Corrigendum: Absolute oxygen-guided radiation therapy improves tumor control in three preclinical tumor models.

[This corrects the article DOI: 10.3389/fmed.2023.1269689.].

Absolute oxygen-guided radiation therapy improves tumor control in three preclinical tumor models.

Background: Clinical attempts to find benefit from specifically targeting and boosting resistant hypoxic tumor subvolumes have been promising but inconclusive. While a first preclinical murine tumor type showed significant improved control with hypoxic tumor boosts, a more thorough investigation of efficacy from boosting hypoxic subvolumes defined by electron paramagnetic resonance oxygen imaging (EPROI) is necessary. The present study confirms improved hypoxic tumor control results in three different tumor types using a clonogenic assay and explores potential confounding experimental conditions. Materials and methods: Three murine tumor models were used for multi-modal imaging and radiotherapy: MCa-4 mammary adenocarcinomas, SCC7 squamous cell carcinomas, and FSa fibrosarcomas. Registered T2-weighted MRI tumor boundaries, hypoxia defined by EPROI as pO2 ≤ 10 mmHg, and X-RAD 225Cx CT boost boundaries were obtained for all animals. 13 Gy boosts were directed to hypoxic or equal-integral-volume oxygenated tumor regions and monitored for regrowth. Kaplan-Meier survival analysis was used to assess local tumor control probability (LTCP). The Cox proportional hazards model was used to assess the hazard ratio of tumor progression of Hypoxic Boost vs. Oxygenated Boost for each tumor type controlling for experimental confounding variables such as EPROI radiofrequency, tumor volume, hypoxic fraction, and delay between imaging and radiation treatment. Results: An overall significant increase in LTCP from Hypoxia Boost vs. Oxygenated Boost treatments was observed in the full group of three tumor types (p < 0.0001). The effects of tumor volume and hypoxic fraction on LTCP were dependent on tumor type. The delay between imaging and boost treatments did not have a significant effect on LTCP for all tumor types. Conclusion: This study confirms that EPROI locates resistant tumor hypoxic regions for radiation boost, increasing clonogenic LTCP, with potential enhanced therapeutic index in three tumor types. Preclinical absolute EPROI may provide correction for clinical hypoxia images using additional clinical physiologic MRI.

Oxygen-Guided Radiation Therapy.

PURPOSE: It has been known for over 100 years that tumor hypoxia, a near-universal characteristic of solid tumors, decreases the curative effectiveness of radiation therapy. However, to date, there are no reports that demonstrate an improvement in radiation effectiveness in a mammalian tumor on the basis of tumor hypoxia localization and local hypoxia treatment. METHODS AND MATERIALS: For radiation targeting of hypoxic subregions in mouse fibrosarcoma, we used oxygen images obtained using pulse electron paramagnetic resonance pO2 imaging combined with 3D-printed radiation blocks. This achieved conformal radiation delivery to all hypoxic areas in FSa fibrosarcomas in mice. RESULTS: We demonstrate that treatment delivering a radiation boost to hypoxic volumes has a significant (P = .04) doubling of tumor control relative to boosts to well-oxygenated volumes. Additional dose to well-oxygenated tumor regions minimally increases tumor control beyond the 15% control dose to the entire tumor. If we can identify portions of the tumor that are more resistant to radiation, it might be possible to reduce the dose to more sensitive tumor volumes without significant compromise in tumor control. CONCLUSIONS: This work demonstrates in a single, intact mammalian tumor type that tumor hypoxia is a local tumor phenomenon whose treatment can be enhanced by local radiation. Despite enormous clinical effort to overcome hypoxic radiation resistance, to our knowledge this is the first such demonstration, even in preclinical models, of targeting additional radiation to hypoxic tumor to improve the therapeutic ratio.

TP53 Mutational Status and ROS Effect the Expression of the Survivin-Associated Radio-Adaptive Response.

