCT116 and HT-29, a fact that may play a role in their pro-apoptotic activity. Pro-apoptotic bcl-2 family member, bad is down-regulated in cell lines HCT116 and CaCo2 by bortezomib treatment, a neoplasia-promoting event that is reversed by combination treatment. CONCLUSION: The combination of bortezomib and ASA cooperates to decrease proliferation and induce apoptosis in three human colorectal cell lines with different genetic lesions. These effects are at least in some cases Cox-2 independent and involve common and diverse mechanisms in the three lines.

Benign Intracranial Lesions - Radiotherapy: An Overview of Treatment Options, Indications and Therapeutic Results.

BACKGROUND: Radiation Therapy (RT) is an established treatment option for benign intracranial lesions. The aim of this study is to display an update on the role of RT concerning the most frequent benign brain lesions and tumors. METHODS: Published articles about RT and meningiomas, Vestibular Schwannomas (VSs), Pituitary Adenomas (PAs), Arteriovenous Malformations (AVMs) and craniopharyngiomas were reviewed and extracted data were used. RESULTS: In meningiomas RT is applied as an adjuvant therapy, in case of patientrefusing surgery or in unresectable tumors. The available techniques are External Beam RT (EBRT) and stereotactic ones such as Stereotactic Radiosurgery (SRS), Fractionated Stereotactic RT (FSRT), Intensity Modulated RT (IMRT) and proton-beam therapy. The same indications are considered in PAs, in which SRS and FSRT achieve excellent tumor control rate (92-100%), acceptable hormone remission rates (>50%) and decreased Adverse Radiation Effects (AREs). Upon tumor growth or neurological deterioration, RT emerges as alone or adjuvant treatment against VSs, with SRS, FSRT, EBRT or protonbeam therapy presenting excellent tumor control growth (>90%), facial nerve (84-100%), trigeminal nerve (74-99%) and hearing (>50%) preservation. SRS poses an effective treatment modality of certain AVMs, demonstrating a 3-year obliteration rate of 80%. Lastly, a combination of microsurgery and RT presents equal local control and 5-year survival rate (>90%) but improved toxicity profile compared to total resection in case of craniopharyngiomas. CONCLUSION: RT comprises an effective treatment modality of benign brain and intracranial lesions. By minimizing its AREs with optimal use, RT projects as a potent tool against such diseases.

PD-1 and PD-L1 as immunotherapy targets and biomarkers in non-small cell lung cancer.

The integration of immunotherapeutic agents in the treatment of non-small cell lung cancer (NSCLC) has revolutionized the approach of the prevalent type of lung cancer. Although PD-1 and its ligands (PD-L1 and PD-L2) are stimulating molecules of the immune-checkpoint pathway, with primary function to limit inflammatory response and autoimmunity, tumor cells have found a way to exploit these molecules by obtaining the opportunity to respond with PD-L1 expression in cytokine signals and thus to evade immune surveillance. Several immunotherapeutic agents targeting these molecules have already been tested and show quick and remarkable responses and survival prolongation in about 14-20% of chemo-resistant patients in NSCLC, resulting to FDA approval of some PD-1 inhibitors (pebrolizumab, nivolumab), even for first-line treatment of patients with metastatic NSCLC whose tumors have high PD-L1 expression (pebrolizumab). Regarding to the prognostic value of PD-L1 and PD-1 expression as biomarkers in NSCLC, the results still remain contradictory. However, the elevated expression of PD-L1 has been correlated with higher efficacy of the various immunotherapeutic agents, implying a high predictive value of this biomarker, even if the truth about specificity and sensitivity of the aforementioned molecules is generally more complicated.

Advanced small cell lung cancer (SCLC): new challenges and new expectations.

Small cell lung cancer (SCLC) remains one of the most lethal malignancies and a major health riddle. The therapeutic options are limited. The combination of etoposide or irinotecan with platinum chemotherapy is the standard of care at any stage. The last decade systemic efforts have been done to reveal specific therapeutic targets for small cell lung carcinomas. In this review, we focus on the new therapeutic strategies of SCLC, including immune-related treatment that may change the prognosis of the disease. The main genetic mutations observed in SCLC are TP53 and RB1 mutations; however, it is well known that these molecules are not yet targetable. In recent years, research has revealed other frequent genetic alterations and activated signaling pathways that might be an effective treatment target. Loss of PTEN, activating PI3K mutations, inhibition of NOTCH pathway and aurora kinase activation are among them. Moreover, FDGFR1 amplification, activation of the Hedgehog pathway and repair-protein PARP1 seem to participate in SCLC tumorigenesis. These new findings have identified some interesting targets. Moreover, immunotherapy tries to find its place in the treatment of SCLC. Immune checkpoint inhibitors are under investigation in phase I to III clinical trials. We hope that in next years the treatment of SCLC patients will be improved with the administration of targeting therapy and the introduction of immunotherapy.

Advances on systemic treatment for lung neuroendocrine neoplasms.

Lung well-to-moderately differentiated neuroendocrine tumors (also known as carcinoids) and large cell neuroendocrine lung carcinoma (poorly differentiated neuroendocrine tumor) are rare neuroendocrine neoplasms, which account for less than 4% of all lung neoplasms. Due to their low incidence, their systemic treatment is greatly influenced by therapeutic evidence derived from the more frequent gastroenteropancreatic neuroendocrine neoplasms and/or small cell lung carcinoma leading to significant bias. Currently, employed systemic therapies for lung carcinoids, aiming at controlling tumor growth include long acting somatostatin analogues (SSAs), peptide receptor radionuclide therapy, chemotherapy and molecular-targeted therapy. In this review, each of those treatments is presented based upon available clinical evidence from retrospective and prospective studies particularly focused on the role of everolimus in the advanced setting and on ongoing clinical trials reflecting our expectations in the near future. In addition, we critically analyse currently employed treatment of large cell neuroendocrine carcinoma where the appropriate chemotherapeutic regimen is still a matter of debate.

Chromogranin A as a valid marker in oncology: Clinical application or false hopes?

Chromogranin A, due to its primary expression throughout the neuroendocrine system, is a widely accepted biomarker for the assessment of neuro-endocrine tumors. It has been traditionally used in the management of patients with tumors of gastro-enteropancreatic origin. Lately, it has also been implicated in various conditions and diseases, both benign and malignant. However, the paucity of data of adequate strength, as well as its relation with common physiologic conditions and its interaction with commonly prescribed medications, limit its clinical use in only a narrow spectrum. Herein, we present a thorough review to the most frequent conditions where its levels are affected, focusing specifically on its potential use as a prognostic and predictive biomarker in oncology.

A Case of Cervical Carcinoid and Review of the Literature.

Uterine cervix carcinoids are distinct neuroendocrine cervical tumors, representing a comparatively small percentage of them. These well-differentiated neoplasms are far less prevalent than small- and large-cell carcinomas, characterized by a more favorable biological course. We report a case of a 43-year-old woman with a nonmetastatic cervical carcinoid, managed with radical hysterectomy. She still remains free of disease. Scant reports in the literature prohibit any reliable prediction of cervical carcinoid prognosis. Thus, prompt identification of the disease and subsequent therapeutic intervention could alter the final outcome.