Radiation exposure of astronauts following an intense solar particle event: analysis and comparison of doses in male and female voxel phantoms.

According to NASA's plans, a human travel to the Moon is planned by the end of 2025 with the Artemis II mission, and humans should land on the Moon again in 2026. Exposure to space radiation is one of the main risks for the crew members; while for these short missions the doses from galactic cosmic rays would be relatively low, the possible occurrence of an intense solar particle event (SPE) represents a major concern, especially considering that in 2025 the Sun activity will be at its peak. Quantifying the amount and the effects of such exposure is therefore crucial, to identify shielding conditions that allow respecting the dose limits established by the various space agencies. By exploiting an interface between the BIANCA biophysical model and the FLUKA Monte Carlo radiation transport code, in this work we implemented a male and a female voxel phantom and we calculated absorbed doses and Gy-Eq doses in the various tissues/organs, as well as effective doses, following exposure to the August 1972 SPE, the most intense event of the modern era. The calculations were performed respect the organ dose limits for 30 d missions. A detailed comparison between male and female doses was then carried out, also considering that the Artemis II crew will include a woman. The results showed that female doses tend to be higher than male doses, especially with light shielding. This should be taken into account in mission design, also considering that, in a typical lunar mission, up to 15% of time may be spent in extra-vehicular activities, and thus with light shielding. More generally, this work outlines the importance of performing separate calculations for male and female astronauts when dealing with radiation doses and effects.

A Mission to Mars: Prediction of GCR Doses and Comparison with Astronaut Dose Limits.

Long-term human space missions such as a future journey to Mars could be characterized by several hazards, among which radiation is one the highest-priority problems for astronaut health. In this work, exploiting a pre-existing interface between the BIANCA biophysical model and the FLUKA Monte Carlo transport code, a study was performed to calculate astronaut absorbed doses and equivalent doses following GCR exposure under different shielding conditions. More specifically, the interface with BIANCA allowed us to calculate both the RBE for cell survival, which is related to non-cancer effects, and that for chromosome aberrations, related to the induction of stochastic effects, including cancer. The results were then compared with cancer and non-cancer astronaut dose limits. Concerning the stochastic effects, the equivalent doses calculated by multiplying the absorbed dose by the RBE for chromosome aberrations ("high-dose method") were similar to those calculated using the Q-values recommended by ICRP. For a 650-day mission at solar minimum (representative of a possible Mars mission scenario), the obtained values are always lower than the career limit recommended by ICRP (1 Sv), but higher than the limit of 600 mSv recently adopted by NASA. The comparison with the JAXA limits is more complex, since they are age and sex dependent. Concerning the deterministic limits, even for a 650-day mission at solar minimum, the values obtained by multiplying the absorbed dose by the RBE for cell survival are largely below the limits established by the various space agencies. Following this work, BIANCA, interfaced with an MC transport code such as FLUKA, can now predict RBE values for cell death and chromosome aberrations following GCR exposure. More generally, both at solar minimum and at solar maximum, shielding of 10 g/cm2 Al seems to be a better choice than 20 g/cm2 for astronaut protection against GCR.

Radiobiological damage by space radiation: extension of the BIANCA model to heavy ions up to iron, and pilot application to cosmic ray exposure.

Space research seems to be object of a renewed interest, also considering that human missions to the Moon, and possibly Mars, are being planned. Among the risks affecting such missions, astronauts' exposure to space radiation is a major concern. In this work, the question of the evaluation of biological damage by Galactic Cosmic Rays (GCR) was addressed by a biophysical model called BIophysical ANalysis of Cell death and chromosome Aberrations (BIANCA), which simulates the induction of cell death and chromosome aberrations by different ions. While previously BIANCA has been validated for calculating cell death along hadrontherapy beams up to oxygen, herein the approach was extended up to Fe ions. Specifically, experimental survival curves available in literature for V79 cells irradiated by Si-, Ne-, Ar- and Fe-ions were reproduced, and a reference radiobiological database describing V79 cell survival as a function of ion type (1 ⩽Z⩽ 26), energy and dose was constructed. Analogous databases were generated for Chinese hamster ovary hamster cells and human skin fibroblasts, finding good agreement between simulations and data. Concerning chromosome aberrations, which are regarded as radiation risk biomarkers, dicentric data in human lymphocytes irradiated by heavy ions up to iron were reproduced, and a radiobiological database allowing calculation of lymphocyte dicentric yields as a function of dose, ion type (1 ⩽Z⩽ 26) and energy was constructed. Following interface between BIANCA and the FLUKA Monte Carlo transport code, a feasibility study was performed to calculate the relative biological effectiveness (RBE) of different GCR spectrum components, for both dicentrics and cell death. Fe-ions, although representing only 10% of the total absorbed dose, were found to be responsible for about 35%-40% of the RBE-weighted dose. Interestingly, the RBE for dicentrics was higher than that for cell survival. More generally, this work shows that BIANCA can calculate RBE values for cell death and lymphocyte dicentrics not only for ion therapy, but also for space radiation.

