Radiation therapy with curative intention in men with de novo metastatic prostate carcinoma: shoot‘em all!

BackgroundAbout 5% of prostate cancer cases are metastatic at diagnoses. Radiotherapy of both primary tumor and secondary lesions can be, in addition to systemic treatments, a radical alternative for selected patients.Materials and methodsPatients with de novo prostate carcinoma with bone or lymph node metastases were retrospectively reviewed. All patients received moderate hypofractionated IMRT/VMAT up to 63 Gy in 21 daily fractions of 3 Gy to prostate and metastases with neoadjuvant and concurrent androgen deprivation therapy (ADT). According to known advances some patients also received abiraterone, enzalutamide, or docetaxel.ResultsBetween 2015–2020, we attended 26 prostate cancer patients (median age 69.5 years, range 52–84) with simultaneous oligometastases [mean 2.1 metastases, median 1.5 metastases (range 1–6)]. Eighteen patients (69%) presented lymph node metastases, 4 (15.5%) bone metastases and 4 (15.5%) both lymph node and bone metastases. With a median follow-up of 15.5 months (range 3–65 months), 16 patients (62%) are alive and tumor free while 10 (38%) are alive with tumor. Four patients (17%) developed tumor progression, out of irradiated area in all cases, with a median time to progression of 43.5 months (range 27–56 months). Actuarial progression-free survival (PFS) rates at 12 and 24 months were 94.1% and 84.7%, respectively. No grade > 2 acute or late complications were recorded.ConclusionsSimultaneous directed radical hypofractionated radiation therapy for prostate and metastases is feasible, well tolerated and achieves an acceptable PFS rate. However, further studies with longer follow-up are necessary to definitively address these observations.     

Improved long-term results of intensity-modulated radiotherapy for a non-endemic European nasopharyngeal carcinoma cohort: single-center retrospective study

PurposeReport our matured outcomes of European nasopharyngeal carcinoma (NPC) treatment from a non-endemic region in the IMRT era.MethodsWe reviewed 109 consecutive patients with biopsy proven NPC treated between 2009 and 2013. All received IMRT as per RTOG 0615. Toxicity was scored accordingly to CTCAE 4.03. Platinum-based chemotherapy was delivered following the Intergroup 0099.ResultsMedian age of 53 years; 97% Caucasian; 74% male; 72% WHO grade III; 43% T1; 14% T2; 18% T3, 25% T4; 17% N0; 17% N1; 39% N2; 27% N3. Compliance to adjuvant chemotherapy was 88%. With a median follow up of 56 months, the 4-year local control was 90.2% (88.6% for T1; 100% for T2; 85% for T3; and 91.7% for T4), the 4-year distant metastases-free survival was 86% and an overall survival rate was 77%. Local control and survival were better in G3 (p < 0.001 and p = 0.032, respectively). Xerostomia was the most frequent late toxicity in 55% (n = 60). Hypothyroidism requiring hormonal reposition occurred in 15.5% (n = 17). From the 36 deaths, 20 were due to distant metastases, 3 grade 5 toxicity, 2 from local progression, 5 non-cancer deaths and unknown cause in the remaining 6. On multivariable analysis, age (p = 0.017), local recurrence and distant metastases were associated with death (p < 0.001, both).ConclusionOur matured data from the IMRT era showed a major improvement from our 3D cohort series reaching excellent local and regional control, even in T4. Local recurrences, despite few, and distant metastases were correlated with the risk of death.     

Treatment patterns and overall survival in metastatic urothelial carcinoma in a real-world,US setting

BackgroundMetastatic urothelial carcinoma (mUC) treated with chemotherapy is associated with poor survival; however, as the field of immuno-oncology continues to evolve, new immunotherapies have recently become available. The current study aimed to assess real-world characteristics, treatment patterns, and overall survival (OS) of patients with mUC treated in the United States (US).MethodsWe conducted a retrospective, observational analysis of patients with mUC from the Flatiron Health longitudinal database from 2011 to 2017. Treatment patterns of patients who started systemic first-line therapy (1 L cohort) or second-line therapy following platinum-based first-line therapy (2 L cohort) were described using medication order and administration data. Kaplan-Meier analyses were used to assess OS from the start of first- and second-line therapy in the 1 L and 2 L cohorts, respectively.ResultsA total of 1811 patients qualified for the 1 L cohort (median age [range], 72 [32–84] years); 476 met the criteria for the 2 L cohort (median age [range], 71 [40–84] years). The most common first- and second-line therapies were carboplatin + gemcitabine (n = 562 [34.6%]) and atezolizumab (n = 90 [13.1%]), respectively, in the 1 L cohort. Median OS was 12.7 months (95% confidence interval [CI] 11.8, 13.4) in the 1 L cohort and 8.3 months (95% CI 7.2, 8.9) in the 2 L cohort.ConclusionsConsistent with clinical trial results, survival was poor in this real-world study in patients with mUC, indicating a continued unmet need. As immunotherapy becomes more commonplace in the treatment of mUC, future studies are needed to understand its real-world impact on survival.     

