A spectroscopic liquid biopsy for the earlier detection of multiple cancer types.

BACKGROUND: A rapid, low-cost blood test that can be applied to reliably detect multiple different cancer types would be transformational. METHODS: In this large-scale discovery study (n = 2092 patients) we applied the Dxcover® Cancer Liquid Biopsy to examine eight different cancers. The test uses Fourier transform infrared (FTIR) spectroscopy and machine-learning algorithms to detect cancer. RESULTS: Area under the receiver operating characteristic curve (ROC) values were calculated for eight cancer types versus symptomatic non-cancer controls: brain (0.90), breast (0.76), colorectal (0.91), kidney (0.91), lung (0.91), ovarian (0.86), pancreatic (0.84) and prostate (0.86). We assessed the test performance when all eight cancer types were pooled to classify 'any cancer' against non-cancer patients. The cancer versus asymptomatic non-cancer classification detected 64% of Stage I cancers when specificity was 99% (overall sensitivity 57%). When tuned for higher sensitivity, this model identified 99% of Stage I cancers (with specificity 59%). CONCLUSIONS: This spectroscopic blood test can effectively detect early-stage disease and can be fine-tuned to maximise either sensitivity or specificity depending on the requirements from different healthcare systems and cancer diagnostic pathways. This low-cost strategy could facilitate the requisite earlier diagnosis, when cancer treatment can be more effective, or less toxic. STATEMENT OF TRANSLATIONAL RELEVANCE: The earlier diagnosis of cancer is of paramount importance to improve patient survival. Current liquid biopsies are mainly focused on single tumour-derived biomarkers, which limits test sensitivity, especially for early-stage cancers that do not shed enough genetic material. This pan-omic liquid biopsy analyses the full complement of tumour and immune-derived markers present within blood derivatives and could facilitate the earlier detection of multiple cancer types. There is a low barrier to integrating this blood test into existing diagnostic pathways since the technology is rapid, simple to use, only minute sample volumes are required, and sample preparation is minimal. In addition, the spectroscopic liquid biopsy described in this study has the potential to be combined with other orthogonal tests, such as cell-free DNA, which could provide an efficient route to diagnosis. Cancer treatment can be more effective when given earlier, and this low-cost strategy has the potential to improve patient prognosis.

Augmentation of FTIR spectral datasets using Wasserstein generative adversarial networks for cancer liquid biopsies.

Over recent years, deep learning (DL) has become more widely used within the field of cancer diagnostics. However, DL often requires large training datasets to prevent overfitting, which can be difficult and expensive to acquire. Data augmentation is a method that can be used to generate new data points to train DL models. In this study, we use attenuated total reflectance Fourier-transform infrared (ATR-FTIR) spectra of patient dried serum samples and compare non-generative data augmentation methods to Wasserstein generative adversarial networks (WGANs) in their ability to improve the performance of a convolutional neural network (CNN) to differentiate between pancreatic cancer and non-cancer samples in a total cohort of 625 patients. The results show that WGAN augmented spectra improve CNN performance more than non-generative augmented spectra. When compared with a model that utilised no augmented spectra, adding WGAN augmented spectra to a CNN with the same architecture and same parameters, increased the area under the receiver operating characteristic curve (AUC) from 0.661 to 0.757, presenting a 15% increase in diagnostic performance. In a separate test on a colorectal cancer dataset, data augmentation using a WGAN led to an increase in AUC from 0.905 to 0.955. This demonstrates the impact data augmentation can have on DL performance for cancer diagnosis when the amount of real data available for model training is limited.

Recurrent neural networks for time domain modelling of FTIR spectra: application to brain tumour detection.