Healthy Tissue Damage Following Cancer Ion Therapy: A Radiobiological Database Predicting Lymphocyte Chromosome Aberrations Based on the BIANCA Biophysical Model.

Chromosome aberrations are widely considered among the best biomarkers of radiation health risk due to their relationship with late cancer incidence. In particular, aberrations in peripheral blood lymphocytes (PBL) can be regarded as indicators of hematologic toxicity, which is a major limiting factor of radiotherapy total dose. In this framework, a radiobiological database describing the induction of PBL dicentrics as a function of ion type and energy was developed by means of the BIANCA (BIophysical ANalysis of Cell death and chromosome Aberrations) biophysical model, which has been previously applied to predict the effectiveness of therapeutic-like ion beams at killing tumour cells. This database was then read by the FLUKA Monte Carlo transport code, thus allowing us to calculate the Relative Biological Effectiveness (RBE) for dicentric induction along therapeutic C-ion beams. A comparison with previous results showed that, while in the higher-dose regions (e.g., the Spread-Out Bragg Peak, SOBP), the RBE for dicentrics was lower than that for cell survival. In the lower-dose regions (e.g., the fragmentation tail), the opposite trend was observed. This work suggests that, at least for some irradiation scenarios, calculating the biological effectiveness of a hadrontherapy beam solely based on the RBE for cell survival may lead to an underestimation of the risk of (late) damage to healthy tissues. More generally, following this work, BIANCA has gained the capability of providing RBE predictions not only for cell killing, but also for healthy tissue damage.

Measuring Changes in the Atmospheric Neutrino Rate over Gigayear Timescales.

Measuring the cosmic ray flux over timescales comparable to the age of the Solar System, ∼4.5 Gyr, could provide a new window on the history of the Earth, the Solar System, and even our Galaxy. We present a technique to indirectly measure the rate of cosmic rays as a function of time using the imprints of atmospheric neutrinos in "paleo-detectors," natural minerals that record damage tracks from nuclear recoils. Minerals commonly found on Earth are ≲1 Gyr old, providing the ability to look back across cosmic ray history on timescales of the same order as the age of the Solar System. Given a collection of differently aged samples dated with reasonable accuracy, this technique is particularly well-suited to measuring historical changes in the cosmic ray flux at Earth and is broadly applicable in astrophysics and geophysics.

In Vivo Validation of the BIANCA Biophysical Model: Benchmarking against Rat Spinal Cord RBE Data.

(1) Background: Cancer ion therapy is constantly growing thanks to its increased precision and, for heavy ions, its increased biological effectiveness (RBE) with respect to conventional photon therapy. The complex dependence of RBE on many factors demands biophysical modeling. Up to now, only the Local Effect Model (LEM), the Microdosimetric Kinetic Model (MKM), and the "mixed-beam" model are used in clinics. (2) Methods: In this work, the BIANCA biophysical model, after extensive benchmarking in vitro, was applied to develop a database predicting cell survival for different ions, energies, and doses. Following interface with the FLUKA Monte Carlo transport code, for the first time, BIANCA was benchmarked against in vivo data obtained by C-ion or proton irradiation of the rat spinal cord. The latter is a well-established model for CNS (central nervous system) late effects, which, in turn, are the main dose-limiting factors for head-and-neck tumors. Furthermore, these data have been considered to validate the LEM version applied in clinics. (3) Results: Although further benchmarking is desirable, the agreement between simulations and data suggests that BIANCA can predict RBE for C-ion or proton treatment of head-and-neck tumors. In particular, the agreement with proton data may be relevant if the current assumption of a constant proton RBE of 1.1 is revised. (4) Conclusions: This work provides the basis for future benchmarking against patient data, as well as the development of other databases for specific tumor types and/or normal tissues.

Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database.

OBJECTIVE: Estimates of cancer risk and the effects of surveillance in Lynch syndrome have been subject to bias, partly through reliance on retrospective studies. We sought to establish more robust estimates in patients undergoing prospective cancer surveillance. DESIGN: We undertook a multicentre study of patients carrying Lynch syndrome-associated mutations affecting MLH1, MSH2, MSH6 or PMS2. Standardised information on surveillance, cancers and outcomes were collated in an Oracle relational database and analysed by age, sex and mutated gene. RESULTS: 1942 mutation carriers without previous cancer had follow-up including colonoscopic surveillance for 13 782 observation years. 314 patients developed cancer, mostly colorectal (n=151), endometrial (n=72) and ovarian (n=19). Cancers were detected from 25 years onwards in MLH1 and MSH2 mutation carriers, and from about 40 years in MSH6 and PMS2 carriers. Among first cancer detected in each patient the colorectal cancer cumulative incidences at 70 years by gene were 46%, 35%, 20% and 10% for MLH1, MSH2, MSH6 and PMS2 mutation carriers, respectively. The equivalent cumulative incidences for endometrial cancer were 34%, 51%, 49% and 24%; and for ovarian cancer 11%, 15%, 0% and 0%. Ten-year crude survival was 87% after any cancer, 91% if the first cancer was colorectal, 98% if endometrial and 89% if ovarian. CONCLUSIONS: The four Lynch syndrome-associated genes had different penetrance and expression. Colorectal cancer occurred frequently despite colonoscopic surveillance but resulted in few deaths. Using our data, a website has been established at http://LScarisk.org enabling calculation of cumulative cancer risks as an aid to genetic counselling in Lynch syndrome.

Incidence of and survival after subsequent cancers in carriers of pathogenic MMR variants with previous cancer: a report from the prospective Lynch syndrome database.

OBJECTIVE: Today most patients with Lynch syndrome (LS) survive their first cancer. There is limited information on the incidences and outcome of subsequent cancers. The present study addresses three questions: (i) what is the cumulative incidence of a subsequent cancer; (ii) in which organs do subsequent cancers occur; and (iii) what is the survival following these cancers? DESIGN: Information was collated on prospectively organised surveillance and prospectively observed outcomes in patients with LS who had cancer prior to inclusion and analysed by age, gender and genetic variants. RESULTS: 1273 patients with LS from 10 countries were followed up for 7753 observation years. 318 patients (25.7%) developed 341 first subsequent cancers, including colorectal (n=147, 43%), upper GI, pancreas or bile duct (n=37, 11%) and urinary tract (n=32, 10%). The cumulative incidences for any subsequent cancer from age 40 to age 70 years were 73% for pathogenic MLH1 (path_MLH1), 76% for path_MSH2 carriers and 52% for path_MSH6 carriers, and for colorectal cancer (CRC) the cumulative incidences were 46%, 48% and 23%, respectively. Crude survival after any subsequent cancer was 82% (95% CI 76% to 87%) and 10-year crude survival after CRC was 91% (95% CI 83% to 95%). CONCLUSIONS: Relative incidence of subsequent cancer compared with incidence of first cancer was slightly but insignificantly higher than cancer incidence in patients with LS without previous cancer (range 0.94-1.49). The favourable survival after subsequent cancers validated continued follow-up to prevent death from cancer. The interactive website http://lscarisk.org was expanded to calculate the risks by gender, genetic variant and age for subsequent cancer for any patient with LS with previous cancer.

Colorectal cancer incidence in path_MLH1 carriers subjected to different follow-up protocols: a Prospective Lynch Syndrome Database report.

