Prediction of microcephaly at birth using three reference ranges for fetal head circumference: can we improve prenatal diagnosis?

OBJECTIVE: To evaluate the prediction of microcephaly at birth (micB) using established and two new reference ranges for fetal head circumference (HC) and to assess whether integrating additional parameters can improve prediction. METHODS: Microcephaly in utero was defined as a fetal HC 3SD below the mean for gestational age according to Jeanty et al.'s reference range. The records of cases with fetal microcephaly (Fmic) were evaluated for medical history, imaging findings, biometry and postnatal examination/autopsy findings. Microcephaly was confirmed at birth (micB) by an occipitofrontal circumference (OFC) or a brain weight at autopsy 2SD below the mean for gestational age. The new INTERGROWTH-21(st) Project and a recent Israeli reference for fetal growth were applied for evaluation of the Fmic positive predictive value (PPV) for diagnosis of micB cases. Optimal HC cut-offs were determined for each of the new references with the aim of detecting all micB cases whilst minimizing the number of false positives found to have a normal HC at birth. We also assessed the difference between the Z-scores of the prenatal HC and the corresponding OFC at birth, the frequency of small-for-gestational age (SGA), decreased HC/abdominal circumference (AC) and HC/femur length (FL) ratios, the prevalence of associated malformations and family history. RESULTS: Forty-two fetuses were diagnosed as having Fmic according to the Jeanty reference, but micB was confirmed in only 24 (PPV, 57.1%). The optimal INTERGROWTH and Israeli reference HC cut-offs for micB diagnosis were mean - 3SD and mean - 2.3SD, resulting in a statistically non-significant improvement in PPV to 61.5% and 66.7%, respectively. The presence of a family history of microcephaly, SGA, associated malformations and application of stricter HC cut-offs resulted in a higher PPV of micB, although not statistically significant and with a concurrent increase in the number of false-negative results. The deviation of the HC from the mean, by all references, was significantly larger compared with the actual deviation of the OFC at birth, with mean differences between the corresponding Z-scores of -1.15, -1.95 and -0.74 for the Jeanty, INTERGROWTH and Israeli references, respectively. CONCLUSIONS: The evaluated reference ranges all result in considerable over-diagnosis of fetal microcephaly. The use of the two new HC reference ranges did not significantly improve micB prediction compared with that of Jeanty et al., whilst use of additional characteristics and stricter HC cut-offs could improve the PPV with an increase in false negatives. The postnatal OFC deviates significantly less from the mean compared with the prenatal HC, and we propose that adjustment for this would enable better prediction of the actual OFC deviation at birth. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Application of a novel prenatal vertical cranial biometric measurement can improve accuracy of microcephaly diagnosis in utero.