A survivin-associated radio-adaptive response, characterized by increased radiation resistance or sensitization, was induced by exposure to 5 mGy of ionizing radiation and was correlated to the TP53 mutational status of exposed cells. Ten human cancer lines were investigated: colorectal carcinomas HCT116 and RKO [TP53 wild-type (WT)] and their respective TP53 null isogenic lines; breast adenocarcinomas MCF7 (TP53 WT) and MDA-MB-231 (TP53 Mut); lung carcinomas A549 (TP53 WT) and NCI-H1975 (TP53 Mut); and pancreatic carcinomas Hs766T (TP53 WT) and Panc-1 (TP53 Mut). Radiation induced (5 mGy) changes in the subsequent responses to 2 Gy in a multi-dose paradigm. Effects on radiation sensitivity were associated with changes in survivin's intracellular translocation to the cytoplasm (TP53 WT) or nucleus (TP53 Mut). Survival responses were determined using a colony forming assay. Intracellular localization of survivin was determined by ELISA and correlated with survival response. Two 2 Gy doses had minimal effects on the intracellular translocation of survivin. When preceded 15 min earlier by a 5 mGy exposure, survivin translocated to the cytoplasm in all of the TP53 WT cell lines, and to the nuclei in the TP53 null and Mut cells. All TP53 WT cells were protected (P < 0.001) by 5 mGy exposures, while Mut cells were sensitized (P < 0.001). HCT116 and RKO TP53 WT cells were admixed with their respective isogenic TP53 null counterparts in different proportions: 75% to 25%, 50% to 50% and 25% to 75%, respectively. All mixed confluent cultures expressed enhanced radio-sensitization (P ≤ 0.047) characteristic of TP53 Mut cells, which could be inhibited by their exposure to the antioxidant N-acetyl-l-cysteine (NAC) indicating a role for intercellular signaling by reactive oxygen species (ROS). ROS signaling in propagating the survivin-mediated response is involved in both intra- and intercellular communication processes.

Correlation Between Hypoxia Proteins and EPR-Detected Hypoxia in Tumors.

Rapid expansion of tumor cells that outpace existing vasculature essential for nutrient and oxygen support as well as waste removal, correlates with profound changes in the microenvironment including angiogenesis, vasodilation, glucose metabolism, and cell cycle perturbations. Since hypoxic cells are up to three times more radioresistant than normoxic cells, identification of hypoxic populations to predict radiotherapeutic outcome is important. The consequences of hypoxia and activated proteins contribute to radioresistant tumors and radiotherapeutic failure. Stereotactic MCa4 tumor tissue biopsies from mouse tumors that were guided by electron paramagnetic resonance (EPR) O2 imaging were examined for hypoxia-induced proteins. The oxygen broadening of narrow EPR spectral lines or, equivalently, the increase in relaxation rates of electron magnetization, report pO2 with 1-2 torr resolution in image voxels less than 1 mm3. The pO2 reporter molecule OX063d64 (trityl) was used to acquire the data described here. Trityl appears to be selectively retained in tumors with a half-life of ~30 min. We used an inversion recovery electron spin echo (IRESE) to measure the T1 rate of the trityl inside the tumor bearing leg. We estimate our uncertainty in pO2 measurement to be 1-3 torr per voxel. Three hypoxic cell biomarkers, hypoxic-induced factor 1-alpha (HIF-1α), vascular endothelial growth factor (VEGF), and carbonic anhydrase IX (CA9), were examined using the ELISA assay. Quantification of these proteins based on results from the ELISA immunoassay kits indicate a strong correlation between EPR pO2-identified hypoxic fractions (<10 torr) and HIF-1α, VEGF, and CA9. We clearly demonstrate that hypoxic regions in tumors generate substantial amounts of HIF- 1α, VEGF, and CA9 protein.

Altered expression of a metformin-mediated radiation response in SA-NH and FSa tumor cells treated under in vitro and in vivo growth conditions.