Attenuated total reflectance (ATR)-Fourier transform infrared (FTIR) spectroscopy alongside machine learning (ML) techniques is an emerging approach for the early detection of brain cancer in clinical practice. A crucial step in the acquisition of an IR spectrum is the transformation of the time domain signal from the biological sample to a frequency domain spectrum via a discrete Fourier transform. Further pre-processing of the spectrum is typically applied to reduce non-biological sample variance, and thus to improve subsequent analysis. However, the Fourier transformation is often assumed to be essential even though modelling of time domain data is common in other fields. We apply an inverse Fourier transform to frequency domain data to map these to the time domain. We use the transformed data to develop deep learning models utilising Recurrent Neural Networks (RNNs) to differentiate between brain cancer and control in a cohort of 1438 patients. The best performing model achieves a mean (cross-validated score) area under the receiver operating characteristic (ROC) curve (AUC) of 0.97 with sensitivity of 0.91 and specificity of 0.91. This is better than the optimal model trained on frequency domain data which achieves an AUC of 0.93 with sensitivity of 0.85 and specificity of 0.85. A dataset comprising 385 patient samples which were prospectively collected in the clinic is used to test a model defined with the best performing configuration and fit to the time domain. Its classification accuracy is found to be comparable to the gold-standard for this dataset demonstrating that RNNs can accurately classify disease states using spectroscopic data represented in the time domain.

Clinical validation of a spectroscopic liquid biopsy for earlier detection of brain cancer.

Background: Diagnostic delays impact the quality of life and survival of patients with brain tumors. Earlier and expeditious diagnoses in these patients are crucial to reduce the morbidities and mortalities associated with brain tumors. A simple, rapid blood test that can be administered easily in a primary care setting to efficiently identify symptomatic patients who are most likely to have a brain tumor would enable quicker referral to brain imaging for those who need it most. Methods: Blood serum samples from 603 patients were prospectively collected and analyzed. Patients either had non-specific symptoms that could be indicative of a brain tumor on presentation to the Emergency Department, or a new brain tumor diagnosis and referral to the neurosurgical unit, NHS Lothian, Scotland. Patient blood serum samples were analyzed using the Dxcover® Brain Cancer liquid biopsy. This technology utilizes infrared spectroscopy combined with a diagnostic algorithm to predict the presence of intracranial disease. Results: Our liquid biopsy approach reported an area under the receiver operating characteristic curve of 0.8. The sensitivity-tuned model achieves a 96% sensitivity with 45% specificity (NPV 99.3%) and identified 100% of glioblastoma multiforme patients. When tuned for a higher specificity, the model yields a sensitivity of 47% with 90% specificity (PPV 28.4%). Conclusions: This simple, non-invasive blood test facilitates the triage and radiographic diagnosis of brain tumor patients while providing reassurance to healthy patients. Minimizing time to diagnosis would facilitate the identification of brain tumor patients at an earlier stage, enabling more effective, less morbid surgical and adjuvant care.

Immunotherapy in Patients with Advanced Non-Small Cell Lung Cancer Lacking Driver Mutations and Future Perspectives.

From a complete literature review, we were able to present in this paper what is most current in the treatment with immunotherapy for advanced non-small cell lung cancer (NSCLC). Especially the use of immunotherapy, particularly inhibitors of PD-1 (programmed cell death protein 1), PDL-1 (programmed cell death protein ligand 1), and CTLA-4 (cytotoxic T-lymphocyte antigen 4). Since 2015, these drugs have transformed the treatment of advanced NSCLC lacking driver mutations, evolving from second-line therapy to first-line, with excellent results. The arrival of new checkpoint inhibitors such as cemiplimab and the use of checkpoint inhibitors earlier in the therapy of advanced and metastatic cancers has been making the future prospects for treating NSCLC lacking driver mutations more favorable and optimistic. In addition, for those patients who have low PDL-1 positivity tumors, the combination of cytotoxic chemotherapy, VEGF inhibitor, and immunotherapy have shown an important improvement in global survival and progression free survival regardless the PDL-1 status. We also explored the effectiveness of adding radiotherapy to immunotherapy and the most current results about this combination. One concern that cannot be overlooked is the safety profile of immune checkpoint inhibitors (ICI) and the most common toxicities are described throughout this paper as well as tumor resistance to ICI.

The Role of MET Inhibitor Therapies in the Treatment of Advanced Non-Small Cell Lung Cancer.