A metabolic discrimination model for nasopharyngeal carcinoma and its potential role in the therapeutic evaluation of radiotherapy

Nasopharyngeal carcinoma (NPC) is one of the most common malignancies in Southeast Asia and radiotherapy or radiotherapy, in combination with chemotherapy is the primary treatment strategy. In this study, we adopted a metabolomic method to investigate the metabolic disorders in NPC and evaluate the effect of radiotherapy on metabolic profile alterations in NPC patients. To generate the NPC metabolic profiles, 402 serum samples were collected from 100 newly-diagnosed NPC patients and 100 healthy volunteers. Based on gas chromatography–mass spectrometry (GC–MS) metabolomics coupled with partial least squares-discriminant analysis, a NPC discrimination model was constructed with a sensitivity of 88 % (88/100) and a specificity of 92 % (92/100). Seven metabolites, including glucose, linoleic acid, stearic acid, arachidonic acid, proline, β-hydroxy butyrate and glycerol 1-hexadecanoate, were identified as contributing mostly to the discrimination of NPC serum from healthy controls. To validate if the model can be applied for therapeutic evaluation, 202 serum samples were collected from 20 patients receiving standard radiotherapy for up to a 3-year follow-up period. The metabolic footprints of 20 NPC patients treated with standard radiotherapy are visually presented. Based on the footprint trends of the sera samples in irradiation-treated NPC patients who were gradually closer to healthy controls or not, patients were divided into positive and negative groups, respectively. The coincident rate of the trends of metabolic footprints to the actual clinical prognosis trend was approximately 80 %. This study demonstrates that a GC–MS-based metabolic profiling approach as a novel strategy may be capable to delineating the potential of metabolite alterations in discrimination and therapeutic evaluation of NPC patients.     

Scanning electronic microscopy study of nasopharyngeal carcinoma

The nasopharyngeal carcinoma is a greatly interesting model of study. Its morphology has been studied in 8 patients affected by squamous cells carcinoma (4 cases) and by undifferentiated carcinoma (4 cases). By means of a fibre-optic pharyngoscope equipped with mechanical biopsy forceps, biopsies have been taken and subsequently studied by scanning electron microscopy (SEM). Squamous cells carcinoma is characterized by large, flattened elements, generally equipped with a network of microridges. Irregular microvilli or smooth apices have been observed too. Desquamating elements often accumulated in waves or vortices, as far as little cornified structures have been described. Undifferentiated carcinoma shows a great morpho-structural disorder. In a rugged surface, it is possible to observe element highly varying for size and shape. The apical plasmalemma is characterized by pleomorphic microvilli, while it must be emphasized the presence of little pseudopod-like extrusions of some cellular apices. Ciliated elements have been observed too, whose apical specializations are distorted or irregularly disposed. Necrotic zones are particularly frequent, in which bacteria or mycetes proliferate. The role of SEM in the study of this tumour is emphasized, because of the close relation between epithelial patterns and natural history of nasopharyngeal carcinoma.     

Raf kinase inhibitor protein correlates with sensitivity of nasopharyngeal carcinoma to radiotherapy

Raf kinase inhibitory protein (RKIP) is a metastasis suppressor whose expression is reduced in nasopharyngeal carcinoma (NPC) tissues and is absent in NPC metastases. To investigate the effect of RKIP on radiosensitivity of NPC, high metastatic 5‐8F with low RKIP expression and non‐metastatic 6‐10B with high RKIP expression were stably transfected with plasmids that expressed sense and antisense RKIP cDNA. Overexpression of RKIP sensitized 5‐8F cells to radiation‐induced cell death, G₂‐M cell cycle arrest and apoptosis. In contrast, downexpression of RKIP in 6‐10B cells protected cells from radiation‐induced cell death, G₂‐M cell cycle arrest and apoptosis. In addition, RKIP expression altered the radiosensitivity of NPC cells through MEK and ERK phosphorylation changes of Raf‐1/MEK/ERK signaling pathway. We further investigated the RKIP expression in NPC patients and its association with patients' survival after radiotherapy. Downexpression of RKIP was significantly correlated with advanced clinical stage, lymph node metastasis and radioresistance. Furthermore, survival curves showed that patients with RKIP downexpression had a poor prognosis and induced relapse. Multivariate analysis confirmed that RKIP expression was an independent prognostic indicator. The data suggested that RKIP was a potential biomarker for the radiosensitivity and prognosis of NPC, and its dysregulation might play an important role in the radioresistance of NPC. J. Cell. Biochem. 110: 975–984, 2010. © 2010 Wiley‐Liss, Inc.     