BACKGROUND: We have previously reported a high incidence of colorectal cancer (CRC) in carriers of pathogenic MLH1 variants (path_MLH1) despite follow-up with colonoscopy including polypectomy. METHODS: The cohort included Finnish carriers enrolled in 3-yearly colonoscopy (n = 505; 4625 observation years) and carriers from other countries enrolled in colonoscopy 2-yearly or more frequently (n = 439; 3299 observation years). We examined whether the longer interval between colonoscopies in Finland could explain the high incidence of CRC and whether disease expression correlated with differences in population CRC incidence. RESULTS: Cumulative CRC incidences in carriers of path_MLH1 at 70-years of age were 41% for males and 36% for females in the Finnish series and 58% and 55% in the non-Finnish series, respectively (p > 0.05). Mean time from last colonoscopy to CRC was 32.7 months in the Finnish compared to 31.0 months in the non-Finnish (p > 0.05) and was therefore unaffected by the recommended colonoscopy interval. Differences in population incidence of CRC could not explain the lower point estimates for CRC in the Finnish series. Ten-year overall survival after CRC was similar for the Finnish and non-Finnish series (88% and 91%, respectively; p > 0.05). CONCLUSIONS: The hypothesis that the high incidence of CRC in path_MLH1 carriers was caused by a higher incidence in the Finnish series was not valid. We discuss whether the results were influenced by methodological shortcomings in our study or whether the assumption that a shorter interval between colonoscopies leads to a lower CRC incidence may be wrong. This second possibility is intriguing, because it suggests the dogma that CRC in path_MLH1 carriers develops from polyps that can be detected at colonoscopy and removed to prevent CRC may be erroneous. In view of the excellent 10-year overall survival in the Finnish and non-Finnish series we remain strong advocates of current surveillance practices for those with LS pending studies that will inform new recommendations on the best surveillance interval.

Concomitant mutation and epimutation of the MLH1 gene in a Lynch syndrome family.

Lynch syndrome (LS) is an inherited predisposition cancer syndrome, typically caused by germline mutations in the mismatch repair genes MLH1, MSH2, MSH6 and PMS2. In the last years, a role for epimutations of the same genes has also been reported. MLH1 promoter methylation is a well known mechanism of somatic inactivation in tumors, and more recently, several cases of constitutional methylation have been identified. In four subjects affected by multiple tumors and belonging to a suspected LS family, we detected a novel secondary MLH1 gene epimutation. The methylation of MLH1 promoter was always linked in cis with a 997 bp-deletion (c.-168_c.116+713del), that removed exon 1 and partially involved the promoter of the same gene. Differently from cases with constitutional primary MLH1 inactivation, this secondary methylation was allele-specific and CpGs of the residual promoter region were totally methylated, leading to complete allele silencing. In the colon tumor of the proband, MLH1 and PMS2 expression was completely lost as a consequence of a pathogenic somatic point mutation (MLH1 c.199G>A, p.Gly67Arg) that also abrogated local methylation by destroying a CpG site. The evidences obtained highlight how MLH1 mutations and epimutations can reciprocally influence each other and suggest that an altered structure of the MLH1 locus results in epigenetic alteration.

Effects of celecoxib on prostanoid biosynthesis and circulating angiogenesis proteins in familial adenomatous polyposis.

Vascular cyclooxygenase (COX)-2-dependent prostacyclin (PGI(2)) may affect angiogenesis by preventing endothelial activation and platelet release of angiogenic factors present in platelet α-granules. Thus, a profound inhibition of COX-2-dependent PGI(2) might be associated with changes in circulating markers of angiogenesis. We aimed to address this issue by performing a clinical study with celecoxib in familial adenomatous polyposis (FAP). In nine patients with FAP and healthy controls, pair-matched for gender and age, we compared systemic biosynthesis of PGI(2), thromboxane (TX) A(2), and prostaglandin (PG) E(2), assessing their urinary enzymatic metabolites, 2,3-dinor-6-keto PGF(1α) (PGI-M), 11-dehydro-TXB(2) (TX-M), and 11-α-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M), respectively. The impact of celecoxib (400 mg b.i.d. for 7 days) on prostanoid biosynthesis and 14 circulating biomarkers of angiogenesis was evaluated in FAP. Intestinal tumorigenesis was associated with enhanced urinary TX-M levels, but unaffected by celecoxib, suggesting the involvement of a COX-1-dependent pathway, presumably from platelets. This was supported by the finding that in cocultures of a human colon adenocarcinoma cell line (HT-29) and platelets enhanced TXA(2) generation was almost completely inhibited by pretreatment of platelets with aspirin, a preferential inhibitor of COX-1. In FAP, celecoxib profoundly suppressed PGE(2) and PGI(2) biosynthesis that was associated with a significant increase in circulating levels of most proangiogenesis proteins but also the antiangiogenic tissue inhibitor of metalloproteinase 2. Urinary PGI-M, but not PGE-M, was negatively correlated with circulating levels of fibroblast growth factor 2 and angiogenin. In conclusion, inhibition of tumor COX-2-dependent PGE(2) by celecoxib may reduce tumor progression. However, the coincident depression of vascular PGI(2), in a context of enhanced TXA(2) biosynthesis, may modulate the attendant angiogenesis, contributing to variability in the chemopreventive efficacy of COX-2 inhibitors such as celecoxib.

