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Introduction: Radiation plays a major role in treatment of locoregional control of Head and Neck Squamous cell carcinoma (HNSCC). Anaemia is considered a contributor to intra-tumour hypoxia and tumour resistance to ionizing radiation and most evidences are from developed world, we prospectively investigated the exact role of anaemia in treatment outcome of Stage III/IVA HNSCC in our patient population. Aim of the Study: Primary end point: To analyse the PreRadiotherapy haemoglobin level and early response of treatment in stage III/IVA HNSCC and to determine the relationship of Pre-Radiotherapy haemoglobin level with other prognostic factors. Materials and Methods: This non-interventional single blinded randomized study enrolled patients attending the OPD consecutively, who met our eligibility criteria. Inclusion Criteria: HNSCC patients of Stage III/IVA aged ≥18 years and ≤ 70 years with ECOG status of 1or 2 and willing for concurrent chemoradiation and at least 6 weeks of follow up. Exclusion Criteria: 1) Previous history of treatment for malignancy or radiation in head and neck site. 2) Patients with other fatal and non-fatal pre-morbid or co-morbid conditions that can affect the outcome or the overall survival. Patients with Pre-radiotherapy haemoglobin status < 10 g/dl were given haematinic support and/or blood transfusion. All patients received concurrent chemotherapy (weekly cisplatin) and radiation in conventionally fractionated dose of 66Gy. Early treatment responses were evaluated with Revised RECIST version 1.1 and Data analysis using SPSS version 17.0. Results: Ninety one patients enrolled had mean age of 55.63 (range: 32-69), a median of 56 and mode of 60. Seventy one were males (78%) and 20 females (22%) with a performance status of ECOG 1 in 43 (47%) patients and ECOG 2 in 48 (53%); Pre-RT Hb level of 5 days (p = 5 days and nondevelopment of grade III mucositis was found to be significantly associated with good loco-regional control. Haemoglobin level ≥10.7 g/dl was associated with better treatment outcome, higher performance status, fewer treatment interruptions and lesser degree of mucositis. Transfusion did not affect the outcome. Definitive conclusions and recommendations need further expansion of our study for better statistical power.

Purpose To estimate the rate constant for pyruvate to lactate conversion in tumours in response to a hypoxic challenge, using hyperpolarised 13 C 1 -pyruvate and magnetic resonance spectroscopy. Methods and materials Hypoxic inspired gas was used to manipulate rat P22 fibrosarcoma oxygen tension (pO 2 ), confirmed by luminescence decay of oxygen-sensitive probes. Hyperpolarised 13 C 1 -pyruvate was injected into the femoral vein of anaesthetised rats and slice-localised 13 C magnetic resonance (MR) spectra acquired. Spectral integral versus time curves for pyruvate and lactate were fitted to a precursor-product model to estimate the rate constant for tumour conversion of pyruvate to lactate ( k pl ). Mean arterial blood pressure (MABP) and oxygen tension (ArtpO 2 ) were monitored. Pyruvate and lactate concentrations were measured in freeze-clamped tumours. Results MABP, ArtpO 2 and tumour pO 2 decreased significantly during hypoxia. k pl increased significantly ( p < 0.01) from 0.029 ± 0.002 s −1 to 0.049 ± 0.006 s −1 (mean ± SEM) when animals breathing air were switched to hypoxic conditions, whereas pyruvate and lactate concentrations were minimally affected by hypoxia. Both ArtpO 2 and MABP influenced the estimate of k pl , with a strong negative correlation between k pl and the product of ArtpO 2 and MABP under hypoxia. Conclusion The rate constant for pyruvate to lactate conversion, k pl , responds significantly to a rapid reduction in tumour oxygenation. [ABSTRACT FROM AUTHOR]