Introduction: Non-small cell lung cancer (NSCLC) is the second most common cancer globally. The mesenchymal-epithelial transition (MET) proto-oncogene can be targeted in NSCLC patients. Methods: We performed a literature search on PubMed in December 2019 for studies on MET inhibitors and NSCLC. Phase II and III clinical trials published in English between 2014 and 2019 were selected. Results: Data on MET inhibitors (tivantinib, cabozantinib, and crizotinib) and anti-MET antibodies (emibetuzumab and onartuzumab) are reported in the text. Conclusion: Emibetuzumab could be used for NSCLC cases with high MET expression. Further, studies on onartuzumab failed to prove its efficacy, while the results of tivantinib trials were clinically but not statistically significant. Additionally, cabozantinib was effective, but adverse reactions were common, and crizotinib was generally well-tolerated.

Role of Chemotherapy, VEGFR Inhibitors, and mTOR Inhibitors in Advanced Perivascular Epithelioid Cell Tumors (PEComas).

PURPOSE: Perivascular epitheliod cell tumors (PEComas) are rare mesenchymal neoplasms for which the role of systemic treatments is not established as there are no published prospective clinical trials or sufficiently large retrospective case series. The aim of this study is to clarify the activity of conventional chemotherapy and biological agents in advanced/metastatic PEComas. EXPERIMENTAL DESIGN: This was an observational, retrospective, international study that included patients with advanced/metastatic PEComa treated with systemic therapy at 5 European sarcoma reference centers and within the Italian Rare Cancer Network. Survival analyses were performed using the Kaplan-Meier method and the Cox hazards regression models. RESULTS: A total of 53 patients were included. Cytotoxic chemotherapy regimens were active only in a small proportion of PEComas. Gemcitabine-based regimens [objective response rate (ORR): 20%, median progression-free survival (PFS): 3.4 months] seemed to have the same activity of anthracycline-based regimens (ORR: 13%, median PFS: 3.2 months). Antiangiogenic agents resulted in disease stabilization in some patients, with a number having density changes/tissue response on imaging, with an ORR of 8.3% and a median PFS of 5.4 months. mTOR inhibitors were the most active agents, with an ORR of 41% and a median PFS of 9 months. CONCLUSIONS: Our study provides data for the selection of systemic therapy in patients with advanced/metastatic PEComa: mTOR inhibitors are the most active agents. Antiangiogenics and chemotherapy with gemcitabine-based regimens or anthracycline-based regimens are options in further line, but with a lower response rate and PFS.

Gemcitabine Re-challenge in Metastatic Soft Tissue Sarcomas: A Therapeutic Option for Selected Patients.

BACKGROUND/AIM: Treatment options for patients with metastatic soft tissue sarcomas are limited. Re-challenge with a previously successful gemcitabine-based regimen is common. There are no published data to support this practice. PATIENTS AND METHODS: We conducted a retrospective search to identify patients re-challenged with gemcitabine-based chemotherapy (GBC) from 2003 to 2015. RESULTS: Twenty-nine patients re-challenged with gemcitabine were identified. The response rate for initial GBC was 55% (n=15) and for re-challenge GBC 26% (n=6). The median progression-free survival was 11.1 months (95%CI=7.2-11.9) for initial GBC and 5.3 months (95%CI=2.0-7.5) for re-challenge GBC. Overall survival following gemcitabine re-challenge was 12.2 months (95%CI=7.0-18.2). Twelve out of 26 evaluable patients (46%) treated with re-challenge GBC experienced grade 3-4 adverse events (CTCAE 4.03) with 31% (n=8) of patients requiring dose reduction. CONCLUSION: In selected patients, gemcitabine re-challenge can be considered in advanced sarcomas, however, this approach is associated with toxicity.

Olaratumab in soft tissue sarcoma - Current status and future perspectives.

