Does FDG PET-Based Radiomics Have an Added Value for Prediction of Overall Survival in Non-Small Cell Lung Cancer?

Objectives: Radiomics and machine learning are innovative approaches to improve the clinical management of NSCLC. However, there is less information about the additive value of FDG PET-based radiomics compared with clinical and imaging variables. Methods: This retrospective study included 320 NSCLC patients who underwent PET/CT with FDG at initial staging. VOIs were placed on primary tumors only. We included a total of 94 variables, including 87 textural features extracted from PET studies, SUVmax, MTV, TLG, TNM stage, histology, age, and gender. We used the least absolute shrinkage and selection operator (LASSO) regression to select variables with the highest predictive value. Although several radiomics variables are available, the added value of these predictors compared with clinical and imaging variables is still under evaluation. Three hundred and twenty NSCLC patients were included in this retrospective study and underwent 18F-FDG PET/CT at initial staging. In this study, we evaluated 94 variables, including 87 textural features, SUVmax, MTV, TLG, TNM stage, histology, age, and gender. Image-based predictors were extracted from a volume of interest (VOI) positioned on the primary tumor. The least absolute shrinkage and selection operator (LASSO) Cox regression was used to reduce the number of variables and select only those with the highest predictive value. The predictive model implemented with the variables selected using the LASSO analysis was compared with a reference model using only a tumor stage and SUVmax. Results: NGTDM coarseness, SUVmax, and TNM stage survived the LASSO analysis and were used for the radiomic model. The AUCs obtained from the reference and radiomic models were 80.82 (95%CI, 69.01-92.63) and 81.02 (95%CI, 69.07-92.97), respectively (p = 0.98). The median OS in the reference model was 17.0 months in high-risk patients (95%CI, 11-21) and 113 months in low-risk patients (HR 7.47, p < 0.001). In the radiomic model, the median OS was 16.5 months (95%CI, 11-20) and 113 months in high- and low-risk groups, respectively (HR 9.64, p < 0.001). Conclusions: Our results indicate that a radiomic model composed using the tumor stage, SUVmax, and a selected radiomic feature (NGTDM_Coarseness) predicts survival in NSCLC patients similarly to a reference model composed only by the tumor stage and SUVmax. Replication of these preliminary results is necessary.

Multivariable Risk Modelling and Survival Analysis with Machine Learning in SARS-CoV-2 Infection.

AIM: To evaluate the performance of a machine learning model based on demographic variables, blood tests, pre-existing comorbidities, and computed tomography(CT)-based radiomic features to predict critical outcome in patients with acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: We retrospectively enrolled 694 SARS-CoV-2-positive patients. Clinical and demographic data were extracted from clinical records. Radiomic data were extracted from CT. Patients were randomized to the training (80%, n = 556) or test (20%, n = 138) dataset. The training set was used to define the association between severity of disease and comorbidities, laboratory tests, demographic, and CT-based radiomic variables, and to implement a risk-prediction model. The model was evaluated using the C statistic and Brier scores. The test set was used to assess model prediction performance. RESULTS: Patients who died (n = 157) were predominantly male (66%) over the age of 50 with median (range) C-reactive protein (CRP) = 5 [1, 37] mg/dL, lactate dehydrogenase (LDH) = 494 [141, 3631] U/I, and D-dimer = 6.006 [168, 152.015] ng/mL. Surviving patients (n = 537) had median (range) CRP = 3 [0, 27] mg/dL, LDH = 484 [78, 3.745] U/I, and D-dimer = 1.133 [96, 55.660] ng/mL. The strongest risk factors were D-dimer, age, and cardiovascular disease. The model implemented using the variables identified using the LASSO Cox regression analysis classified 90% of non-survivors as high-risk individuals in the testing dataset. In this sample, the estimated median survival in the high-risk group was 9 days (95% CI; 9-37), while the low-risk group did not reach the median survival of 50% (p < 0.001). CONCLUSIONS: A machine learning model based on combined data available on the first days of hospitalization (demographics, CT-radiomics, comorbidities, and blood biomarkers), can identify SARS-CoV-2 patients at risk of serious illness and death.

