Immune Response and Immune Checkpoint Molecules in Patients with Rectal Cancer Undergoing Neoadjuvant Chemoradiotherapy: A Review.

It is well-established that tumor antigens and molecules expressed and secreted by cancer cells trigger innate and adaptive immune responses. These two types of anti-tumor immunity lead to the infiltration of the tumor's microenvironment by immune cells with either regulatory or cytotoxic properties. Whether this response is associated with tumor eradication after radiotherapy and chemotherapy or regrowth has been a matter of extensive research through the years, mainly focusing on tumor-infiltrating lymphocytes and monocytes and their subtypes, and the expression of immune checkpoint and other immune-related molecules by both immune and cancer cells in the tumor microenvironment. A literature search has been conducted on studies dealing with the immune response in patients with rectal cancer treated with neoadjuvant radiotherapy or chemoradiotherapy, assessing its impact on locoregional control and survival and underlying the potential role of immunotherapy in the treatment of this cancer subtype. Here, we provide an overview of the interactions between local/systemic anti-tumor immunity, cancer-related immune checkpoint, and other immunological pathways and radiotherapy, and how these affect the prognosis of rectal cancer patients. Chemoradiotherapy induces critical immunological changes in the tumor microenvironment and cancer cells that can be exploited for therapeutic interventions in rectal cancer.

Isodose surface differences: A novel tool for the comparison of dose distributions.

BACKGROUND: Comparing dose distributions is a routine task in radiotherapy, mainly in patient-specific quality assurance (PSQA). Currently, the evaluation of the dose distributions is being performed mainly with statistical methods, which could underestimate the clinical importance of the spotted differences, as per the literature. PURPOSE: This paper aims to provide proof-of-concept for a novel dose distribution comparison method based on the difference of the isodose surfaces. The new method connects acceptance tolerance to QA limitations (equipment capabilities) and integrates a clinical approach into the analysis procedure. METHODS: The distance of dose points from the isocenter can be used as a function to define the shape of an isodose surface expressed as a histogram. Isodose surface differences (ISD) are defined as the normalized differences of reference and evaluated surface histograms plotted against their corresponding isodose. Acceptance tolerances originate from actual QA tolerances and are presented clinically intuitively. The ISD method was compared to the gamma index using intentionally erroneous VMAT and IMRT plans. RESULTS: Results revealed that the ISD method is sensitive to all errors induced in the plans. Discrepancies are presented per isodose, enabling the evaluation of the plan in two regions representing PTV and Normal Tissue. ISD manages to flag errors that would remain undetected under the gamma analysis. CONCLUSION: The ISD method is a meaningful, QA-related, registration-free, and clinically oriented technique of dose distribution evaluation. This method can be used either as a standalone or an auxiliary tool to the well-established evaluation procedures, overcoming significant limitations reported in the literature.

Dosimetric comparison and evaluation of two computational algorithms in VMAT treatment plans.

PURPOSE: This study aimed to assess the accuracy and dosimetric impact of the Acuros XB (AXB) algorithm compared to the Anisotropic Analytical Algorithm (AAA) in two situations. First, simple phantom geometries were set and analyzed; moreover, volumetric modulated arc therapy (VMAT) clinical plans for Head & Neck and lung cases were calculated and compared. METHODS: First, a phantom study was performed to compare the algorithms with radiochromic EBT3 film doses using one PMMA slab phantom and two others containing foam or air gap. Subsequently, a clinical study was conducted, including 20 Head & Neck and 15 lung cases irradiated with the VMAT technique. The treatment plans calculated by AXB and AAA were evaluated in terms of planning target volume (PTV) coverage (V95% ), dose received by relevant organs at risk (OARs), and the impact of using AXB with a grid size of 1 mm. Finally, patient-specific quality assurance (PSQA) was performed and compared for 17 treatment plans. RESULTS: Phantom dose calculations showed a better agreement of AXB with the film measurements. In the clinical study, AXB plans exhibited lower Conformity Index and PTV V95% , higher maximum PTV dose, and lower mean and minimum PTV doses for all anatomical sites. The most notable differences were detected in regions of intense heterogeneity. AXB predicted lower doses for the OARs, while the calculation time with a grid size of 1 mm was remarkably higher. Regarding PSQA, although AAA was found to exhibit slightly higher gamma passing rates, the difference did not affect the AXB treatment plan quality. CONCLUSIONS: AXB demonstrated higher accuracy than AAA in dose calculations of both phantom and clinical conditions, specifically in interface regions, making it suitable for sites with large heterogeneities. Hence, such dosimetric differences between the two algorithms should always be considered in clinical practice.