Serum proteomic pattern for predicting recurrence of undifferentiated nasopharyngeal carcinoma after radiotherapy

Although most patients with early-stage nasopharyngeal carcinoma (NPC) can be cured by radiotherapy, there is a high recurrence rate in patients with advanced NPC. We attempted to identify proteomic patterns in sera for predicting tumor recurrence. Pretreatment sera were collected from 64 NPC patients with complete remission after radiotherapy. Serum proteins were profiled by SELDI ProteinChip technology, and correlated with local/distant recurrence. Forty proteomic features were significantly different between the patient groups with and without tumor recurrence. Univariate analyses showed that 32 of them were significantly associated with time to first recurrence. Multivariate Cox-regression analyses identified International Union Against Cancer (UICC) stage and two proteomic features with mass/charge (m/z) values of 8808 and 6626 as independent prognostic indicators for tumor recurrence. The hazard ratios were 2.0 (95% confidence interval, CI 1.3–3.2) and 0.79 (95% CI 0.64–0.96) for a double of peak intensity of proteomic feature m/z 8808 and m/z 6626, respectively. These two proteomic features were also independent prognosticators for overall survival. A decision tree was constructed to predict the tumor recurrence by using UICC stage, proteomic feature m/z 8808, and proteomic feature m/z 6626, and evaluated by Leave-One-Out crossvalidation. Kaplan-Meier analysis confirmed that the decision tree could predict both recurrencefree survival and overall survival. The positive and negative predictive values for tumor recurrence within 4 yr were 74 and 89%, respectively. A serum proteomic pattern comprising features m/z 8808 and m/z 6626 is a potential surrogate marker of disease recurrence after radiotherapy in NPC.     

Dosimetric impact on changes in target volumes during intensity-modulated radiotherapy for nasopharyngeal carcinoma

Background and purposeTo assess anatomic changes during intensity modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC) and to determine its dosimetric impact.Patients and methodsTwenty patients treated with IMRT for NPC were enrolled in this study. A second CT was performed at 38 Gy. Manual contouring of the macroscopic tumor volumes (GTV) and the planning target volumes (PTV) were done on the second CT. We recorded the volumes of the different structures, D98 %, the conformity, and the homogeneity indexes for each PTV. Volume percent changes were calculated.ResultsWe observed a significant reduction in tumor volumes (58.56 % for the GTV N and 29.52 % for the GTV T). It was accompanied by a significant decrease in the D98 % for the 3 PTV (1.4 Gy for PTV H, p = 0.007; 0.3 Gy for PTV I, p = 0.03 and 1.15 Gy for PTV L, p = 0 0.0066). In addition, we observed a significant reduction in the conformity index in the order of 0.02 (p = 0.001) and 0.01 (p = 0.007) for PTV H and PTV I, respectively. The conformity variation was not significant for PTV L. Moreover, results showed a significant increase of the homogeneity index for PTV H (+ 0.03, p = 0.04) and PTV L (+ 0.04, p = 0.01).ConclusionTumor volume reduction during the IMRT of NPC was accompanied by deterioration of the dosimetric coverage for the different target volumes. It is essential that a careful adaptation of the treatment plan be considered during therapy for selected patients.     

Changes of serum copper and zinc levels in patients with nasopharyngeal carcinoma by radiotherapy

Serum copper levels (SCL) and serum zinc levels (SZJ) were evaluated in 128 patients with nasopharyngeal carcinoma (NPC) of varying stages before, during, and after radiotherapy, and then compared with normal age-matched subjects. Among these patients, there were 119 undifferentiated squamous cell carcinoma, 5 differentiated squamous cell carcinoma, and 4 moderately differentiated squamous cell carcinoma, respectively. Before radiotherapy, SCLs were significantly higher in NPC patients than in normal subjects, but the difference of SZLs was not significant. The ratio of Cu/Zn also showed a significant difference between normal subjects and NPC patients preradiotherapy. Moreover, except stage II, patients with more advanced stages of the disease had more elevated Cu/Zn ratios. During and after the period of radiotherapy, the SCL decreased as compared with the level of preradiotherapy. The Cu/Zn ratio also decreased after radiotherapy but not significant. However, Cu/Zn ratio of expired patients at least 2 yr after radiotherapy did not show the significant decrease in contrast to the alive ones.     

A selectionist account of de novo action learning

How are novel actions generated and learned? We introduce a selectionist view of de novo action learning, and present some of the main postulates of such a view. This view contrasts with the notion that all actions are generated in response to particular stimuli and hence instructed by the world. It postulates that actions are generated in the actor (the organism) and selected by the environment (stimuli). Selection may occur iteratively until actions can be executed more rapidly and precisely, less variably, and eventually be elicited by particular stimuli. We also discuss experiments that support the particular predictions of this theory.     