Is laparoscopic surgery an option to support prophylactic colectomy in adolescent patients with Familial Adenomatous Polyposis (FAP)?

BACKGROUND: Prophylactic surgery is still considered the standard treatment for patients with Familial Adenomatous Polyposis (FAP). Laparoscopic (Lap) surgery has been introduced as an alternative approach. The aim was to evaluate the feasibility and short- to long-term outcomes after prophylactic FAP surgery in adolescent. PROCEDURES: A retrospective review of a database of adolescent patients with FAP identified through the Hereditary Colorectal Tumor Registry in a single Institution between 2005 and 2011. Patients underwent Lap total colectomy (TC) with ileo-rectal anastomosis (IRA) or proctocolectomy (PC) with ileal-pouch anal anastomosis (IPAA). The main outcomes were: Hospital stay, postoperative complications, desmoid tumor rates, tumor recurrence, long-term complications. RESULTS: Sixteen consecutive patients with median age 16 (range 13-19) and median BMI 22 (17-29) underwent surgery. [correction made here after initial online publication]. Of them 14 patients had LAP TC with IRA and 2 had PC with IPAA. Operative time (median, range) was TC/IRA 270 (210-330) minutes; PC/IPAA 370 (360-380) minutes. Length of extraction site was cm (median, range) 6(5-8). Lymph Node harvest (median, range) 81 (32-139). Postoperative stay days (median, range) were 6 (4-24). Five patients (31.2%) showed dysplasia on the pathological report and 3 of them showed severe dysplasia. Median follow-up time (FU) was 39 months, range (10-82). The anastomotic leak rate for 30 days was 2 (12.5%). Pouch failure was 0. Post-surgical desmoid tumors rate was 1 (6.2%) and there was no tumor recurrence. Anastomotic stricture, SBO and mortality were zero. CONCLUSIONS: Lap approach is feasible and shows acceptable postoperative outcomes. Lap surgery can be an appealing alternative for prophylactic surgery in adolescent FAP patients. Pediatr Blood Cancer 2012; 59: 1223-1228. © 2012 Wiley Periodicals, Inc.

Metastatic cancer and endentulism: Exploring comorbidity to assist with differential diagnosis in a case from Vico nel Lazio (Fr, Italy), 13th-15th century CE.

OBJECTIVE: To differentially diagnose cranial lesions noted on a medieval skeleton and explore the importance of comorbidity. MATERIALS: A skull of an adult female with osteolytic and osteoblastic lesions, edentulism, and an ectopic tooth from an ossuary of the Church of Santa Maria in Vico del Lazio, Frosinone Italy, dating to the Middle Ages. METHODS: Macroscopic observations of the remains, CT scan, and differential diagnosis was undertaken. RESULTS: A diagnosis of metastatic cancer (potentially breast cancer) or metastatic neuroblastoma (NBL) is offered. CONCLUSIONS: Considering the noted comorbidities, this case might represent a rare case of metastatic neuroblastoma. SIGNIFICANCE: The exploration of comorbidity, in this case the presence of metastatic carcinoma and edentulism, has tremendous potential to expand our knowledge about cancer in the past. LIMITATIONS: Lack of postcranial elements. SUGGESTIONS FOR FURTHER RESEARCH: Clinical and paleopathological investigation of comorbidity in modern and archeological populations to develop an evolutionary perspective on the presence of cancer in the past.