Prostate Cancer Stem Cells: Biology and Treatment Implications.

Stem cells differentiate into mature organ/tissue-specific cells at a steady pace under normal conditions, but their growth can be accelerated during the process of tissue healing or in the context of certain diseases. It is postulated that the proliferation and growth of carcinomas are sustained by the presence of a vital cellular compartment resembling stem cells residing in normal tissues: 'stem-like cancer cells' or cancer stem cells (CSCs). Mutations in prostate stem cells can lead to the formation of prostate cancer. Prostate CSCs (PCSCs) have been identified and partially characterized. These express surface markers include CD44, CD133, integrin α2ß1, and pluripotency factors like OCT4, NANOG, and SOX2. Several signaling pathways are also over-activated, including Notch, PTEN/Akt/PI3K, RAS-RAF-MEK-ERK and HH. Moreover, PCSCs appear to induce resistance to radiotherapy and chemotherapy, while their presence has been linked to aggressive cancer behavior and higher relapse rates. The development of treatment policies to target PCSCs in tumors is appealing as radiotherapy and chemotherapy, through cancer cell killing, trigger tumor repopulation via activated stem cells. Thus, blocking this reactive stem cell mobilization may facilitate a positive outcome through cytotoxic treatment.

Stereotactic radiosurgery and radiotherapy for acoustic neuromas.

Neuromas are benign intracranial tumors with indolent natural history. Surgery is the mainstay of treatment and only after the introduction of single-fraction stereotactic radiosurgery (SRS), radiotherapy emerged as an alternative viable option. In this review, we focused on SRS or conventionally fractionated stereotactic radiotherapeutic (FSRT) approaches. We described the results of different doses used for SRS and FSRT, the current status, and a comparison between the two radiotherapy approaches. Stereotactic radiotherapy techniques aim to control tumor growth with minimal toxicity. SRS using either a cobalt unit or a linear accelerator has given high rates of tumor control and of cranial nerve function preservation with marginal doses range of 12-14 Gy. Fractionated stereotactic radiotherapy (FSRT) is optimal for tumors larger than 3 cm. Doses as low as 50.4 Gy provide excellent control rates and low morbidity. Overall, both SRS and FSRT are equally effective and safe options for neuroma patients who do not need immediate surgical decompression.

Clinical implications of in silico mathematical modeling for glioblastoma: a critical review.

Glioblastoma remains a clinical challenge in spite of years of extensive research. Novel approaches are needed in order to integrate the existing knowledge. This is the potential role of mathematical oncology. This paper reviews mathematical models on glioblastoma from the clinical doctor's point of view, with focus on 3D modeling approaches of radiation response of in vivo glioblastomas based on contemporary imaging techniques. As these models aim to provide a clinically useful tool in the era of personalized medicine, the integration of the latest advances in molecular and imaging science and in clinical practice by the in silico models is crucial for their clinical relevance. Our aim is to indicate areas of GBM research that have not yet been addressed by in silico models and to point out evidence that has come up from in silico experiments, which may be worth considering in the clinic. This review examines how close these models have come in predicting the outcome of treatment protocols and in shaping the future of radiotherapy treatments.

First application of hemi-body electron beam irradiation for Kaposi sarcoma at the lower extremities.