PURPOSE: To assess the radiosensitizing effect of the biguanide drug metformin used alone or in combination with reactive oxygen species (ROS) modifying agents N-acetyl-L-cysteine (NAC) or emodin, and contrasted to the mitochondrial complex 1 inhibitor rotenone in altering the radiation responses of the p53 wild-type SA-NH and p53 mutant FSa mouse tumor lines grown either in vitro or in vivo. MATERIALS AND METHODS: Tumor cells were grown to confluence in vitro and exposed to a single 4 Gy dose in the presence or absence of metformin (5 mM) and ROS modifiers or to 10 Gy with or without metformin as tumors in the flanks of C3H mice using a tumor growth delay assay. RESULTS: Both metformin and rotenone protected SA-NH (p < .001) while sensitizing FSa (p < .001) to 4 Gy. Neither NAC nor emodin altered metformin's action. Metformin was also directly toxic to FSa cells (p = .002). In contrast, in vivo metformin (250 mg/kg) sensitized both SA-NH (9-day growth delay, p < .05) and FSa (4-day growth delay, p < .05) tumors if administered 1 h before irradiation. CONCLUSION: Metformin effects on tumor cells measured under in vitro conditions may differ from those determined in vivo due to p53 and heterogeneous environmental factors.

Very low doses of ionizing radiation and redox associated modifiers affect survivin-associated changes in radiation sensitivity.

Exposure of cells to a dose of ionizing radiation as low as 5mGy can induce changes in radiation sensitivity expressed by cells exposed to subsequent higher doses at later times. This is referred to as an adaptive effect. We describe a unique survivin-associated adaptive response in which increased radiation resistance or sensitization of cells can be induced by exposure to 5mGy or to the reactive oxygen species (ROS) generating drug Emodin (1,3,8-trihydroxy-6-methylanthraquinone), a naturally occurring anthraquinone. The purpose of this study was to determine the role of ROS generating processes in affecting both the intracellular localization of the inhibitor of apoptosis protein survivin and its subsequent effect on radiation response in the presence or absence of the anti-oxidant N-acetyl-L-cysteine (NAC). Experiments were performed using two well characterized murine sarcomas: SA-NH p53 wild-type (WT) and FSa p53 mutant (Mut), grown either in culture or as solid tumors in the right hind legs of C3H mice. Doses of 5mGy or 50µM Emodin were used to induce changes in the response of these tumor cells to higher radiation exposures using a multi-dosing paradigm. Effects on radiation sensitivity were determined for SA-NH and FSa cells as a function of survivin translocation either to the cytoplasm or nucleus in the presence or absence of 10mM NAC treatment. In vitro survival assays (2Gy per fraction, two once daily fractions) and tumor growth delay (TGD) (5Gy per fraction, five once daily fractions) studies were performed. Intracellular localization of survivin was determined by enzyme-linked immunosorbent assay (ELISA) and correlated to survival response and treatment conditions. 2Gy alone had no effect on intracellular translocation of survivin. When preceded 15min earlier by 5mGy or Emodin exposures, survivin became elevated in the cytoplasm of p53 WT SA-NH as compared to the nuclei of p53 Mut FSa cells. SA-NH cells transfected with p53 small interfering RNA (siRNA), in contrast, responded similarly to p53 Mut FSa cells by becoming more radiation sensitive if exposed to 5mGy prior to each 2Gy irradiation. In contrast to their respective responses to five once daily 5Gy fractions, SA-NH tumors were protected by 5mGy exposures administered 15min prior to each daily 5Gy dose as evidenced by a more rapid growth (1.9 day decrease in TGD, P=0.032), while FSa tumors were sensitized, growing at a much slower rate (4.5 day increase in TGD, P<0.001). Exposure of SA-NH and FSa tumor cells to 10mM NAC inhibited the ability of 5mGy and Emodin to induce intracellular translocation of survivin and the corresponding altered adaptive survival response. The survivin-associated adaptive response can be induced following a multi-dosing scheme in which very low radiation doses are followed shortly thereafter by higher doses consistent with a standard image guided radiotherapy protocol that is currently widely used in the treatment of cancer. While induced by exposure to ROS generating stresses, the ultimate expression of changes in radiation response is dependent upon the bi-functionality of the tumor associated protein survivin and its intracellular translocation.

