Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers.

BACKGROUND: Whole-genome sequencing (WGS) is a powerful method for revealing the diversity and complexity of the somatic mutation burden of tumours. Here, we investigated the utility of tumour and matched germline WGS for understanding aetiology and treatment opportunities for high-risk individuals with familial breast cancer. PATIENTS AND METHODS: We carried out WGS on 78 paired germline and tumour DNA samples from individuals carrying pathogenic variants in BRCA1 (n = 26) or BRCA2 (n = 22) or from non-carriers (non-BRCA1/2; n = 30). RESULTS: Matched germline/tumour WGS and somatic mutational signature analysis revealed patients with unreported, dual pathogenic germline variants in cancer risk genes (BRCA1/BRCA2; BRCA1/MUTYH). The strategy identified that 100% of tumours from BRCA1 carriers and 91% of tumours from BRCA2 carriers exhibited biallelic inactivation of the respective gene, together with somatic mutational signatures suggestive of a functional deficiency in homologous recombination. A set of non-BRCA1/2 tumours also had somatic signatures indicative of BRCA-deficiency, including tumours with BRCA1 promoter methylation, and tumours from carriers of a PALB2 pathogenic germline variant and a BRCA2 variant of uncertain significance. A subset of 13 non-BRCA1/2 tumours from early onset cases were BRCA-proficient, yet displayed complex clustered structural rearrangements associated with the amplification of oncogenes and pathogenic germline variants in TP53, ATM and CHEK2. CONCLUSIONS: Our study highlights the role that WGS of matched germline/tumour DNA and the somatic mutational signatures can play in the discovery of pathogenic germline variants and for providing supporting evidence for variant pathogenicity. WGS-derived signatures were more robust than germline status and other genomic predictors of homologous recombination deficiency, thus impacting the selection of platinum-based or PARP inhibitor therapy. In this first examination of non-BRCA1/2 tumours by WGS, we illustrate the considerable heterogeneity of these tumour genomes and highlight that complex genomic rearrangements may drive tumourigenesis in a subset of cases.

Prospective randomized study of x-ray pelvimetry in the primigravida.

A prospective randomized study was performed to determine the usefulness of x-ray pelvimetry before oxytocin induction or augmentation. Two hundred primiparous women were entered into this study. Agreement on pelvic size by the clinical and radiologic assessment occurred in 76.5% of the cases. When the total groups were compared, there were no differences in pregnancy outcome. In the induction of labor subgroups there were less forcep deliveries and lower five-minute Apgar scores in the pelvimetry group. In the augmentation subgroups there were no differences. The subgroup of patients diagnosed clinically to have a borderline pelvis, had a higher incidence of cesarean section (P less than .05) if they had x-ray pelvimetry. These results suggest that the elimination of x-ray pelvimetry in primigravida women does not lead to a compromise in infant outcome when electronic fetal monitoring is used.

The prevention of meconium aspiration in labor using amnioinfusion.

In an effort to improve maternal and fetal outcome in patients laboring with thick meconium, 85 patients presenting with thick meconium were randomized to receive either amnioinfusion with 1000 mL normal saline initially and every 6 hours until delivery, or routine care. Meconium was discovered on initial examination during labor, after artificial rupture of membranes, through the use of an intrauterine pressure catheter, or on amniocentesis. Labor management was otherwise routine. Forceps operations and cesarean sections were for distress or failure to progress, as indicated. Patients receiving amnioinfusion had significantly fewer low 1-minute Apgar scores, less meconium below the cords, and a significantly lower incidence of operative delivery. The only three cases of meconium aspiration syndrome occurred in infants delivered of patients receiving routine management. No adverse side effects of amnioinfusion were detected. Amnioinfusion is a simple, inexpensive, and safe technique that reduces the incidence of meconium below the cords and improves obstetric outcome in patients laboring with thick meconium.

Thermic effects of tocolytic agents: decreased temperature with magnesium sulfate.

The effect of the tocolytic agents terbutaline and magnesium sulfate on patients' temperatures was examined. Fifty-two women admitted for preterm labor were randomized to a treatment protocol for one of the two agents. Oral temperatures were measured initially and every two hours during treatment. There was no significant difference between the initial temperature and the lowest temperature recorded during treatment in the terbutaline group, but temperature decreased significantly during treatment with magnesium sulfate. This decrease in maternal temperature may have importance in the treatment of preterm labor with magnesium sulfate in patients with an infectious etiology for uterine activity.

Appendectomy at cesarean section: a prospective study.