Kaposi's sarcoma (KS) is a systemic neoplastic disease that can present cutaneous symptoms and is usually treated with a systematic approach due to its extent. Due to its radiosensitivity, radiotherapy is considered one of its main treatments, for palliation and local control of the skin and mucosal lesions. The aim of this paper was to report the first case of KS treated by hemi-body electron irradiation protocol in Greece. A fractionated 40 Gy hemi-body electron irradiation was prescribed to a 60-year-old male patient with KS at his legs. Dose uniformity was verified on a daily basis by thermoluminescence dosimetry (TLD). The treatment resulted to complete clinical response. Limited irradiation-derived side effects appeared. This is the first case ever to be treated with hemi-body electron irradiation protocol in Greece. To the best of our knowledge, this is also the first time that a single field hemi-body electron beam irradiation at a total skin electron beam (TSEB)-like configuration is reported to be used for KS.

Quality assurance protocol for superficial and deep hyperthermia systems established by the Hellenic Association of Medical Physicists (HAMP) in cooperation with the Hellenic Society of Oncologic Hyperthemia (HSOH): A study based on European Society for Hyperthermic Oncology (ESHO) quality assurance guidelines.

PURPOSE: During the last years hyperthermia is a developing therapeutic modality in Greece. Quality assurance (QA) procedures are essential for ensuring the correct operation of the hyperthermia system and therefore the selective heating of the tumor with minimum toxicity to the surrounding healthy tissues. The European Society for Hyperthermic Oncology (ESHO) has proposed QA guidelines for superficial as well as deep hyperthermia systems. The purpose of this study was to describe the adapted QA protocol for superficial and deep hyperthermia systems established in Greece. METHODS: A working group was created by the Hellenic Association of Medical Physicists (HAMP) for the proposal of QA guidelines for superficial and deep hyperthermia systems. A review of the protocol proposed by ESHO, together with the existing protocols in other European and International centers, as well as protocols suggested by European or International organizations, was performed. Then, a protocol was suggested, describing procedures for QA according to the current technology and the existing equipment used in Greece. RESULTS: A protocol describing the procedures for QA of superficial and deep hyperthermia systems was proposed. These procedures aim to evaluate the correct operation of the device, the thermometric system, the generator, the incorporated power meter and the applicators. It will also ensure the electrical safety of the devices. CONCLUSIONS: The proposed protocol, applied by medical physicists in Greece, will ensure an efficient treatment with safety and minimum adverse effects. This protocol has been approved by the Hellenic Society of Oncologic Hyperthermia and the Hellenic Association of Medical Physicists.

A five split-field three dimensional conformal technique versus an anterior-posterior on in postoperative radiotherapy for gastric carcinoma: a multicenter comparative study using quality of life measurements as well as clinical and dosimetric parameters.

PURPOSE: Several adjuvant approaches are regarded as available options in the management of localized, resectable gastric cancer .The objective of our study was to evaluate multiple field and anteroposterior conformal technique. METHODS: Ninety-seven patients received three dimensional conformal (3DCRT) postoperative adjuvant radiation therapy for gastric carcinoma. Thirty-five patients received anteroposterior (AP/PA) fields (Group B), while 62 patients were irradiated with multifield technique (Group A). Their ages ranged between 29-85 years. The objective of the study was to evaluate the quality of life (QoL) for all patients after the completion of radiotherapy using the QLQ-C30 of the EORTC questionnaire (European Organization for Research and Treatment of Cancer) and to investigate any measurable differences between those two radiation techniques according to QUANTEC criteria and the radiotoxicity. RESULTS: In terms of QUANTEC criteria, the multifield technique was superior concerning the left kidney (p=0.025), right kidney (p<0.001), spinal cord (p<0.001) and planning target volume (PTV) coverage (p<0.001). According to EORTC/ RTOG toxicity criteria, the rate of diarrhea was higher in AP/ PA technique (p=0.028). In terms of QLQ-C30, the multifield technique was superior concerning appetite loss (p=0.022), diarrhea (p=0.046) and global QoL (p<0.001). CONCLUSION: On the basis of QLQ-C30 questionnaire, EORTC/ RTOG toxicity and dosimetric parameters, the present report has shown that the three dimensional multifield conformal radiotherapy is superior compared to AP-PA techniques.

Toxicity and efficacy of a hypofractionated (3 weekly fractions of 850c Gy) irradiation schedule for stage IIIb / IV non-small cell lung cancer elderly patients with low performance status and unfit for chemotherapy.