Introduction: Radiation plays a major role in treatment of locoregional control of Head and Neck Squamous cell carcinoma (HNSCC). Anaemia is considered a contributor to intra-tumour hypoxia and tumour resistance to ionizing radiation and most evidences are from developed world, we prospectively investigated the exact role of anaemia in treatment outcome of Stage III/IVA HNSCC in our patient population. Aim of the Study: Primary end point: To analyse the Pre- Radiotherapy haemoglobin level and early response of treatment in stage III/IVA HNSCC and to determine the relationship of Pre-Radiotherapy haemoglobin level with other prognostic factors. Materials and Methods: This non-interventional single blinded randomized study enrolled patients attending the OPD consecutively, who met our eligibility criteria. Inclusion Criteria: HNSCC patients of Stage III/IVA aged ≥18 years and ≤ 70 years with ECOG status of 1or 2 and willing for concurrent chemoradiation and at least 6 weeks of follow up. Exclusion Criteria: 1) Previous history of treatment for malignancy or radiation in head and neck site. 2) Patients with other fatal and non-fatal pre-morbid or co-morbid conditions that can affect the outcome or the overall survival. Patients with Pre-radiotherapy haemoglobin status < 10 g/dl were given haematinic support and/or blood transfusion. All patients received concurrent chemotherapy (weekly cisplatin) and radiation in conventionally fractionated dose of 66Gy. Early treatment responses were evaluated with Revised RECIST version 1.1 and Data analysis using SPSS version 17.0. Results: Ninety one patients enrolled had mean age of 55.63 (range: 32-69), a median of 56 and mode of 60. Seventy one were males (78%) and 20 females (22%) with a performance status of ECOG 1 in 43 (47%) patients and ECOG 2 in 48 (53%); Pre-RT Hb level of <10.7 g/dl in 38 (42%) patients and ≥10.7 in 53 (58%) patients; Pre-RT Hb level was <12 g/dl in 67 (74%) patients and ≥12 in 24 (26%) patients. Tumour sites were - Nasopharynx 7 (8 %), Oral Cavity 18 (20 %), Oropharynx 32 (35 %), Hypopharynx 23 (25 %) and Larynx 11 (12 %). Twenty five (27%) had Grade 2 mucositis and 66 (73%) had Grade 3 mucositis. Fifty eight (64%) patients completed treatment with NO breaks and 33 (36%) with treatment breaks for ≥5 days. Pre-radiotherapy haemoglobin ≥ 10.7 g/dl (p < 0.001), ECOG performance status (p = 0.0002), Treatment interruptions for > 5 days (p = <0.0001), Mucositis reaction (p = <0.0001) showed statistical significance with outcome of response. Conclusion: The study found that performance status, pre-RT haemoglobin level, radiotherapy interruptions > 5 days and nondevelopment of grade III mucositis was found to be significantly associated with good loco-regional control. Haemoglobin level ≥10.7 g/dl was associated with better treatment outcome, higher performance status, fewer treatment interruptions and lesser degree of mucositis. Transfusion did not affect the outcome. Definitive conclusions and recommendations need further expansion of our study for better statistical power. [ABSTRACT FROM AUTHOR]

Purpose: Hyperthermic isolated limb perfusion (ILP) with recombinant tumour necrosis factor alpha (TNF) and melphalan contributes to limb-saving treatment in patients with locally advanced extremity soft tissue sarcoma (STS). This study was conducted to evaluate the dynamic changes of tumour oxygenation and temperature during ILP and their effects on treatment response. Patients and methods: Tumour oxygenation (pO2) and tumour temperature were measured by intratumourally placed O2-sensitive catheter electrodes in 34 patients who underwent ILP for locally advanced or recurrent STS. Tumour response to ILP was assessed by the fraction of tumour necrosis in the resection specimen. Results: Mean tumour pO2 prior to application of TNF and melphalan was 36 mm Hg (range: 2-116 mm Hg) and dropped significantly to 13 mm Hg (range: 0-67 mm Hg, p = 0.03) during ILP. Mean tumour tissue temperature increased from 34.4°C (range 32.4-36.4) to 38.5°C (range 34.1-40.4, p = 0.0001). The mean fraction of necrosis in the resection specimen was 65% (range 5-99). Only the tumour tissue temperature at the onset of ILP correlated with the extent of tumour necrosis ( p = 0.01). Conclusion: ILP with TNF and melphalan induces severe oxygen deprivation in soft tissue sarcoma. However, changes in tumour oxygenation did not correlate with treatment response. [ABSTRACT FROM AUTHOR]

Tumour blood flow before and during clinically relevant mild hyperthermia exhibits pronounced heterogeneity. Flow changes upon heating are not predictable and are both spatially and temporally highly variable. Flow increases may result in improved heat dissipation to the extent that therapeutically relevant tissue temperatures may not be achieved. This holds especially true for tumours or tumour regions in which flow rates are substantially higher than in the surrounding normal tissues. Changes in tumour oxygenation tend to reflect alterations in blood flow upon hyperthermia. An initial improvement in the oxygenation status, followed by a return to baseline levels (or even a drop to below baseline at high thermal doses) has been reported for some tumours, whereas a predictable and universal occurrence of sustained increases in O2 tensions upon mild hyperthermia is questionable and still needs to be verified in the clinical setting. Clarification of the pathogenetic mechanisms behind possible sustained increases is mandatory. High-dose hyperthermia leads to a decrease in the extracellular and intracellular pH and a deterioration of the energy status, both of which are known to be parameters capable of acting as direct sensitisers and thus pivotal factors in hyperthermia treatment. The role of the tumour microcirculatory function, hypoxia, acidosis and energy status is complex and is further complicated by a pronounced heterogeneity. These latter aspects require additional critical evaluation in clinically relevant tumour models in order for their impact on the response to heat to be clarified. [ABSTRACT FROM AUTHOR]