Recent randomised phase II trial data have indicated that the addition of olaratumab, a novel monoclonal antibody against platelet-derived growth factor receptor alpha (PDGFRα), to doxorubicin confers an unprecedented improvement in overall survival to patients with anthracycline-naïve advanced soft tissue sarcoma. However, this result was disproportionate with progression-free survival and response rate, and consequently there are unanswered questions regarding the precise mechanism of action of olaratumab. While preclinical data show that olaratumab specifically inhibits PDGFRα-mediated oncogenic signalling with attendant anti-tumour effects, a lack of correlation between pharmacodynamics markers of PDGFRα inhibition and clinical benefit from olaratumab suggest other mechanisms beyond modulation of downstream PDGFRα molecular pathways. Proposed mechanisms of olaratumab activity include engagement of anti-tumour immune responses and alterations of the tumour stroma, but these require further evaluation. Meanwhile, the drug-specific contribution of cytotoxic agents to olaratumab-containing combinations has yet to be characterised. Ongoing and future preclinical and translational studies, coupled with the anticipated results of a phase III trial that has completed enrolment, should provide greater insight into the efficacy and mode of action of olaratumab in soft tissue sarcomas.

Potential role of immunotherapy in advanced non-small-cell lung cancer.

Immuno checkpoint inhibitors have ushered in a new era with respect to the treatment of advanced non-small-cell lung cancer. Many patients are not suitable for treatment with epidermal growth factor receptor tyrosine kinase inhibitors (eg, gefitinib, erlotinib, and afatinib) or with anaplastic lymphoma kinase inhibitors (eg, crizotinib and ceritinib). As a result, anti-PD-1/PD-L1 and CTLA-4 inhibitors may play a novel role in the improvement of outcomes in a metastatic setting. The regulation of immune surveillance, immunoediting, and immunoescape mechanisms may play an interesting role in this regard either alone or in combination with current drugs. Here, we discuss advances in immunotherapy for the treatment of metastatic non-small-cell lung cancer as well as future perspectives within this framework.

Hybrid procedures for chronic lower limb ischemia: what determines the outcome?

BACKGROUND: To report the long term outcome of hybrid (combined open and endovascular) procedures for the management of multisegmental chronic peripheral arterial disease. METHODS: A retrospective analysis from a single center during the period 2009-2013. Patency rates, survival and limb salvage were the primary outcomes. Univariate and multivariate analyses were used to assess the association with various factors. RESULTS: A total of 132 patients (116 males) with mean age of 69±1.4 years, were treated. The technical and hemodynamic success rates were 94% and 97.7% respectively. The primary and assisted primary patency rates in 36 months were 69.7% and 94.7%, respectively. The Hazard Ratio for primary and assisted primary patency failure was 1.94 (95% CI: 1.07-3.51, P=0.029) and 5.55 (95% CI: 1.15-26.79, P=0.033) times higher in diabetic patients, respectively. Limb salvage rate in 36 months was 87.9%. Rutherford category (P=0.046) and previous ipsilateral reconstruction (P=0.011) were the only factors associated with limb loss. CONCLUSIONS: Hybrid procedures are associated with good long term outcomes in the treatment of multisegmental chronic peripheral arterial disease. Diabetes mellitus remains a determinant of worse outcome, while the severity of the disease and previous ipsilateral revascularization are associated with poorer limb salvage.

Single-Center Experience With Remote Endarterectomy for the Treatment of Long-Segment Superficial Femoral Artery Occlusion: Long-Term Results.

OBJECTIVES: Remote endarterectomy (RE) is a relatively minimally invasive procedure as an alternative to femoropopliteal above-knee bypass for the treatment of long-segment superficial femoral artery (SFA) occlusion. The objective of this study was to report our experience and to evaluate the long-term outcome. DESIGN: Single-center nonrandomized retrospective study with prospective collection of patients' data. METHODS: Twelve patients (11 men; mean age 72 years, range 55-81 years) with long (>10 cm) SFA occlusion underwent RE followed by stent (aSpire) placement at the distal end of the endarterectomy. All patients had at least 2 tibial vessels outflow. Indications were severe claudication in 9 (75%), rest pain in 1(8%), and gangrene in 2 (17%) cases. Technical, hemodynamic success rates and clinical improvement were recorded. Assessment of patency and limb loss was made at a mean follow-up of 50 months (range 12-66 months). RESULTS: Technical success rate was 100%. Immediate hemodynamic and clinical improvement were 92% and 75%, respectively. The mean increase in the Ankle-Brachial pressure index was 0.24. The primary, primary-assisted, and secondary patency rates were 50%, 83%, and 100%, respectively. The perioperative mortality rate was 8% (one death due to myocardial infarction). There was no early (30-day) reocclusion. During the follow-up, 5 (41.6%) cases underwent 7 reinterventions, all by endovascular means. The amputation rate was 16% (2 of 12). CONCLUSIONS: The RE for long SFA occlusion is a feasible procedure with acceptable short- and long-term outcomes in the presence of distal arterial outflow. Good long-term patency and limb salvage can be achieved with close surveillance and with the compensation of endovascular reintervention procedures.