PET translates neurophysiology into images: A review to stimulate a network between neuroimaging and basic research.

In the last decades there has been a progressive advance in the development of techniques able to explore in humans neurophysiologic and neurochemical processes. Positron emission tomography (PET) is a very powerful technique allowing to study a quite variable range of physiological and biochemical processes in the healthy subjects and in diseases. Apart from its capacity to provide pathophysiological information, PET is also important for the objective assessment of therapeutic efficacy. Initial studies were performed measuring cerebral metabolic rate for glucose (CMRglc) and cerebral blood flow (CBF), representing an indirect index of synaptic activity. The advent of receptor tracers allowed measuring other important physiological parameters, such as receptor occupancy, and endogenous release. In neuropsychiatric disorders, as Alzheimer disease, schizophrenia, epilepsy and Huntington disease, PET has been useful to elaborate hypothesis of the pathogenesis, to relate symptoms to biological variables and to study individuals at increased risk. The new concepts of neurovascular unit and default network, preferentially active at rest, can significantly change the approach of PET, with images reflecting a complex scenario, not merely limited to neural activity, but involving the activity of the entire neurovascular unit and the multifunctional role of astrocytes. To detect dysfunction of the dialog between glutamatergic neurons and astrocytes could lead to a better understanding of altered functional brain images. In this direction a professional network between PET researchers and basic scientists, could give a determinant improvement in the capability to understand the complex physiological and pathophysiological cerebral world.

Phase II study of rubitecan in recurrent or metastatic head and neck cancer.

PURPOSE: Rubitecan is an oral camptothecin analogue that has shown activity against a broad spectrum of human tumor xenografts and has been tested in several diseases. PATIENTS AND METHODS: In the present study, 19 patients with incurable, recurrent or metastatic head and neck cancer were treated with rubitecan at the initial dose of 1.5 mg/m(2) x 5 days per week. An appropriate dose modification program was set up according to the observed toxicities. RESULTS: Thirteen out of the 19 treated patients were formally evaluable for tumor response. Ten patients had a disease progression and three patients had a stabilization of disease as their best response. The mean duration of stable disease was 141 days. Median survival was 16 weeks (range 2-22 weeks). Three patients died during the study or less than a month after their last dose of study medication. Hematologic toxicity was serious in this study since four patients discontinued their participation because of severe anemia. The drug was also associated with grade 1-4 neutropenia, and with 1-3 thrombocytopenia. CONCLUSION: We conclude that rubitecan is not effective as a single-agent in recurrent or metastatic head and neck cancer with the doses and schedule used in this study.

The proteasome: a worthwhile target for the treatment of solid tumours?

Proteasomes have a fundamental function since they degrade numerous different proteins, including those involved in the regulation of the cell cycle. Proteasome inhibition is a novel approach to the treatment of solid tumours. PS-341 (bortezomib) is a small, cell-permeable molecule that selectively inhibits the proteasome binding it in a reversible manner. The proteasome has been established as an important target in haematologic malignancies and has been approved for the treatment of multiple myeloma. Bortezomib induces apoptosis of malignant cells through the inhibition of NF-kappaB and stabilisation of proapoptotic proteins. In preclinical studies, bortezomib also promoted chemo and radiosensitisation of malignant cells in vitro and inhibited tumour growth in murine xenografts models. The single-agent and combination studies of bortezomib in solid tumours are detailed.

Recent advances in the treatment of salivary gland cancers: emphasis on molecular targeted therapy.