NFκB and Survivin-Mediated Radio-Adaptive Response.

A survivin-mediated radio-adaptive response was induced in SA-NH murine sarcoma cells following activation of nuclear transcription factor κB (NFκB) by very low doses of ionizing radiation of 5, 20 or 100 mGy. SA-NH cells and a clone stably transfected with a plasmid containing a mutated IκBα gene that prevents the activation of NFκB (SA-NH+mIκBα1) were used to investigate the role of NFκB activation in the development and expression of the survivin-mediated radio-adaptive response. Tumor cells were exposed to very low doses of radiation 30 min prior to or at times ranging from 30 min to 6 h after the first of two 2 Gy doses separated by 24 h under in vitro conditions. Evidence of very low dose radiation induced a radio-adaptive response only in SA-NH but not SA-NH+mIκBα1 cells was shown by both an increase in SA-NH cell survival of 20-40% using a standard colony forming assay and reduced apoptosis frequencies of 20-40% as determined by the TUNEL assay. Changes in survivin protein levels as a function of irradiation conditions were monitored by Western blot. A 100 mGy exposure 30 min prior to a 2 Gy dose resulted in an elevation in total survivin protein 24 h later in SA-NH but not SA-NH+mIκBα1 cells. Transfection of cells with survivin siRNA inhibited elevation of survivin protein by very low dose radiation and the subsequent radio-adaptive response in SA-NH cells. These data suggest that the survivin-mediated radio-adaptive response is dependent upon the ability of cells to activate NFκB.

Metformin exhibits radiation countermeasures efficacy when used alone or in combination with sulfhydryl containing drugs.

Metformin, a biguanide drug used in the treatment of type II diabetes, was evaluated alone and in combination with amifostine, captopril, MESNA or N-acetyl-cysteine (NAC) for its ability to protect when administered 24 h after irradiation. Mouse embryo fibroblasts (MEF), human microvascular endothelial cells (HMEC) and SA-NH mouse sarcoma cells were exposed to 4 Gy in vitro. C3H mice were exposed to 7 Gy and evaluated utilizing an endogenous spleen colony assay system. Amifostine and WR1065, administered 30 min prior to irradiation, were used as positive controls. Treatment of MEF, HMEC and SA-NH cells with metformin elevated survival levels by 1.4-, 1.5- and 1.3-fold compared to 1.9-, 1.8- and 1.6-fold for these same cells treated with WR1065, respectively. Metformin (250 mg/kg) was effective in protecting splenic cells from a 7 Gy dose in vivo (protection factor = 1.8). Amifostine (400 mg/kg), administered 30 min prior to irradiation resulted in a 2.6-fold survival elevation, while metformin administered 24 h after irradiation in combination with NAC (400 mg/kg), MESNA (300 mg/kg) or captopril (200 mg/kg) enhanced survival by 2.6-, 2.8- and 2.4-fold, respectively. Each of these agents has been approved by the FDA for human use and each has a well characterized human safety profile. Metformin alone or in combination with selected sulfhydryl agents possesses radioprotective properties when administered 24 h after radiation exposure comparable to that observed for amifostine administered 30 min prior to irradiation making it a potentially useful agent for radiation countermeasures use.

A survivin-associated adaptive response in radiation therapy.