PURPOSE: To evaluate in an observational way the clinical impact of a hypofractionated irradiation schedule in patients with unresectable non-small cell lung cancer (NSCLC). METHODS: Forty elderly patients (24 men/16 women) diagnosed with unresectable stage IIIb/IV NSCLC unfit for chemotherapy, were treated with once-a-week hypofractionation schedule. All patients had a poor performance status. A dose of 255 Gy in 3 weekly fractions was prescribed while a 3D conformal technique (3D-CRT) was used for irradiation. The primary study endpoints were to assess the therapeutic impact of this schedule in terms of relapse free survival (RFS), overall survival (OS) survival and palliation of symptoms. The secondary endpoints were the evaluation of acute toxicity of the lung, esophagus and the skin. The intended followup was 3 years. The median age was 73.5 years (range 71-85). RESULTS: The median RFS was 12 months, while the median OS was 17 months. Symptoms relief was up to 20% for cough, 52.5% for haemoptysis, 40% for thoracic pain and 17.5% for dyspnoea. Acute lung toxicity in terms of radiation pneumonitis was recorded as 6/40 (15%) grade 1, 26/40 (65%) grade 2 and 8/40 (25%) grade 3. Additionally, grade 1 and 2 acute esophageal toxicity was recorded in 10/40 (25%) and 30/40 (75%) patients, respectively. Acute skin toxicity with grade 2 erythema was recorded in only 2/40 (5%) patients while most patients developed grade 1 skin erythema. Grade 3 late lung toxicity was recorded in 10/40 (25%) patients. CONCLUSIONS: This study showed that the proposed scheme has a moderate radiation-induced lung toxicity rate and an acceptable therapeutic ratio. Taking into consideration its cost effectiveness, the proposed hypofractionated scheme is a good alternative to conventional fractionation.

What is the connection between serum phosphorus, cancer and heroin? A medical hypothesis based on observational studies.

Considering the results of a previous study in which 2321 regular heroin addicts who died without having stopped taking the drug since they had started - from various causes but none from cancer, may mean something. Our first thought was: Can't we hypothesize, reinforcing our previous view that heroin is a "barrier" against cancer and as the user gets in the methadone program he/she lacks the "barrier" and therefore is liable to develop cancer? We have already reported that the amount of blood phosphorus in heroin addicted is significantly lower than in healthy ones. Additionally we have introduced the potential clinical impact of serum phosphorus as a screening test for cancer. Phosphorus regulated by heroin might be the key for preventing the development of cancer in human organism, in terms of keeping the phosphorus in normal levels in the blood. Cases of cancer patients after methadone detox treatment are reported. In the present study, in 200 cancer patients who underwent radical radiotherapy (RT), the phosphorus level is generally returning to normal levels three months postirradiation. Phosphorus and cancer seem to be significantly associated, with heroin adapting phosphorus in normal values. The pharmaceutical companies should look deep inside the molecule of heroin, by means of an analogue with the potential impact against cancer but without the addictive effect to humans. It's obvious that further research is needed to obtain reliable statistical data.

The impact of dose matrix and voxel dimensions to dose calculation for stereotactic radiosurgery.

PURPOSE: The purpose of the present study was the optimization of dose calculation for intracranial stereotactic radiosurgery. METHODS: We evaluated the Singular Value Decomposition (SVD) analysis as a novel optimization technique. Our approach to dose distribution optimization was to recover estimates of minibeams weights from well-defined provisional dose matrices. The dose delivered by a set of minibeams is formulated as a matrix equation. We studied the influence of dose matrix and voxel dimensions on the conditioning of stereotactic radiotherapy inverse problem. Dose matrix dimensions varied from 16 to 96 mm3, while voxel dimension was kept constant at 2 mm3. In the assessment of voxel dimension, matrix dimension was kept constant at 80 mm3 while voxel dimensions varied from 1 to 8 mm3. The reconstruction of dose distributions was studied using a truncated SVD expansion in the calculation of approximation to the generalised matrix inverse. RESULTS: The conditioning was deteriorated by either the decreasing of dose matrix dimensions or by the increasing of voxel size. The condition number was equal to 89×103 and 7×103 for the 16 mm3 and 96 mm3 dose matrix dimensions, respectively. The condition number was equal to 9.9×103 and to 2.7×106 for 1 mm3 and 8 mm3 voxel size, respectively. The reconstruction of dose distributions revealed that an ill-conditioned problem yields poor quality reconstruction. CONCLUSION: We considered that a good compromise between quality of dose distribution, time calculation and hard disk memory would be the use of a 64 mm3 matrix dimension with a 2 mm3 voxel size.