First application of the BIANCA biophysical model to carbon-ion patient cases.

Objective.The main objective of this work consists of applying, for the first time, the BIANCA (BIophysical ANalysis of Cell death and chromosome Aberrations) biophysical model to the RBE calculation for C-ion cancer patients, and comparing the outcomes with those obtained by the LEM I model, which is applied in clinics. Indeed, the continuous development of heavy-ion cancer therapy requires modelling of biological effects of ion beams on tumours and normal tissues. The relative biological effectiveness (RBE) of heavy ions is higher than that of protons, with a significant variation along the beam path. Therefore, it requires a precise modelling, especially for the pencil-beam scanning technique. Currently, two radiobiological models, LEM I and MKM, are in use for heavy ions in scanned pencil-beam facilities.Approach.Utilizing an interface with the FLUKA Particle Therapy Tool, BIANCA was applied to re-calculate the RBE-weighted dose distribution for carbon-ion treatment of three patients (chordoma, head-and-neck and prostate) previously irradiated at CNAO, where radiobiological optimization was based on LEM I. The predictions obtained by BIANCA were based either on chordoma cell survival (RBEsurv), or on dicentric aberrations in peripheral blood lymphocytes (RBEab), which are indicators of late normal tissue damage, including secondary tumours. The simulation outcomes were then compared with those provided by LEM I.Main results.While in the target and in the entrance channel BIANCA predictions were lower than those obtained by LEM I, the two models provided very similar results in the considered OAR. The observed differences betweenRBEsurvandRBEab(which were also dependent on fractional dose and LET) suggest that in normal tissues the information on cell survival should be integrated by information more closely related to the induction of late damage, such as chromosome aberrations.Significance.This work showed that BIANCA is suitable for treatment plan optimization in ion-beam therapy, especially considering that it can predict both cell survival and chromosome aberrations and has previously shown good agreement with carbon-ion experimental data.

Roadmap: helium ion therapy.

Helium ion beam therapy for the treatment of cancer was one of several developed and studied particle treatments in the 1950s, leading to clinical trials beginning in 1975 at the Lawrence Berkeley National Laboratory. The trial shutdown was followed by decades of research and clinical silence on the topic while proton and carbon ion therapy made debuts at research facilities and academic hospitals worldwide. The lack of progression in understanding the principle facets of helium ion beam therapy in terms of physics, biological and clinical findings persists today, mainly attributable to its highly limited availability. Despite this major setback, there is an increasing focus on evaluating and establishing clinical and research programs using helium ion beams, with both therapy and imaging initiatives to supplement the clinical palette of radiotherapy in the treatment of aggressive disease and sensitive clinical cases. Moreover, due its intermediate physical and radio-biological properties between proton and carbon ion beams, helium ions may provide a streamlined economic steppingstone towards an era of widespread use of different particle species in light and heavy ion therapy. With respect to the clinical proton beams, helium ions exhibit superior physical properties such as reduced lateral scattering and range straggling with higher relative biological effectiveness (RBE) and dose-weighted linear energy transfer (LETd) ranging from ∼4 keVµm-1to ∼40 keVµm-1. In the frame of heavy ion therapy using carbon, oxygen or neon ions, where LETdincreases beyond 100 keVµm-1, helium ions exhibit similar physical attributes such as a sharp lateral penumbra, however, with reduced radio-biological uncertainties and without potentially spoiling dose distributions due to excess fragmentation of heavier ion beams, particularly for higher penetration depths. This roadmap presents an overview of the current state-of-the-art and future directions of helium ion therapy: understanding physics and improving modeling, understanding biology and improving modeling, imaging techniques using helium ions and refining and establishing clinical approaches and aims from learned experience with protons. These topics are organized and presented into three main sections, outlining current and future tasks in establishing clinical and research programs using helium ion beams-A. Physics B. Biological and C. Clinical Perspectives.

Laparoscopic colectomy and restorative proctocolectomy for familial adenomatous polyposis.