OBJECTIVE: To construct a reference range for a new vertical measurement of the fetal head and to assess whether its combination with fetal head circumference (HC) can prevent the misdiagnosis of microcephaly in fetuses with an acrocephalic-like head deformation. METHODS: A new vertical cranial biometric measurement was defined: the foramen magnum-to-cranium distance (FCD), measured between the foramen magnum and the upper inner cranial border along the posterior wall of the brainstem. The measurement was performed in a precise mid-sagittal plane using a three-dimensional multiplanar display of a sagittally acquired sonographic volume of the fetal head. The normal reference range was developed by measuring 396 healthy fetuses of low-risk singleton pregnancies between 15 and 40 gestational weeks. This reference was applied to 25 fetuses with microcephaly diagnosed prenatally (Fmic) based on HC ≥ 3 SD below the mean for gestational age. We determined an optimal FCD cut-off for combination with HC to detect all cases found with microcephaly at birth (micB), while excluding the fetuses with normal head circumference at birth (NHCB), who were described postnatally as having an acrocephalic-like cranial deformation. RESULTS: In the healthy singleton fetuses, FCD increased with gestational age, with a quadratic equation providing an optimal fit to the data (adjusted R(2) = 0.934). The measurement could be assessed in 95.2% of cases. Of the 25 cases diagnosed with Fmic prenatally, on the basis of HC alone, 14 were micB and 11 were NHCB. We observed FCD below the mean - 2SD for gestational age in all 14 micB cases, but in only four of the 11 NHCB cases (P < 0.003). An acrocephalic-like cranial deformation was described at birth in five of the seven NHCB cases with normal FCD. The mean ± SD FCD Z-score of the micB cases was significantly lower (P < 0.001) than that of the false-positive ones: -3.85 ± 0.96 SD and -1.59 ± 1.45 SD, respectively. Based on HC measurement alone, the positive predictive value (PPV) was 56%. Combination of the HC and FCD criteria raised the PPV to 78%, decreasing the number of false positives from 11 to four, without missing any of the 14 micB cases. CONCLUSIONS: Fetal vertical cranial biometric assessment in the mid-sagittal plane is feasible and correlates well with gestational age. In our series, a vertical cranial deformation was a frequent cause of a false Fmic diagnosis made on the basis of HC alone. Combination of the new vertical cranial biometric measurement with HC measurement can exclude these cases and thus improve diagnostic accuracy for Fmic. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Alternating radiotherapy and chemotherapy schedules in small cell lung cancer, limited disease.

Sixty-three evaluable patients with limited small cell lung carcinoma were entered into two pilot studies alternating 6 cycles of combination chemotherapy (Doxorubicin 40 mg/m2 d 1; VP16213 75 mg/m2 d 1, 2, 3; Cyclophosphamide 300 mg/m2 d 3, 4, 5, 6; and Methotrexate 400 mg/m2 d 2--plus folinic acid rescue--or Cis-Platinum 100 mg/m2 d 2) with 3 courses of mediastinal radiotherapy as induction treatment. The first course of radiotherapy started 10 days after the second cycle of chemotherapy; there was a 7 day rest between chemotherapy and radiotherapy courses. This 6 month induction treatment was followed by a maintenance chemotherapy. The total mediastinal radiation dose was increased from 4500 rad in the first study to 5500 rad in the second. Both protocols obtained a complete response (CR) rate of greater than 85% (with fiberoptic bronchoscopy and histological verification). Local control at 2 years was 61% in the first study and 82% in the second. Relapse-free survival at 2 years was 32 and 37%, respectively. Toxicity was acceptable. We conclude that our results justify further clinical research in alternating radiotherapy and chemotherapy schedules.

Alternating radiotherapy and chemotherapy schedules in limited small cell lung cancer: analysis of local chest recurrences.

An analysis of the chest recurrences was conducted in 72 consecutive patients with limited small cell lung cancer treated in two successive phase II trials alternating six induction chemotherapy courses and three series of thoracic radiotherapy, followed by maintenance chemotherapy. The total radiation dose was 45 Gy (3 series of 15 Gy) in the first trial, and 55 (20, 20 and 15 Gy) in the second. The effect of the irradiated volume was investigated by comparing the local relapse rates in the group of patients treated by radiation fields encompassing the initial tumor volume to another group in which the initial target volume was not fully covered by radiation fields. The definition of these two groups was performed retrospectively by examination of radiological, fiberoptic bronchoscopy initial findings, technical radiation charts and check films. The local recurrence rate were 33 and 36% in each group (no significant difference). This finding could suggest that tumor shrinkage after chemotherapy might allow the use of "reduced" radiation volumes. However, the limited number of patients does not permit a definite conclusion. The effect of radiation dose was investigated by comparing the local control rates in the two consecutive trials which delivered 45 and 55 Gy, respectively. No difference in long-term local control was found: the addition of 10 Gy in the second trial only seemed to delay the appearance of local recurrences by 6 months. Twenty percent of patients died from a local relapse without evidence of distant metastases.(ABSTRACT TRUNCATED AT 250 WORDS)

Control of reproductive and energetic status by environmental cues in a desert rodent, Shaw's jird.