Introduction. Tumour hypoxia is an important factor that confers radioresistance to the affected cells and could thus decrease the tumour response to radiotherapy. The development of advanced imaging methods that quantify both the extent and the spatial distribution of the hypoxic regions has created the premises to devise therapies that target the hypoxic regions in the tumour. Materials and methods. The present study proposes an original method to prescribe objectively dose distributions that focus the radiation dose to the radioresistant tumour regions and could therefore spare adjacent normal tissues. The effectiveness of the method was tested for clinically relevant simulations of tumour hypoxia that take into consideration dynamics and heterogeneity of oxygenation. Results and discussion. The results have shown that highly heterogeneous dose distributions may lead to significant improvements of the outcome only for static oxygenations. In contrast, the proposed method that involves the segmentation of the dose distributions and the optimisation of the dose prescribed to each segment to account for local heterogeneity may lead to significantly improved local control for clinically-relevant patterns of oxygenation. The clinical applicability of the method is warranted by its relatively easy adaptation to functional imaging of tumour hypoxia obtained with markers with known uptake properties. [ABSTRACT FROM AUTHOR]

Abstract: Hypoxia and blood flow heterogeneities are characteristics of solid tumours and are major obstacles for therapy. Exploiting the biology of nitric oxide (NO), a small radical with multiple functions, is particularly attractive to circumvent these sources of resistance and to sensitise tumour to cytotoxic treatments such as radiotherapy and chemotherapy. Indeed, while NO mediates angiogenic effects, NO may also promote tumour perfusion, drug delivery and oxygenation. Different strategies to deliver NO to tumours and pertaining to the FECS-EJC award laureate’s work are reviewed, with a focus on their therapeutic potential. The development of techniques to monitor how and to which extent NO delivery influences the phenotype of a given tumour in a given patient is also discussed. [Copyright &y& Elsevier]

Abstract: Background and purpose: Hypoxia adversely affects treatment outcome in human uterine cervical cancer. Here, we present the results of a prospective international multi-centre study evaluating the prognostic value of pre-treatment tumour oxygen partial pressure (pO2) and the hypoxia marker pimonidazole (pimo). Materials and methods: One hundred and twenty-seven patients with primary cervix cancer were entered. Pre-treatment tumour pO2 measurements were obtained, and reported by the median tumour pO2, the fraction of pO2 values ⩽10mmHg (HP10), ⩽5mmHg (HP5) and ⩽2.5mmHg (HP2.5). Following intravenous pimonidazole administration, biopsies were taken, stained for pimonidazole adducts, and scored for the area of labelled tumour cells on a scale from 0 to 4. Treatment modalities were surgery (11%), radiotherapy (98%), chemotherapy (33%) and carbogen (14%). Results: None of the hypoxia descriptors were statistically significant prognostic factors for loco-regional tumour control or overall survival when analyzed as continuous variables or divided by the sample median. By univariate analysis only tumour size and nodal status were significant prognostic factors for local control. Tumour size and FIGO stage were significant for overall survival. In a multivariate analysis stratified by centre, only tumour size above 5cm and lower pre-treatment haemoglobin predicted poorer overall survival among FIGO stage, nodal involvement, tumour size, pre-treatment haemoglobin dichotomized at 12g/dl and pimo 1, pimo 4 and HP5 as continuous variables. Conclusion: Neither Eppendorf nor pimonidazole should be dismissed based on the current results. However, further investigations are needed to readdress the hypotheses of the current study having optimized statistical designs, and a population of sufficient size treated more homogenously following rigorous protocols. [Copyright &y& Elsevier]