Salivary gland cancers include tumors of different histologic characteristics and biological behavior. Radical surgery, followed or not by radiation therapy, represents the main treatment approach for this disease. The role of systemic chemotherapy is less clearly defined since trials of single-agent chemotherapy have consistently shown low response rates. Polychemotherapy is likely to induce a higher response rate, but does not improve survival. The determination of the molecular abnormalities underlying the different subtypes of salivary gland cancers might lead to more active targeted therapies. C-kit is overexpressed in a wide percentage of salivary gland carcinomas, but clinical trials with single-agent imatinib have been negative. ErbB1 and ErbB2 are also frequently overexpressed in salivary gland cancers and this has provided the rationale for clinical trials with trastuzumab, cetuximab, gefitinib, lapatinib. Finally, new pathways, such as vascular endothelial growth factor, might be worth targeting and clinical trials with anti-angiogenic agents are ongoing.

New emerging drugs in soft tissue sarcoma.

Doxorubicin and ifosfamide are the two most active drugs in the treatment of patients with advanced, soft tissue sarcoma (STS) of most histologic subtypes, aside from gastrointestinal stromal tumor (GIST). However, after failure of these drugs, alone or in combination, patients with advanced STS have few therapeutic options and the search for new active drugs is well worth pursuing. ET-743, a DNA minor groove binder, which blocks cell cycle progression in G2/M phase through a p53-independent apoptotic process, represents the most promising among novel compounds in STS, since recently completed phase II trials have consistently shown high survival, in spite of the relatively low incidence of major objective responses. The potential for combination with other active compounds further increases the appeal of ET-743. Imatinib mesylate is being tested also in STS other than GIST, which can overexpress one or more of the tyrosine kinases inhibited by imatinib; however, negative data have recently been presented. Clinical studies with a number of other compounds are ongoing or planned. However, investigators involved in the management of patients with advanced STS are to be increasingly aware of the emergence of new molecular targets and genetic profiles in different histologic subtypes, according to which treatment strategies should be adapted.

What clinicians need to know about antioestrogen resistance in breast cancer therapy.

Tamoxifen is the drug most used for early breast cancer treatment in oestrogen receptor (ER) positive patients. Unfortunately, despite high ER tumour levels in a tumour, resistance to endocrine therapy, either de novo or acquired after prolonged treatment, can occur. In this review, we will try to summarise the postulated mechanisms of hormonal-resistance, namely, the role of co-regulators and the crosstalk between the HER-2, IGF-IR, Cox-2 and ER pathways. Other predictive markers of tamoxifen-resistance/response, such as cyclin E and UPA/PAI-1, are also discussed.

Recent advances in head and neck cancer therapy: the role of new cytotoxic and molecular-targeted agents.

PURPOSE OF REVIEW: To provide an update on novel compounds in head and neck cancer (HNC) therapy, with emphasis on biologic agents. RECENT FINDINGS: Cisplatin-5-fluorouracil (5-FU) is the standard chemotherapeutic approach in HNC. Strategies to improve its activity include the substitution of 5-FU with oral fluoropyrimidines; the substitution of cisplatin with different analogs or formulations; and the use of additional or alternative compounds. Epidermal growth factor receptor (EGFR) is the most appealing target for novel therapies in HNC. Cetuximab, a chimeric anti-EGFR monoclonal antibody, has undergone evaluation in platinum-refractory recurrent or metastatic HNC with a satisfactory and consistent response rate (10-13%) across three different Phase II studies in association with platinum or as single agent. A recent Phase III placebo-controlled trial has shown better response rate for patients treated with cetuximab and cisplatin, with respect to those treated with cisplatin alone. EGFR tyrosine kinase inhibitors (TKIs) are under investigation in HNC, and efforts are made to understand which molecular features are associated with objective responses. One appealing way to use EGFR TKIs is in combination with other biologic compounds, such as anti-angiogenic agents. SUMMARY: New molecular-targeted therapies are inducing consistent, small improvements in HNC management. The major challenge regards how to better combine them with the final aim of obtaining long-term stabilization of advanced disease.

Biological prognostic factors in adult soft tissue sarcomas.