Appendectomy was performed on 40 consecutive consenting patients undergoing elective cesarean section in a clinic population. The control group consisted of all other patients undergoing elective cesarean section during the period of study. The populations were similar. Clinical infection, blood loss, gastrointestinal tract recovery rates were equal in both groups. Appendectomy added 15 minutes to the operation time and extended the hospital stay by about one-half day. There were no wound infections or serious morbidity. A fifth of the appendixes removed were abnormal, including two with inflammation and one with a carcinoid tumor. Prophylactic appendectomy does not seem to add to the risk of elective cesarean section.

Human fetal response to vibroacoustic stimulation as a function of stimulus duration.

The effect of stimulus duration on the initial fetal heart rate (FHR) acceleration response was evaluated by assessing its amplitude and span following a single vibroacoustic stimulation with durations of 0 (sham), 1, 3, or 5 seconds. Statistically significant differences were observed in the mean amplitude and duration of acceleration in groups 3 and 5 when compared with groups 0 and 1 (P less than .05). In addition, groups 3 and 5 demonstrated significantly greater fetal reactivity than group 0 and a decrease in testing time over groups 0 and 1 (P less than .05). Our results suggest that the magnitude of the FHR acceleration response is dependent on the duration of the stimulus. Furthermore, a 3-second sound stimulus appears to be adequate for a shift to the fetal behavioral "awake" state.

Preterm premature rupture of membranes: a randomized study of home versus hospital management.

OBJECTIVE: To compare length of latency period, gestational age at delivery, and safety in a carefully selected group of patients with preterm premature rupture of the membranes (PROM) randomized to home versus hospital management. METHODS: After meeting strict inclusion criteria, 67 patients with preterm PROM were randomized by sealed envelope to home versus hospital expectant management. The groups were managed similarly with pelvic and bed rest. Management included recording of temperature and pulse every 6 hours, daily charting of fetal movements, twice-weekly nonstress test and complete blood count, and weekly ultrasound and visual examination of the cervix. RESULTS: There was no significant difference in clinical characteristics or perinatal outcome between the groups. There was, however, a significant decrease in both the days of maternal hospitalization and maternal hospital expenses in the home group. CONCLUSION: Only a very small proportion of cases of preterm PROM (18%) could meet the strict safety criteria for inclusion used in the study. In the home-management group, length of the latency period and gestational age at delivery were not significantly different than in hospitalized patients.

Peritoneal closure or non-closure at cesarean.

The value of peritoneal closure at the time of cesarean birth was evaluated prospectively. Two hundred forty-eight women undergoing low transverse cesarean through a Pfannenstiel skin incision were assigned to one of two groups: peritoneum open (N = 127) or peritoneum closed (N = 121). The mean (+/- SEM) surgical time in the open group (48.1 +/- 1.2 minutes) was significantly less than for the closed group (53.2 +/- 1.4 minutes) (P less than .005). There were no postoperative differences between the groups in the incidence of wound infection, dehiscence, endometritis, ileus, and length of hospital stay. Our study suggests that leaving the parietal peritoneum unsutured is an acceptable way to manage patients at cesarean delivery.

Comparison of the in vivo activity of different oxytocin antagonists in the pregnant baboon.

OBJECTIVE: To ascertain the relative activity of five oxytocin antagonists (OTAs) in vivo in a tethered pregnant baboon model and compare these results to previously reported affinities in human and rat oxytocin receptor assays and median effective dose in rat uterotonic bioassays. METHODS: Pregnant tethered baboons between days 130 and 160 of pregnancy were given an oxytocin challenge test 1 minute after infusion of 1 mg of one of five randomly selected OTAs: ANTAG I, ANTAG II, ANTAG III, L366948, and Atosiban. Once the uterine response to oxytocin returned to normal (1-8 days) the OCT was repeated with one of the remaining, untested OTAs during the 130-160 day period. Uterine activity, the time until the first significant response, and the dose of oxytocin needed to induce this response were all factored into one expression, the antagonist-response interval (ARI). RESULTS: When expressed as ratio to ANTAG I the relative ARI for the OTAs were 0, .5, 1.0, 2.4 and 59.2 for L366948, Atosiban, ANTAG I, ANTAG II, and ANTAG III, respectively. ANTAG III and L366948 were significantly different from each other and the three other OTAs (P < .05). The log10 ARI for the 4 active OTAs when correlated with the log10 of the human and rat oxytocin receptor affinities and the rat uterotonic bioassay were all highly correlated (r = .99; P < .05). CONCLUSION: ANTAG III is a potent, long-acting OTA in vivo in the pregnant baboon and has the potential as a tocolytic in humans.

Fetal head molding. Diagnosis by ultrasound and a review of the literature.