Darbepoetin alfa (Aranesp), Amgen) is a novel erythropoiesis-stimulating protein with a serum half-life longer than recombinant human erythropoietin (Epo), used in the treatment of cancer-associated anaemia. Anaemia is known to adversely affect prognosis and response to treatment in cancer patients. Solid tumours contain regions of hypoxia due to poor vascular supply and cellular compaction. Although hypoxic stress usually results in cell death, hypoxia-resistant tumour cells are genetically unstable and often acquire a drug-resistant phenotype. Increasing tumour oxygenation and perfusion during treatment could have the doubly beneficial outcome of reducing the fraction of treatment-resistant cells, while increasing drug delivery to previously hypoxic tissue. In this study, we examined the effect of darbepoetin alfa on chemotherapy sensitivity and delivery in an in vivo model of Lewis lung carcinoma, shown here to express the Epo receptor (EpoR). We identified that weekly darbepoetin alfa treatment, commencing 10 days before chemotherapy, resulted in a significant reduction in tumour volume compared to chemotherapy alone. This was mediated by the prevention of anaemia, a reduction in tumour hypoxia and a concomitant increase in drug delivery. Darbepoetin alfa treatment alone did not modulate the growth of the EpoR-expressing tumour cells. This study identifies an important role for darbepoetin alfa in increasing the therapeutic index of chemotherapy. [ABSTRACT FROM AUTHOR]

Anaemia is not an inconsequential side effect of cancer and its treatment should not be ignored. Current practice for anaemia management varies and its role in influencing outcome in cancer patients is under recognized. As a common complication of cancer, anaemia is prevalent in virtually all tumour types to varying degrees. Predictive factors for anaemia include baseline haemoglobin concentration, decrease in haemoglobin concentration within the first month of treatment, tumour type, duration of treatment and prior blood transfusions. Interest in the prognostic significance of anaemia in cancer patients has generated extensive clinical research. Data is now published in a wide range of tumour types confirming that anaemia is a negative prognostic indicator of outcome (e.g. survival, disease-free recurrence and local relapse), with the strongest association in patients receiving radiotherapy. The association has also been documented in patients undergoing chemotherapy and chemoradiation. A retrospective meta-analysis has shown an overall 65% increased risk of death associated with anaemia in cancer patients. The impact of anaemia as an independent prognostic factor for outcome may be mediated by several factors, however the emerging consensus is on the central role of tumour hypoxia. It has been nearly 50 years since R. Thomlinson and L. Gray (British Journal of Cancer1955,9: 539) first documented the existence of hypoxia in tumours and it is now well accepted that tumour hypoxia protects tumour cells from therapeutic damage directly by reducing the availability of oxygen-free radicals which are necessary for optimal impact of radiotherapy, certain chemotherapeutic agents and photodynamic therapy. The indirect effects include the impact of hypoxia on gene expression, which affects genetic stability, proliferation kinetics and cellular metabolism. There has been an emergence of preclinical and circumstantial data over recent years that are suggestive of the ability to correct the negative effect of anaemia on outcome by the use of repeated blood transfusions or recombinant human erythropoietin. This has led to some attempts to measure the impact on survival in cancer patients of treating anaemia, but early attempts have served to underline the complexity of the relationship and have produced unexpected results. [ABSTRACT FROM AUTHOR]

Aim: To investigate the influence of deep inspiration breath-hold on the oxygen tension of in-vivo tumours measured using an Eppendorf pO2histograph.Materials and methods: Patients with accessible primary or metastatic tumours ≥2 cm diameter were entered into a protocol measuring tumour oxygenation with an Eppendorf pO2histograph during normal breathing (NB) and deep inspiration breath-hold (DIBH). Change in oxygen tension was assessed using the Wilcoxon Signed Ranks test.Results: Thirty patients were entered in to this protocol. The median maximum tumour dimension was 4 cm. The median of the median pO2of these tumours was 18 mmHg. Tumours were assessed during NB and DIBH. Oxygen tension measurements along 1–3 pairs of tracks per tumour (median of 2) were obtained. The median number of measurements per track was 30 for NB and 29 for DIBH (range 17–59). In six tumours, the values during NB were significantly higher than during DIBH, whereas, for six other tumours, the relationship was the opposite; for the remaining 18 patients, no significant difference was observed.Conclusion: These data show heterogeneity of tumour oxygenation seen with in-situ tumours both at baseline and as a result of DIBH. No systematic change in the Eppendorf pO2measurements was seen as a result of DIBH; however, the individual tumour responses to DIBH varied dramatically. [Copyright &y& Elsevier]