Adjuvant Chemoradiation Therapy in Gastric Cancer: Critically Reviewing the Past and Visualizing the Next Step Forward.

Gastric cancer remains one of the most common malignancies worldwide. Despite the significant advances in surgical treatment and multimodality strategies, prognosis has modestly improved over the last two decades. Locoregional relapse remains one of the main issues and the combined chemoradiation treatment seems to be one of the preferred approaches. However, more than ten years after the hallmark INT-0116 trial, minimal progress has been made both in terms of effectiveness and toxicity. Moreover, new regimens added to combined therapy failed to prove favourable results. Herein, we attempt a thorough literature review comparing pros and cons of all relative studies and potential bias, targeting well-designed future approaches.

Endovascular treatment of infrarenal abdominal aortic aneurysm with short and angulated neck in high-risk patient.

Endovascular treatment of abdominal aortic aneurysms (AAA) is an established alternative to open repair. However lifelong surveillance is still required to monitor endograft function and signal the need for secondary interventions (Hobo and Buth 2006). Aortic morphology, especially related to the proximal neck, often complicates the procedure or increases the risk for late device-related complications (Hobo et al. 2007 and Chisci et al. 2009). The definition of a short and angulated neck is based on length (<15 mm), and angulation (>60°) (Hobo et al. 2007 and Chisci et al. 2009). A challenging neck also offers difficulties during open repairs (OR), necessitating extensive dissection with juxta- or suprarenal aortic cross-clamping. Patients with extensive aneurysmal disease typically have more comorbidities and may not tolerate extensive surgical trauma (Sarac et al. 2002). It is, therefore, unclear whether aneurysms with a challenging proximal neck should be offered EVAR or OR (Cox et al. 2006, Choke et al. 2006, Robbins et al. 2005, Sternbergh III et al. 2002, Dillavou et al. 2003, and Greenberg et al. 2003). In our case the insertion of a thoracic endograft followed by the placement of a bifurcated aortic endograft for the treatment of a very short and severely angulated neck proved to be feasible offering acceptable duration of aneurysm exclusion. This adds up to our armamentarium in the treatment of high-risk patients, and it should be considered in emergency cases when the fenestrated and branched endografts are not available.

A critical analysis on the impact of antiplatelet therapy in the patency of infrainguinal bypass grafts.

Antiplatelet therapy plays an important role in the management of atherosclerotic disease and numerous studies have shown their efficacy in the reduction of cardiovascular mortality and morbidity. Antiplatelets are given in patients subjected to lower limb bypass aiming not only to reduce cardiovascular mortality and morbidity but also improve graft patency. Various antiplatelet agents have been used for this purpose. The aim of this review article is to critically evaluate the existing evidence on the impact of antiplatelet therapy for maintaining infrainguinal graft patency and highlight the mechanisms involved along these lines.

Penis deformity after intra-urethral liquid paraffin administration in a young male: a case report.

BACKGROUND: Self-induced injections of liquid substances mainly for penis enlargement is a well-documented but still rather uncommon practice in the western world. CASE PRESENTATION: Herein we present the case of a 30-year-old male who self-inflicted, twice in a six-month-period, intra-urethral liquid paraffin and tied up his penis with a cord in order to achieve both enlargement and elongation. He arrived in our emergency department suffering from suprapubic pain; physical examination revealed a rather unique deformity of the penis. He finally refused any treatment and absconded. CONCLUSION: Side effects after paraffin administration are various and sometimes severe. Most of the times surgical treatment is needed and radical excision together with follow-up seems the best modality. Such practices emphasize on the public's misbelieves and that some aspects of sexual medicine are yet covered with the veil of misconception.