Adaptive responses can be induced in cells by very low doses of ionizing radiation resulting in an enhanced resistance to much larger exposures. The inhibitor of apoptosis protein, survivin, has been implicated in many adaptive responses to cellular stress. Computerized axial tomography used in image-guided radiotherapy to position and monitor tumor response uses very low radiation doses ranging from 0.5 to 100 mGy. We investigated the ability of these very low radiation doses administered along with two 2 Gy doses separated by 24 hours, a standard conventional radiotherapy dosing schedule, to initiate adaptive responses resulting in the elevation of radiation resistance in exposed cells. Human colon carcinoma (RKO36), mouse sarcoma (SA-NH), along with transformed mouse embryo fibroblasts, wild type or cells lacking functional tumor necrosis factor receptors 1 and 2 were used to assess their relative ability to express an adaptive response when grown either to confluence in vitro or as tumors in the flank of C57BL/6 mice. The survival of each of these cells was elevated from 5% to 20% (P ≤ 0.05) as compared to cells not receiving a 100 mGy or lesser dose. In addition, the cells exposed to 100 mGy exhibited elevations in survivin levels, reductions in apoptosis frequencies, and loss of an adaptive response if transfected with survivin siRNA. This survivin-mediated adaptive response has the potential for affecting outcomes if regularly induced throughout a course of image guided radiation therapy.

A manganese superoxide dismutase (SOD2)-mediated adaptive response.

Very low doses of ionizing radiation, 5 to 100 mGy, can induce adaptive responses characterized by elevation in cell survival and reduction in micronuclei formation. Utilizing these end points, RKO human colon carcinoma and transformed mouse embryo fibroblasts (MEF), wild-type or knockout cells missing TNF receptors 1 and 2 (TNFR1(-)R2(-)), and C57BL/6 and TNFR1(-)R2(-) knockout mice, we demonstrate that intact TNF signaling is required for induction of elevated manganese superoxide dismutase (SOD2) activity (P < 0.001) and the subsequent expression of these SOD2-mediated adaptive responses when cells are challenged at a later time with 2 Gy. In contrast, amifostine's free thiol form WR1065 can directly activate NF-κB giving rise to elevated SOD2 activity 24 h later and induce an adaptive response in both MEF wild-type and TNF signaling defective TNFR1(-)R2(-) cells. Transfection of cells with SOD2 siRNA completely abolishes both the elevation in SOD2 activity and expression of the adaptive responses. These results were confirmed in vivo using a micronucleus assay in splenocytes derived from C57BL/6 and TNFR1(-)R2(-) knockout mice that were exposed to 100 mGy or 400 mg/kg amifostine 24 h prior to exposure to a 2 Gy whole-body dose. A dose of 100 mGy also conferred enhanced protection to C57BL/6 mice exposed 24 h later to 100 mg/kg of N-Ethyl-N-nitrosourea (ENU). While very low radiation doses require an intact TNF signaling process to induce a SOD2-mediated adaptive response, amifostine can induce a similar adaptive response in both TNF receptor competent and knockout cells, respectively.

Common respiratory issues in ambulatory obstetrics.

This article reviews the diagnosis and management of the most common respiratory conditions complicating pregnancy--asthma and influenza. We also review strategies for smoking cessation in pregnancy as, in addition to exacerbating all other pulmonary conditions, smoking is the most modifiable risk factor for poor pregnancy outcome. Moreover, the obstetrician frequently encounters each of these conditions in the ambulatory setting. A thorough knowledge of the normal pregnancy-induced physiological respiratory changes combined with a comprehensive understanding of how to manage these conditions, will provide the obstetrician with the armamentarium needed to optimize health outcomes for mothers and their fetuses.

SOD2-mediated effects induced by WR1065 and low-dose ionizing radiation on micronucleus formation in RKO human colon carcinoma cells.