The photoperiod is the controller of reproductive cycles in temperate climates for most mammalian species. Several nonphotoperiodic cues appear to control reproductive status at lower latitudes. We tested the roles of the photoperiod or water availability on the reproductive status of the desert-dwelling Shaw's jird (Meriones shawi) trapped from a moderately temperate climate (approximately 30 degrees N in Egypt). Males and females were transported to the laboratory and, in Experiment 1, were housed in either the longest (LDs) or shortest (SDs) photoperiod that occurs naturally at this latitude (14 h light, 10 h dark, and 10 h light, 14 h dark, respectively). In Experiment 2, LD-housed male jirds were subjected to a water availability schedule that inhibits reproductive status in a closely related species (Meriones unguiculatus). Specifically, one group had no free water, but had lettuce available once a week for 24 h (control jirds received free water for 10-60 min/day). Neither photoperiod nor free-water deprivation affected reproductive status of male or female jirds. That is, neither testes mass nor spermatogenetic activity (males), nor uterine mass nor folliculogenesis (females) were affected by either condition. In addition, photoperiod did not affect body or white adipose tissue (WAT) masses, although SDs decreased carcass lipid in males. Free-water deprivation decreased body and WAT pad masses, and all carcass components. Collectively, these results suggest that changes in day length or water availability alone do not affect reproductive status in Shaw's jird.

Photoperiod, but not a high-fat diet, alters body fat in Shaw's jird.

Many animal species living in temperate zones show annual body fat cycles. In an apparent regulation of total body fat, species showing naturally occurring decreases in adiposity in the fall (e.g., meadow voles and Siberian hamsters) are resistant to high-fat diet (HFD)-induced obesity in short, "winter-like" days (SDs), and in long, "summer-like" days (LDs) at their peak adiposity. SD-exposed Shaw's jirds (Meriones shawi) show SD-induced decreases in body fat; therefore, we predicted they also would be resistant to HFD-induced obesity. Male jirds were fed a standard chow diet or a HFD, and half of each group was exposed to LDs or SDs. SD-exposed jirds significantly decreased their carcass lipid content and testes mass compared with LD controls, but not body or WAT pad masses. HFD feeding in either photoperiod did not affect any of these measures, nor did it trigger overeating. Thus, it appears disadvantageous for this, and other species, that exhibit body fat peaks in the LDs of summer and nadirs in the SDs of winter, to fatten further or dampen their body fat losses, respectively, whereas species that exhibit body fat nadirs in the LDs of summer and peaks in the SDs of winter do become fat in LDs, and even fatter in SDs, when fed a HFD (e.g., Syrian hamsters). This dichotomous separation of HFD-induced body fat responses to HFD feeding among species showing opposite seasonal lipid mass peaks and nadirs may prove useful in understanding resistance or susceptibility to HFD-induced obesity, especially because they are naturally occurring.

Photoperiodic responses of four wild-trapped desert rodent species.

The purpose of this study was to examine the effect of the photoperiod on reproductive status and body and lipid masses in four Egyptian desert rodent species (Dipodillus dasyurus, Acomys cahirinus, Gerbillus andersoni, and Gerbillus pyramidum). Adult males and females were housed in long days for 11 wk. At that time, one-half of the animals were killed and the remaining animals were moved to short days (SDs) for 11 wk. Some individuals of Gerbillus andersoni and Gerbillus pyramidum had access to running wheels. Testes index and spermatogenesis, but not testis mass, were decreased in all species in SDs. In contrast, SDs did not affect female reproductive status in all species. Exercise stimulated spermatogenesis but did not affect female reproductive status. SDs increased body and lipid masses in male Acomys cahirinus, but not in other species. Collectively, these desert rodent species were responsive to day length changes, but these changes alone did not induce robust alterations in reproductive status and body and lipid masses.