Head molding refers to changes in cranial bone relationships that occur in response to external compression force. In the normal term labor with vertex presentation, the suboccipito-bregmatic diameter shortens and the mentovertical diameter lengthens. This is accomplished partially through the unbending or straightening of the parietal bones rather than the frequently taught mechanism of overlapping sutures. The occipital and frontal bones may also contribute by an inward movement of their apex, using their basal portions as a hinge. A locking mechanism may occur in protracted labors as the free edges of the cranial bones are forced into one another, preventing further molding and providing more protection for the fetal brain. The preterm skull has weaker material properties and wider sutures. Thus, more molding at lower pressures is possible and the protective effect of "locking" may not be operational. A case of extreme antenatal preterm fetal head molding discovered at ultrasound is presented as an introduction to review the literature regarding molding.

Hyperparathyroidism in pregnancy with sonographic documentation of a parathyroid adenoma. A case report.

Hyperparathyroidism in pregnancy is associated with significant morbidity for both mother and child. Surgical intervention allows improved outcomes for both. The case presented here illustrates the approach to the pregnant patient with hypercalcemia and the role of ultrasound in visualizing a parathyroid adenoma.

Pregnancy outcomes in short women.

The pregnancy outcomes in 3,059 women who were 122-152 cm (48-60 in) tall with singleton pregnancies were compared to those of 7,414 women who were 160 cm (63 in) tall. The short women were of lower weight at delivery and had slightly higher parity. There were fewer whites in the short group. The higher parity was associated with a slightly higher occurrence of placenta previa. The pregnancies in the short women were characterized by smaller infants and more frequent delivery by cesarean section, depending on race. For whites the cesarean section rate was 43% in the very-short group (122-136 cm, or 48-53 in), 35% in the short group (137-151 cm, or 54-59 in) and 23% in the control group. The results suggest that women less than 152 cm (60 in) tall are a high-risk group.

Intraligamentous pregnancy. A case report.

A patient experienced fetal demise at 33 weeks' gestation. Numerous attempts at induction of labor failed. It was not until a laparotomy was performed that the intraligamentous location of the pregnancy was determined. Although this diagnosis is rarely made preoperatively, repeated failure of induction should raise the suspicion of an abnormal implantation site.

Configuration of the fetal electrocardiogram in ambulatory women in labor monitored with wideband telemetry.

The fetal electrocardiogram (ECG) in 23 ambulatory women in labor was monitored successfully with a single-channel FM telemetry unit with a 0.5-100-Hz wideband receiver to improve the quality of the ECG complex. An inverted QRS complex was seen in a patient with a deceleration and an inverted T wave during a deceleration in a patient confined to bed. A maternal artifact was transmitted in a third. The ECG complex was identical when wired patients were switched to telemetry. Thus, fetal heart rate and ECG configuration can be monitored accurately in ambulatory pregnant women.

Laparoscopic cholecystectomy in pregnancy. A case report.

Laparoscopic cholecystectomy was performed on a pregnant woman at 18 weeks of gestation without complications. Considering the risk/benefit ratio, laparoscopic cholecystectomy in pregnant women is preferable to conventional cholecystectomy.

The benefits of using the loop ligature (Endoloop) laparoscopic sterilization procedure in a residency program.

This study was conducted to determine the impact of the addition of the loop ligation (Endoloop) technique on choice of sterilization surgery in our residency teaching program and to investigate significant differences between this technique and other methods performed at our hospital. A retrospective study of all patients undergoing interval tubal sterilization at Tampa General Hospital in 1989 and 1991 was undertaken. Data were analyzed to determine the frequency of sterilization methods and differences between the loop ligation method and the other procedures performed; p values of less than 0.05 were considered significant. Sixty-one patients in 1989 and 75 in 1991 qualified for the study. Five methods of interval sterilization were performed: loop ligation, minilaparotomy, colpotomy, laparoscopic bipolar fulguration, and Silastic ring application. The frequency of the loop ligature technique increased from 0% in 1989 to 40% in 1991. There were no significant differences in operative time and complication rate among the loop method and other procedures. The loop ligature (Endoloop) method of laparoscopic sterilization does not significantly change the length of surgery, blood loss, or complication rate compared to the other laparoscopic techniques used in our residency program. This method provides a definitive tissue diagnosis, eliminates the risk of thermal injury, theoretically provides an opportunity of later tubal reanastomosis, and subjectively helps develop laparoscopic skills.

Amniotomy to induce labor.

Amniotomy to induce labor is used frequently. The potential risks compared with potential benefits of artificial rupture of membranes have caused the popularity of amniotomy to vary in the last two centuries. Although there are little data available from prospective randomized studies regarding the effectiveness of amniotomy alone to induce labor, several series have showed success in its use. In addition, no well-accepted, prospectively randomized study is available comparing the effectiveness of amniotomy to oxytocin for induction of labor. The most effective combination of amniotomy with uterotonic agents to induce labor is still a fertile area for investigation.