RKO36 cells exposed to either WR1065 or 10 cGy X rays show elevated SOD2 gene expression and SOD2 enzymatic activity. Cells challenged at this time with 2 Gy exhibit enhanced radiation resistance. This phenomenon has been identified as a delayed radioprotective effect or an adaptive response when induced by thiols or low-dose radiation, respectively. In this study we investigated the relative effectiveness of both WR1065 and low-dose radiation in reducing the incidence of radiation-induced micronucleus formation in binucleated RKO36 human colon carcinoma cells. The role of SOD2 in this process was assessed by measuring changes in enzymatic activity as a function of the inducing agent used, the level of protection afforded, and the inhibitory effects of short interfering RNA (SOD2 siRNA). Both WR1065 and 10 cGy X rays effectively induced a greater than threefold elevation in SOD2 activity 24 h after exposure. Cells irradiated at this time with 2 Gy exhibited a significant resistance to micronucleus formation (P < 0.05; Student's two-tailed t test). This protective effect was significantly inhibited in cells transfected with SOD2 siRNA. SOD2 played an important role in the adaptive/delayed radioprotective response by inhibiting the initiation of a superoxide anion-induced ROS cascade leading to enhanced mitochondrial and nuclear damages.

Chemoprevention of human actinic keratoses by topical DL-alpha-tocopherol.

Prior research shows that topical application of free, nonfatty acid-conjugated vitamin E (DL-alpha-tocopherol) prevents skin cancer in mice, as well as immunosuppression induced by UVB radiation. This study investigated the chemopreventive potential of DL-alpha-tocopherol in humans through monitoring surrogate end point biomarkers in sun-damaged skin. Contralateral arms of healthy human volunteers with actinic keratoses (AK) were randomly assigned to receive either 12.5% DL-alpha-tocopherol or placebo in a crème base for 6 months. Changes in number of AKs, levels of p53 protein expression, proliferating cell nuclear antigen, and polyamines were assessed along with skin and systemic vitamin E levels. Following treatment, plasma concentration levels of DL-alpha-tocopherol were unchanged, but skin levels were highly elevated (P < 0.001). Levels of p53 and proliferating cell nuclear antigen did not change significantly, whereas number of AKs declined insignificantly in both placebo and treatment arms. Regression models showed significant decreases in putrescine, spermidine, spermine, and total polyamine concentrations following treatment. Topically applied DL-alpha-tocopherol was substantially absorbed in skin, but the 6-month application did not significantly reduce numbers of preexisting AKs on moderately to severely sun-damaged forearms. Increases in polyamine synthesis are expected during tumor initiation and promotion; conversely, the significant reductions in polyamine levels resulting from the topical DL-alpha-tocopherol application are consistent with reductions in tumorigenesis potential. Topical tocopherol did not normalize established sun-induced lesions, but DL-alpha-tocopherol-induced reductions in polyamine metabolism are consistent with the inhibition of skin squamous cell carcinogenesis as seen in previous human trials and animal models.

Pregnancy complicated by triploidy: a comparison of the three karyotypes.

We evaluated triploid pregnancy to determine whether there are clinically important differences between the three karyotypes: 69,XXX, 69,XXY, and 69,XYY. Prospectively maintained cytogenetic databases at five tertiary care centers were retrospectively reviewed over a 10-year period to identify all triploid pregnancies. Targeted ultrasounds were reviewed to identify fetal and placental findings. Sonographic findings were compared by karyotype. There was a total of 549 triploid gestations; preimplantation genetic diagnosis (PGD) detected 413 triploid embryos, and the cytogenetic databases provided 136 clinical pregnancies with triploidy. In triploid embryos with PGD, the frequency of the 69,XYY karyotype was 8.7% (36/413), compared with 0.74% (1/136) during the first trimester of clinical pregnancies (p = 0.002). In clinical pregnancies, 60% (36/60) of 69,XXY fetuses survived the first trimester of development compared with 69% (52/75) of 69,XXX fetuses (p = NS). No clinically important differences were observed between 69,XXX and 69,XXY karyotypes in terms of type, number, or severity of fetal or placental anomalies. Gestations with a 69,XYY karyotype are found less frequently compared with gestations with a 69,XXX or 69,XXY karyotype. The decline in fetal survival of the 69,XYY triploid karyotype needs further investigation. There are significant abnormalities detected during prenatal sonography in most all clinically recognized cases of triploidy. Sonography cannot reliably distinguish between the 69,XXY and 69,XXX karyotypes.