Adult soft tissue sarcomas (STSs) are a rare group of highly heterogeneous neoplasms arising in different tissues. They are locally aggressive and can produce recurrence and distant metastasis. The most common metastatic sites are lung, lymph nodes, liver, bone and soft tissues. Staging for STSs has been based on some prognostic information: grade (low vs. intermediate/high grade), size (small vs. large tumors), depth of infiltration (superficial vs. deep neoplasms) and presence or not of distant metastasis. In the last 10 years, a plethora of new markers (proliferation markers and DNA alteration, P-gp, p53, TLS-CHOP, cyclins, survivin, TERT, PAX3-PAX7/FKHR, SYT-SSX1/2, VEGF, E-cadherin and beta-catenin, nm23, SKP-2, p27, CD40) has been studied with regard to their role in promoting progression (in a laboratory setting) and then determining prognosis and therapy (in a clinical setting). In the present survey, we focused on the role of new biological prognostic factors in STSs and also reported the quality of such studies with an ad hoc designed questionnaire.

Clinical applications of choline PET/CT in brain tumors.

Malignant gliomas and metastatic tumors are the most common forms of brain tumors. From a clinical perspective, neuroimaging plays a significant role, in diagnosis, treatment planning, and follow-up. To date MRI is considered the current clinical gold standard for imaging, however, despite providing superior structural detail it features poor specificity in identifying viable tumors in brain treated with surgery, radiation, or chemotherapy. In the last years functional neuroimaging has become largely widespread thanks to the use of molecular tracers employed in cellular metabolism which has significantly improved the management of patients with brain tumors, especially in the post-treatment phase. Despite the considerable progress of molecular imaging in oncology its use in the diagnosis of brain tumors is still limited by a few wellknown technical problems. Because 18F-FDG, the most common radiotracer used in oncology, is avidly accumulated by normal cortex, the low tumor/background signal ratio makes it difficult to distinguish the tumor from normal surrounding tissues. By contrast, radiotracers with higher specificity for the tumor are labeled with a short half-life isotopes which restricts their use to those centers equipped with a cyclotron and radiopharmacy facility. 11C-choline has been reported as a suitable tracer for neuroimaging application. The recent availability of choline labeled with a long half-life radioisotope as 18F increases the possibility of studying this tracer's potential role in the staging of brain tumors. The present review focuses on the possible clinical applications of PET/CT with choline tracers in malignant brain tumors and brain metastases, with a special focus on malignant gliomas.

Parametric MR dynamic imaging for breast lesions characterization and prediction of lymph nodes involvement.

The main purpose of this study was to evaluate Gd-DTPA kinetics for the differential diagnosis between malignant and benign breast lesions. As a secondary aim, Gd-DTPA kinetics in malignant lesions was tested for predicting axillary lymph nodes involvement. Eighty-eight patients who underwent MRI for suspected breast tumor were selected from our database. All patients underwent the same acquisition protocol consisting of pre-contrast and dynamic contrastenhanced MRI. For all of them clinical and histopathological data were available. MR studies were performed on the same 1.5T scanner with a standard dedicated breast coil. Pre- and post-contrast dynamic images were used to calculate R1, R2 relaxation rates and proton density maps. The maximum influx rate (MIR) as well as the corresponding time (TMIR) were derived using R1 relaxation rate maps and relative changes as a function of time. Histopatological analysis led to the diagnosis of 46 breast carcinomas and 42 benign lesions. All breast carcinomas and 24 out of 42 benign lesions showed contrast-enhancement. The mean MIR was 0.75±0.14 (SD) sec-(2) in malignant tumors and 0.53±0.14 (SD) sec-(2) in contrast-enhancing benign breast lesions (p<0.0001). The TMIR was 1.40±0.43 min and 3.01±1.92 min (mean±SD) in enhancing malignant and benign lesions, respectively (p<0.0001). In malignant tumors, TMIR was not significantly different in node negative and node positive carcinomas whereas MIR was significantly lower in node negative carcinomas (0.67±0.11 versus 0.83±0.12 respectively, p<0.0001). Our findings suggest that quantitative assessment of Gd-DTPA kinetics may be an additional tool characterized for enhancing breast lesions and for predicting axillary lymph nodes involvement in malignant breast carcinoma.