Background and purpose: The measurement of tumour oxygenation using Eppendorf oxygen-sensitive needle electrodes can provide prognostic information but the method is limited to accessible tumours that are suitable for electrode insertion. In this paper the aim was to study the relationship between such physiological measurements of tumour hypoxia and the labelling of tumours with the hypoxia-specific marker pimonidazole.Materials and methods: Assessment of tumour oxygen partial pressure (pO2) using an Eppendorf pO2 histograph and immunohistochemical pimonidazole labelling was carried out in 86 patients with primary cervix carcinomas. Pimonidazole was given as a single injection (0.5 g/m2 i.v.) and 10–24 h later pO2 measurements were made and biopsies taken. Tumour oxygenation status was evaluated as the median tumour pO2 and the fraction of pO2 values ≤10 mmHg (HP10), ≤5 mmHg (HP5) and ≤2.5 mmHg (HP2.5). Hypoxia was detected by immunohistochemistry using monoclonal antibodies directed against reductively activated pimonidazole. Pimonidazole binding was scored using a light microscope. Each tumour was evaluated by the relative area pimonidazole at highest score and the accumulated area of pimonidazole labelling from score 1 to 4. Necrosis was measured in HE stained sections.Results and conclusions: The degree of hypoxia assessed by either pimonidazole binding or invasive electrode measurements varied significantly between tumours. There was a trend that the most hypoxic tumours measured by oxygen electrodes had the highest score of necrosis, and no or little pimonidazole binding. However, this observation was not consistent and there was no correlation between pimonidazole staining expressed in this way and oxygen electrode measurements of hypoxia. [Copyright &y& Elsevier]

The aim of this study was to evaluate the feasibility of functional MR imaging (fMRI) at 1.5 T, exploiting blood oxygenation level-dependent (BOLD) contrast, for detecting changes in whole-tumour oxygenation induced by carbogen (5% CO2+95% O2) inhalation of the host. Adult WAG/Rij rats with rhabdomyosarcomas growing subcutaneously in the lower flank were imaged when tumours reached sizes between 1 and 11 cm3 (n=12). Air and carbogen were alternatively supplied at 2 l/min using a snout mask. Imaging was done on a 1.5-T MR scanner using a T2*-weighted gradient-echo, echo-planar imaging (GE-EPI) sequence. Analysis of the whole-tumour EPI images was based on statistical parametric maps. Voxels with and without signal intensity changes (SIC) were recorded. Significance thresholds were set at p<0.05, corrected for multiple comparisons. In continuous air breathing condition, 3 of 12 tumours showed significant negative SIC and 1 tumour had a clear-cut positive SIC. The remaining tumours showed very little or no change. When switching to carbogen breathing, the SIC were significantly positive in 10 of 12 tumours. Negative SIC were present in 4 tumours, of which three were simultaneously characterised by positive SIC. The overall analysis indicated that 6 of the 12 tumours could be considered as strong positive responders to carbogen. Our research demonstrates the applicability of fMRI GE-EPI at 1.5 T to study whole-tumour oxygenation non-invasively. The observed negative SIC during air condition may reflect the presence of transient hypoxia during these measurements. Selection of tumours on the basis of their individual response to carbogen is possible, indicating a role of such non-invasive measurements for using tailor-made treatments. [ABSTRACT FROM AUTHOR]

Background/aim: The aim of this study was to investigate radiation-induced tumour vascular damage and its impact thereof on the outcome of stereotactic body radiotherapy (SBRT)., Materials and Methods: Vessel densities in animal tumours before and after a single dose of 20 Gy were quantified and used as input for simulations of three-dimensional tumours with heterogeneous oxygenation. SBRT treatments of the modelled tumours in 1-8 fractions were simulated. The impact of vessel collapse on the outcome of SBRT was investigated by calculating tumour control probability (TCP) and the dose required to obtain a TCP of 50% (D 50 )., Results: A radiation-induced increase of acute hypoxia in tumours during SBRT treatment could be simulated based on the experimental data. The D 50 values for these tumours were higher than for the simulated tumours without vessel collapse., Conclusion: The vascular changes after high doses of radiation could compromise the outcome of SBRT by increasing tumour hypoxia., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: This study investigated the impact of temporary vascular collapse on tumour control probability (TCP) in stereotactic body radiotherapy (SBRT), taking into account different radiosensitivities of chronically and acutely hypoxic cells., Materials and Methods: Three-dimensional tumours with heterogeneous oxygenation were simulated assuming different fractions of collapsed vessels at every treatment fraction. The modelled tumours contained a chronically hypoxic subvolume of 30-60% of the tumour diameter, and a hypoxic fraction ≤5 mm Hg of 30-50%. The rest of the tumours were well-oxygenated at the start of the simulated treatment., Results: For all simulated cases, the largest reduction in TCP from 97% to 2% was found in a tumour with a small chronically hypoxic core treated with 60 Gy in eight fractions and assuming a treatment-induced vascular collapse of 35% in the well-oxygenated region., Conclusion: The timing of SBRT fractions should be considered together with the tumour oxygenation to avoid loss of TCP in SBRT., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)