BACKGROUND: Familial adenomatous polyposis (FAP) is a dominantly inherited syndrome. Risk of cancer begins to increase after age 20 years if not treated. The purpose of this study was to evaluate the feasibility and short- and long-term outcomes after laparoscopic prophylactic surgery for FAP. METHODS: Fifty-five patients with FAP were identified through the Hereditary Colorectal Tumor Registry from 2003 to 2009. Patients with laparoscopic total colectomy (TC)/IRA or proctocolectomy (TPC)/ileal pouch-anal anastomosis IPAA were included. Patients with previous colon or abdominal major surgery, malignancy, and desmoids before surgery were excluded. Main outcomes were: 30 days anastomotic leak and pouch failure; long-term desmoids and malignant recurrence. RESULTS: Of the 55 patients, 32 were men, median age was 28 years, and mean body mass index was 23. Median follow-up time was 36 (range, 5-77) months. Forty-four patients had laparoscopic TC/IRA and ten had laparoscopic TPC/IPAA. One patient was converted to open surgery and received an open TPC/IPAA. Incision length was 7 (range, 5-14) cm. Anastomotic leak was 3 (5.4%: 2 laparoscopic and 1 open), and pouch failure was 0. Median postsurgical length of stay was 7 (range, 4-24) days. Desmoids occurred in three patients (5.4%), and there was no malignant recurrence within the follow-up period. Pathology revealed severe dysplasia in ten patients and adenocarcinoma in nine (8 laparoscopic and 1 open). Long-term small-bowel obstruction was 2 (3.6%). One mortality due to liver metastases occurred at 24 months. CONCLUSIONS: Laparoscopic prophylactic treatment of FAP appears to be safe and feasible and may be an appealing alternative to open surgery. If the goal of prophylactic FAP surgery is to avoid cancer occurrence, laparoscopic surgery could be an important advancement.

Survival in women with MMR mutations and ovarian cancer: a multicentre study in Lynch syndrome kindreds.

BACKGROUND: Women with a germline mutation in one of the MMR genes MLH1, MSH2 or MSH6 reportedly have 4-12% lifetime risk of ovarian cancer, but there is limited knowledge on survival. Prophylactic bilateral salpingo-oophorectomy (PBSO) has been suggested for preventing this condition. AIM: The purpose of this retrospective multicentre study was to describe survival in carriers of pathogenic mutations in one of the MMR genes, and who had contracted ovarian cancer. METHODS: Women who had ovarian cancer, and who tested positive for or were obligate carriers of an MMR mutation, were included from 11 European centres for hereditary cancer. Most women had not attended for gynaecological screening. Crude and disease specific survival was calculated by the Kaplan-Meier algorithm. RESULTS: Among the 144 women included, 81.5% had FIGO stage 1 or 2 at diagnosis. 10 year ovarian cancer specific survival independent of staging was 80.6%, compared to less than 40% that is reported both in population based series and in BRCA mutation carriers. Disease specific 30 year survival for ovarian cancer was 71.5%, and for all hereditary non-polyposis colon cancer (HNPCC)/Lynch syndrome related cancers including ovarian cancer it was 47.3%. CONCLUSIONS: In the series examined, infiltrating ovarian cancer in Lynch syndrome had a better prognosis than infiltrating ovarian cancer in BRCA1/2 mutation carriers or in the general population. Lifetime risk of ovarian cancer of about 10% and a risk of dying of ovarian cancer of 20% gave a lifetime risk of dying of ovarian cancer of about 2% in female MMR mutation carriers.

Enhancement of the ionoacoustic effect through ultrasound and photoacoustic contrast agents.

The characteristic depth dose deposition of ion beams, with a maximum at the end of their range (Bragg peak) allows for local treatment delivery, resulting in better sparing of the adjacent healthy tissues compared to other forms of external beam radiotherapy treatments. However, the optimal clinical exploitation of the favorable ion beam ballistic is hampered by uncertainties in the in vivo Bragg peak position. Ionoacoustics is based on the detection of thermoacoustic pressure waves induced by a properly pulsed ion beam (e.g., produced by modern compact accelerators) to image the irradiated volume. Co-registration between ionoacoustics and ultrasound imaging offers a promising opportunity to monitor the ion beam and patient anatomy during the treatment. Nevertheless, the detection of the ionoacoustic waves is challenging due to very low pressure amplitudes and frequencies (mPa/kHz) observed in clinical applications. We investigate contrast agents to enhance the acoustic emission. Ultrasound microbubbles are used to increase the ionoacoustic frequency around the microbubble resonance frequency. Moreover, India ink is investigated as a possible mean to enhance the signal amplitude by taking advantage of additional optical photon absorption along the ion beam and subsequent photoacoustic effect. We report amplitude increase of up to 200% of the ionoacoustic signal emission in the MHz frequency range by combining microbubbles and India ink contrast agents.