Targeted-therapy and imaging response: a new paradigm for clinical evaluation?

Clinical management of patients with malignant tumors has dramatically changed over the last years with the introduction of novel therapeutics, such as receptor-targeted therapies, downstream effectors and antiangiogenic compounds. This has created a need to re-evaluate the existing criteria used to assess treatment response. Emerging diagnostic techniques, combining functional and structural data may play a relevant role in planning new treatment strategies in individual cancer patients. In the new scenario where biological treatment results in stable disease, standard Response Evaluation Criteria in Solid Tumors (RECIST) and RECIST 1.1 criteria have limitations. Moreover, functional 18- fluorodeoxyglucose ((18)FDG)-positron emission tomography (PET) imaging provides an additional tool to assess tumor activity, particularly consistent in some settings, such as Gastro Intestinal Solid Tumors (GIST), hepatocarcinoma, nonsmall lung cancer, and colorectal cancer. The integration of (18)FDG-PET and computed tomography (CT) enhances the evaluation of oncologic patients treated with molecularly targeted drugs, and accelerates drug development in many types of tumors.

A phase I/II trial of gefitinib and radiotherapy in patients with locally advanced inoperable squamous cell carcinoma of the head and neck.

Two different doses of gefitinib, administered along with standard radiation therapy, were tested in locally advanced inoperable head and neck cancer with the aim of finding the maximum tolerated dose and assessing the toxicity and activity of the combination. The standard '3+3' design was used for the phase I study. Radiation therapy was given according to conventional dose and schedule. Gefitinib dose escalation was stopped if more than one-third of patients of a given cohort had dose-limiting toxicity. Dose-limiting toxicity was observed in three of four patients treated at the dose of 500 mg, and included grade 3 stomatitis in three patients and grade 3 liver toxicities in one patient. The dose level of 250 mg was recommended for the phase II study. Six confirmed objective responses were observed among 16 patients. Our results do not support further trials with gefitinib and radiation therapy, according to our schedule, in this patient population. Integration of gefitinib within chemoradiotherapy regimens and combination with other biological therapies may represent the next challenge.

First line targeted therapies in breast cancer: focus on bevacizumab.

The heterogeneity of metastatic breast cancer mandates the need to select therapies taking into account tumor and patient characteristics. Chemotherapy is indicated in the palliative setting especially when the disease is unresponsive to hormonal therapy or is hormone-receptor negative. The main chemotherapeutic agents are anthracyclines, taxanes, and capecitabine. The knowledge of the effects of currently approved agents and of the biology of breast cancer have paved the way for the evaluation of new treatment options, among which are anti-angiogenic agents. Angiogenesis inhibition has resulted in clinically significant improvements in the outcome of a variety of malignancies, including breast cancer. Bevacizumab, a monoclonal antibody anti-vascular endothelial growth factor (VEGF), is the most extensively studied anti-angiogenic compound. According to the results of a phase III trial in patients with untreated metastatic breast cancer, bevacizumab increases both objective response rate and median progression-free survival when combined with standard chemotherapy vs chemotherapy alone. The combination of anti-angiogenic drugs and other biologic agents is also being explored in an attempt to improve efficacy.

Downstream intracellular effectors of epidermal growth factor receptor as targets for anticancer therapy.

In recent years, the knowledge about mutations in components of the intracellular signal transduction pathway has greatly improved. Pivotal target molecules, such as Ras, PI3K, mammalian target of rapamycin (mTOR) and PKC, form an important biochemical network, which, when mutated, drives cell growth in an unlimited manner. Cancer cells have been shown to be able to harness different growth factor signalling pathways. Protein kinase inhibitors, targeted to the above pathways, have demonstrated activity against several solid tumours and are generally better tolerated than standard cytotoxic agents. The future challenge will be to find the most clever way to use combinations of these novel compounds.