Review of the three-field techniques in breast cancer radiotherapy.

Breast cancer is often treated with radiotherapy (RT), with two opposing tangential fields. When indicated, supraclavicular lymph nodes have to be irradiated, and a third anterior field is applied. The junction region has the potential to be over or underdosed. To overcome this problem, many techniques have been proposed. A literature review of 3 Dimensional Conformal RT (3D CRT) and older 3-field techniques was carried out. Intensity Modulated RT (IMRT) techniques are also briefly discussed. Techniques are categorized, few characteristic examples are presented and a comparison is attempted. Three-field techniques can be divided in monoisocentric and two-isocentric. Two-isocentric techniques can be further divided in full field and half field techniques. Monoisocentric techniques show certain great advantages over two-isocentric techniques. However, they are not always applicable and they require extra caution as they are characterized by high dose gradient in the junction region. IMRT has been proved to give better dosimetric results. Three-field matching is a complicated procedure, with potential of over or undredosage in the junction region. Many techniques have been proposed, each with advantages and disadvantages. Among them, monoisocentric techniques, when carefully applied, are the ideal choice, provided IMRT facility is not available. Otherwise, a two-isocentric half beam technique is recommended.

A New Questionnaire (QRFPC25) Regarding the Religiosity and Spirituality in People with Life-Threatening Disease: Reliability and Validity in a Population of Cancer Patients Undergoing Radiotherapy.

The development of a questionnaire (QRFPC25) assessing the religiosity of cancer patients. The method used for the questionnaire comprises seven multi-item and three single-item scales formed from a 25-question module. The questionnaire was completed on-site and a week after antineoplastic therapy. The final sample included 156 patients. The main topics of the QRFPC25 are the following: worship, relationship with the divine, spiritual discussion, hope, participation in holly communion, faith, life after death, love, bioethics and global quality of life (QoL). The average time of both times taken to complete the questionnaire was approximately 10 min. All multi-item scales met the minimal standards of reliability (Cronbach's alpha coefficient ≥.70) before or after treatment. Test-retest reliability in terms of the intraclass correlation coefficient was also satisfactory (p < 0.01). Validity was assured by inter-item correlations and correlations with the European Organisation for Research and Treatment of Cancer's Core Quality of Life Questionnaire (QLQ-C30, version 3.0), along with factor analysis which showed eight factors incorporated in the model. The QRFPC25 is a reliable and valid gauge for the assessment of religiosity in cancer patients undergoing radiotherapy.

Bone Density as a Marker of Response to Radiotherapy in Bone Metastatic Lesions: A Review of the Published Data.

Metastases to the bone are presenting in a great percentage of patients with cancer, causing a variety of symptoms, affecting the quality of life and survival of patients. A multidisciplinary approach from different health providers is required for treatment, including radiation oncologists, medical oncologists and surgeons. The role of radiotherapy in the management of bone metastases has long been established through multiple randomized trials. The estimation of response to the therapy is subjective and is based on the palliation of the symptoms that the patients report. However, a quantification of the tumor burden and response to the treatment with the use of an objective method to measure those parameters is a clinical expectation in oncology. The change in bone density in affected areas (mainly lytic) after local radiotherapy, representing the cellular changes that have occurred, is a promising marker of response to treatment.

Hypothesis: Is heroin a 'barrier' against cancer? A retrospective analysis of heroin-addicted individuals untreated for opioid dependence between 2001-2010.