Prognostic relevance of MLH1 and MSH2 mutations in hereditary non-polyposis colorectal cancer patients.

AIMS AND BACKGROUND: Colorectal carcinoma patients from hereditary non-polyposis colorectal cancer families are suggested to have a better prognosis than sporadic colorectal carcinoma cases. Since the majority of hereditary non-polyposis colorectal cancer-related colorectal carcinomas are characterized by microsatellite instability due to germline mutations in DNA mismatch repair genes, this is consistent with the prolonged survival observed in sporadic microsatellite instability-positive colorectal carcinoma compared to microsatellite stable cases. However, a fraction of colorectal carcinoma cases belongs to families that, despite fulfilling the clinical criteria for hereditary non-polyposis colorectal cancer, do not carry mismatch repair gene mutations. Our aim was to verify to what extent the genotypic heterogeneity influences the prognosis of hereditary non-polyposis colorectal cancer patients. METHODS: A survival analysis was performed on 526 colorectal carcinoma cases from 204 Amsterdam Criteria-positive hereditary non-polyposis colorectal cancer families. Enrolled cases were classified as MLH1-positive, MSH2-positive and mutation-negative, according to the results of genetic testing in each family. RESULTS: Five-year survival rates were 0.73 (95% CI, 0.66-0.80), 0.75 (95% CI, 0.66-0.84) and 0.62 (95% CI, 0.55-0.68) for MLH1-positive, MSH2-positive and mutation-negative groups, respectively (logrank test, P = 0.01). Hazard ratio, computed using Cox regression analysis and adjusted for age, sex, tumor site and stage, was 0.71 (95% CI, 0.51-0.98) for the mutation-positive compared to the mutation-negative group. Moreover, in the latter group, patients with microsatellite instability-positive colorectal carcinomas showed a better outcome than microsatellite stable cases (5-year survival rates, 0.81 and 0.60, respectively; logrank test, P = 0.006). CONCLUSIONS: Our results suggest that the prognosis of hereditary non-polyposis colorectal cancer-related colorectal carcinoma patients depends on the associated constitutional mismatch repair genotype.

Colorectal carcinoma in children and adolescents: the experience of the Istituto Nazionale Tumori of Milan, Italy.

BACKGROUND: Colorectal carcinoma (CRC) is one of the most common tumors in adults, but extremely rare in young age. This study retrospectively reports on a group of 27 patients <30 years of age, and particularly on 7 cases <18 years old, treated at the Istituto Nazionale Tumori, Milan, Italy, between 1985 and 2005. PATIENTS AND METHODS: Among the children/adolescents (age 9-18, median 12 years), 5/7 had unfavorable CRC histotypes (poorly differentiated or mucinous adenocarcinoma) and all but one had advanced disease at onset. Initial surgical resection was complete in 5/7 cases, and all patients received postoperative chemotherapy. RESULTS: In the subset of patients <18 years, 6/7 had tumor progression or relapse, and 5 died of their tumor: overall survival (OS) was 23% at 5 years. In the group of 19- to 29-year-olds (young adults), 5-year OS was 72.6%. CONCLUSIONS: This study confirms the rarity and poor prognosis of CRC in children and adolescents: advanced stage and an aggressive biology are hallmarks of this tumor in pediatric age, while clinical findings and outcome in young adults seem more similar to those observed in adult series. Therapeutic recommendations should stay the same as for adults. Surgery remains the mainstay of treatment and early diagnosis is crucial: it is important for pediatricians to be aware that CRC does occur in children, in order to refer suspected cases to expert physicians professionally dedicated to the management of this cancer in adults.