Epidermal growth factor receptor as a major anticancer drug target.

Epidermal growth factor receptor (EGFR) is the best characterised member of the ErbB family of receptors. A lot of effort has been made to exploit the therapeutic potential of drugs acting on this receptor pathway. Monoclonal antibodies and oral tyrosine kinase inhibitors have undergone a thorough evaluation, both as single agents and in combination. However, over recent years, cancer cells have been shown to be able to harness different growth factor signalling pathways, so that single-agent therapy may not be the best way to use anti-EGFR drugs. Combinations with downstream effectors or other receptor-targeted therapies, or antiangiogenic compounds can be looked at more optimistically as effective weapons.

Medical treatment of gastrointestinal stromal tumors: state of the art and future perspectives.

Gastrointestinal Stromal Tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract, and it is characterized by the occurrence, in > 90 % of cases, of a gain of function mutation in the c-kit proto-oncogene. STI-571 (imatinib mesylate), a selective KIT tyrosine kinase inhibitor, has changed the natural history of this disease, since it has shown high effectiveness in metastatic GIST, and it is currently under investigation also in the adjuvant and neoadjuvant setting. Mechanisms of resistance to imatinib mesylate include both de novo, and, more frequently, acquired resistance, which may occur after several months of drug administration and possibly depends, in most cases, upon an acquired second mutation. In order to overcome imatinib mesylate resistance, the addition of other drugs may be considered in patients who have less than an optimal response to imatinib mesylate monotherapy. Investigational agents that are being studied in this setting include the mammalian target of rapamycin (mTOR) inhibitor RAD 001 and the protein kinase C inhibitor PKC412. In addition, other KIT tyrosine kinase inhibitors with anti-VEGF receptor inhibitory activity, such as SU11248, PTK787/ZK787 and AMG 706, are currently being explored as second line monotherapy for imatinib mesylate-resistant GIST. Finally, another new drug, ecteinascidin (ET-743), that blocks cell cycle progression in G2/M phase through a p53-independent apoptotic mechanism, has shown important preclinical and clinical activity against a number of human solid tumors, including GIST.

New molecular targeted therapies in thyroid cancer.

Carcinoma of the thyroid gland is the most common malignancy of the endocrine system. Differentiated tumors are often curable with surgical resection and radioactive iodine. A small percentage of such patients, however, do not undergo remission and need new therapeutic approaches. Both anaplastic and medullary thyroid carcinomas exhibit aggressive behavior and are usually resistant to current therapeutic modalities. Thyroid carcinoma represents a fascinating model and a particularly promising paradigm for targeted therapy because some of the key oncogenic events are activating mutations of genes coding for tyrosine kinases, and these occur early in cancer development. A prototype is the RET proto-oncogene, a receptor tyrosine kinase, which is a key regulator of development and a 'hotspot' for oncogenic mutations. Mutations in the RET proto-oncogene have been identified as causative for papillary carcinoma and familial medullary thyroid carcinoma, making it an attractive target for selective inhibition in these subtypes. ZD 6474 has shown promising activity in preclinical models against RET kinase, and its contemporary inhibition of vascular endothelial growth factor and epidermal growth factor pathways renders it a very attractive drug for clinical trials in thyroid cancer. Activating point mutation of B-RAF can occur early in the development of papillary carcinoma. Moreover, papillary carcinomas with these mutations have more aggressive properties and are diagnosed more often at an advanced stage. Clinical evaluation of B-RAF-targeting drugs is undergoing and trials in thyroid cancer are planned. Agents that restore radioiodine uptake, such as histone deacetylase inhibitors and retinoids, represent another exciting field in new drug development in thyroid cancer.