PURPOSE: The findings of previous studies attracted our interest in searching and defining the percentage of deaths from cancer in 'heroin regular addicts' i.e. those who had never stopped taking the drug since they started. METHODS: The archives of the Greek Reitox Focal Point of the years 2001 to 2010 were retrospectively searched, focusing on the number of deaths from cancer of the regular heroin addicts. RESULTS: The records from 2,321 regular heroin addicts showed that none of them died from cancer. It seems that heroin might act as a "barrier" against cancer. CONCLUSION: Further studies are needed to confirm our results and to explore the potential cause for this surprising finding.

In vivo dosimetry in the field junction area for 3D-conformal radiation therapy in breast and head & neck cancer cases: A quality assurance study.

PURPOSE: To investigate the accuracy of field junctioning planning techniques (monoisocentric and rotating couch technique) for 3D-conformal radiotherapy (3D-CRT). METHODS: In vivo dosimetry has been performed using thermo- luminescence dosimeters (TLDs) in 10 head and neck cancer patients (treated with monoisocentric technique) and 10 breast cancer patients (treated with rotating couch technique) irradiated with a 6 MV photon beam. Entrance dose measurements were performed in selected regions including the field junction area. RESULTS: The mean deviation between measured and expected dose in the region of junction was significantly higher in breast cases compared to head and neck irradiation (-2.8±15.4% and 0.2±8.2% respectively; Mann-Whitney U test: p=0.002). A comparison between lateral head and neck fields and tangential breast fields revealed that the latter was associated with larger dose discrepancies (-2.2 ± 4.6% vs -3.5 ± 5.7% respectively; Mann-Whitney U test: p=0.029). CONCLUSIONS: The results indicate the superiority of monoisocentric technique compared to the rotating couch technique in terms of dose delivery accuracy for treatments with field junctioning planning techniques.

Theoretical analysis, design and development of a 27-MHz folded loop antenna as a potential applicator in hyperthermia treatment.

PURPOSE: A hyperthermia system using a folded loop antenna applicator at 27 MHz for soft tissue treatment was investigated both theoretically and experimentally to evaluate its clinical value. MATERIALS AND METHODS: The electromagnetic analysis of a 27-MHz folded loop antenna for use in human tissue was based on a customised software tool and led to the design and development of the proposed hyperthermia system. The system was experimentally validated using specific absorption rate (SAR) distribution estimations through temperature distribution measurements of a muscle tissue phantom after electromagnetic exposure. Various scenarios for optimal antenna positioning were also performed. RESULTS: Comparison of the theoretical and experimental analysis results shows satisfactory agreement. The SAR level of 50% reaches 8 cm depth in the tissue phantom. Thus, based on the maximum observed SAR values that were of the order of 100 W/kg, the antenna specified is suitable for deep tumour heating. CONCLUSIONS: Theoretical and experimental SAR distribution results as derived from this study are in agreement. The proposed folded loop antenna seems appropriate for use in hyperthermia treatment, achieving proper planning and local treatment of deeply seated affected areas and lesions.

The Amount of Phosphorus in the Blood of Heroin Abusers Compared to that of Healthy Subjects.

BACKGROUND: The aim of the current retrospective study was to assess any difference in terms of serum phosphate (P) between heroin addicts and healthy subjects. METHODS: Between 2011 and 2012, under the authority of the Greek Organization Against Drugs (OKANA), 30 regular heroin addicts, 22 males and 8 females (Group A) participated at the study. Between 2010 and 2011, 30 healthy individuals, 22 males and 8 females (Group B), presented on an outpatient basis for either fatigue or common flu symptoms without fever at the 424 Military Hospital of Thessaloniki. RESULTS: No significant difference between group A and B, in terms of either age (p = 0.454, Mann-Whitney test) or male/female ratio (p = 0.573, Chi2 test), suggesting a homogeneity for the population of individuals participating in the study. The mean values of serum-P in group A and B were 3.47 ± 0.65 and 3.35 ± 0.58, respectively (p = 0.45, Mann Whitney test). CONCLUSIONS: The absence of statistical difference of serum-P between heroin addicts and healthy subjects as shown in our results should be confirmed in further studies.