A novel Rhein derivative: Activation of Rac1/NADPH pathway enhances sensitivity of nasopharyngeal carcinoma cells to radiotherapy

Radiation resistance and recurrent have become the major factors resulting in poor prognosis in the clinical treatment of patients with nasopharyngeal carcinoma (NPC). New strategies to enhance the efficacy of radiotherapy have been focused on the development of radiosensitizers and searching for directly targets that modulated tumor radiosensitivity. A novel potential radiosensitizer 1,8-Dihydroxy −3-(2′-(4″-methylpiperazin-1″-yl) ethyl-9,10-anthraquinone −3-carboxylate (RP-4) was designed and synthesized based on molecular docking technology, which was expected to regulate the radiosensitivity of tumor cells through targeting Rac1. In order to assess the radiosensitization activity of RP-4 on NPC cells, the highly differentiated CNE1 and poorly differentiated CNE2 cells NPC lines were employed. According to the results, RP-4 showed higher binding affinity toward the interaction with Rac1 than lead compounds. We found that RP-4 could inhibit cell viability and proliferation in CNE1 and CNE2 cells and significantly induced apoptosis after non-toxic concentration of RP-4 combined with 2Gy irradiation. RP-4 could effectively modulated the radiosensitivity both CNE1 cells and CNE2 cells through activating Rac1/NADPH signaling pathway and its downstream JNK/AP-1 pathway. What's more, Rac1/NADPH signaling pathway were significantly activated in Rac1-overexpressed CNE1 and CNE2 cells after treated with RP-4. Taken together, Rac1 and its downstream pathway may probably be the direct targets of RP-4 in regulating radiosensitivity of NPC cells, our finding provided a novel strategy for the development of therapeutic agents in response to tumorous radiation resistance.     

A de novo redesign of the WW domain

We have used a sequence prediction algorithm and a novel sampling method to design protein sequences for the WW domain, a small beta-sheet motif. The procedure, referred to as SPANS, designs sequences to be compatible with an ensemble of closely related polypeptide backbones, mimicking the inherent flexibility of proteins. Two designed sequences (termed SPANS-WW1 and SPANS-WW2), using only naturally occurring L-amino acids, were selected for study and the corresponding polypeptides were prepared in Escherichia coli. Circular dichroism data suggested that both purified polypeptides adopted secondary structure features related to those of the target without the aid of disulfide bridges or bound cofactors. The structure exhibited by SPANS-WW2 melted cooperatively by raising the temperature of the solution. Further analysis of this polypeptide by proton nuclear magnetic resonance spectroscopy demonstrated that at 5 degrees C, it folds into a structure closely resembling a natural WW domain. This achievement constitutes one of a small number of successful de novo protein designs through fully automated computational methods and highlights the feasibility of including backbone flexibility in the design strategy.     

Kinetic study of de novo chromophore maturation of fluorescent proteins

Green fluorescent protein (GFP) has a chromophore that forms autocatalytically within the folded protein. Although many studies have focused on the precise mechanism of chromophore maturation, little is known about the kinetics of de novo chromophore maturation. Here we present a simple and efficient method for examining the de novo kinetics. GFP with an immature chromophore was synthesized in a reconstituted cell-free protein synthesis system under anaerobic conditions. Chromophore maturation was initiated by rapid dilution in an air-saturated maturation buffer, and the time course of fluorescence development was monitored. Comparison of the de novo maturation rates in various GFP variants revealed that some folding mutations near the chromophore promoted rapid chromophore maturation and that the accumulation of mutations could reduce the maturation rate. Our method will contribute to the design of rapidly maturing fluorescent proteins with improved characteristics for real-time monitoring of cellular events.     

Designing de novo: interdisciplinary debates in synthetic biology

Synthetic biology is often presented as a promissory field that ambitions to produce novelty by design. The ultimate promise is the production of living systems that will perform new and desired functions in predictable ways. Nevertheless, realizing promises of novelty has not proven to be a straightforward endeavour. This paper provides an overview of, and explores the existing debates on, the possibility of designing living systems de novo as they appear in interdisciplinary talks between engineering and biological views within the field of synthetic biology. To broaden such interdisciplinary debates, we include the views from the social sciences and the humanities and we point to some fundamental sources of disagreement within the field. Different views co-exist, sometimes as controversial tensions, but sometimes also pointing to integration in the form of intermediate positions. As the field is emerging, multiple choices are possible. They will inform alternative trajectories in synthetic biology and will certainly shape its future. What direction is best is to be decided in reflexive and socially robust ways.