Ultrasound findings in trisomy 22.

We sought to identify the characteristic sonographic findings of fetal trisomy 22 by performing a retrospective review of nine cases of fetal trisomy 22. All cases of chromosomal mosaicism were excluded, as were first-trimester losses. Indications for sonography, gestational age, and sonographically detected fetal anomalies were analyzed. The majority of patients were referred for advanced maternal age or abnormal ultrasound findings on screening exam. Oligohydramnios was the most common sonographic finding, present in 55% of affected fetuses. Intrauterine growth restriction and increased nuchal thickness were slightly less frequent.

Sonographic findings of trisomy 18 in the second trimester of pregnancy.

OBJECTIVE: The purpose of this study was to examine the sonographic findings in fetuses with trisomy 18 in the second trimester of pregnancy. METHODS: A retrospective review of the cytogenetic laboratory databases at 6 tertiary referral centers identified all cases of trisomy 18. The prenatal sonographic studies in fetuses at 15 to 21 weeks' gestation, done before invasive testing for the karyotype, were reviewed for anatomic and biometric findings. We defined abnormal fetal biometric findings as a biometric measurement (biparietal diameter, abdominal circumference, or femur length) below the fifth percentile in the second trimester. RESULTS: Of 98 fetuses with trisomy 18, 95 (97%) were detected sonographically; an anomaly was found in 92 (94%). A biometric measurement below the fifth percentile was noted in 50 (51%). Cardiac (63%) and central nervous system (34%) anomalies were most frequently detected. Although choroid plexus cysts were commonly seen, no fetuses with trisomy 18 and isolated choroid plexus cysts were found. CONCLUSIONS: Targeted sonography identified abnormal fetal anatomy or abnormal biometric findings in 97% of fetuses with trisomy 18 in the second trimester. A biometric measurement below the fifth percentile was noted in half of the cases in the second trimester.

Sonographic detection of trisomy 13 in the first and second trimesters of pregnancy.

OBJECTIVE: The purpose of this study was to examine sonographic findings in fetuses with trisomy 13. METHODS: A retrospective review of the cytogenetic laboratory databases at 6 tertiary referral centers identified all cases of trisomy 13. The prenatal sonographic studies in fetuses of less than 22 weeks' gestation, done before invasive testing for karyotype, were reviewed for anatomic and biometric findings. We defined abnormal fetal biometric findings as a biometric measurement (biparietal diameter, abdominal circumference, or femur length) below the fifth percentile in the second trimester. RESULTS: There were 8 cases of trisomy 13 found in the first trimester and 54 cases found in the second trimester, a total of 62 in all. In the first trimester, 6 of 8 had an anomaly identified (4 with cystic hygroma). In the second trimester, 49 of 54 were identified by sonography; 45 had an anomaly, and 4 had an abnormal fetal biometric measurement without an anomaly. The 5 missed diagnoses had early gestational age (<17 weeks; n = 3) or an inadequate survey secondary to poor visualization. Overall, 22 of 54 fetuses with trisomy 13 had an abnormal biometric measurement. The most common anomalies detected in the second trimester were heart defects (n = 34), central nervous system anomalies (n = 30), facial clefts (n = 19), abnormal hands (n = 13), and genitourinary anomalies (n = 9). CONCLUSIONS: Targeted sonography identified abnormal fetal anatomy or abnormal biometric measurements in 95% of fetuses with trisomy 13 in the second trimester after 17 weeks' gestation. A biometric measurement below the fifth percentile was noted in nearly half of cases in the second trimester.

Secretory diarrhea owing to a tape bezoar in a child with Hirschsprung's disease.

Bezoars can be composed of a multitude of materials and can present in a wide variety of ways. The authors describe a young boy who had secretory diarrhea caused by an ileal bezoar composed of surgical adhesive tape. This report expands the literature on causes and presentation of intestinal bezoars in children.