Commentary on "DNA damage response and repair gene alterations are associated with improved survival in patients with platinum-treated advanced urothelial carcinoma."

PURPOSE: Platinum-based chemotherapy remains the standard treatment for advanced urothelial carcinoma by inducing DNA damage. We hypothesize that somatic alterations in DNA damage response and repair (DDR) genes are associated with improved sensitivity to platinum-based chemotherapy. EXPERIMENTAL DESIGN: Patients with diagnosis of locally advanced and metastatic urothelial carcinoma treated with platinum-based chemotherapy who had exon sequencing with the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay were identified. Patients were dichotomized based on the presence/absence of alterations in a panel of 34 DDR genes. DDR alteration status was correlated with clinical outcomes and disease features. RESULTS: One hundred patients were identified, of which 47 harbored alterations in DDR genes. Patients with DDR alterations had improved progression-free survival (9.3 vs. 6.0 months, log-rank P = 0.007) and overall survival (23.7 vs. 13.0 months, log-rank P = 0.006). DDR alterations were also associated with higher number mutations and copy-number alterations. A trend toward positive correlation between DDR status and nodal metastases and inverse correlation with visceral metastases were observed. Different DDR pathways also suggested variable effect on clinical outcomes. CONCLUSIONS: Somatic DDR alteration is associated with improved clinical outcomes in platinum-treated patients with advanced urothelial carcinoma. Once validated, it can improve patient selection for clinical practice and future study enrollment.

Evaluation of age of dam effects on maternal performance of multilactation daughters from high- and low-milk EPD sires at three locations in the southern United States.

Angus bulls (n = 16) selected for either high- or low-milk EPD but similar growth EPD were mated within location at random to Angus cows. Daughters were bred to calve at 2 yr of age and annually until 6 yr of age. Milk yield was measured four times during lactation with a portable milking machine to estimate 12-h milk yield. Milk was collected for analysis of the percentage of fat and protein. A mixed model procedure was used to analyze the weaning weight, milk yield, and milk component data. The model for weaning weight included location, genetic line of sire, gender of calf, and age of dam. Calf age at weaning was used as a covariate. The model for the milk yield and components included location, genetic line of sire, gender of calf, period, and age of dam. Random effects for all models included sire of dam nested within line, sire of calf, and year. Genetic line was a significant source of variation for milk yield (P < 0.01) and weaning weight (P < 0.01) but not for percentage of fat or protein. Location was significant for milk yield (P < 0.01), fat (P < 0.01), protein (P < 0.01), and weaning weight (P < 0.01). The interaction of line with location was not significant except for percentage of protein (P < 0.01). Age of dam was significant for milk yield (P < 0.01), weaning weight (P < 0.01), and percentage of protein (P < 0.01), but not for percentage of fat (P = 0.29). Line difference for mean weaning weight was 18.1 kg, which is similar to the difference between lines for milk EPD (19 kg). Weaning weights from high-milk EPD line daughters were heavier (P < 0.01) than low-milk EPD line daughters at each age of dam evaluated. Cows nursed by males had higher milk yields (4.33 kg/12 h) than cows nursed by heifers (4.0 kg/12 h). The difference in yields for gender was significant for 2-, 3-, and 5-yr-old cows, but not for 4- (P < 0.052) and 6-yr old (P < 0.15) cows. Correlation coefficients between weaning weight and weaning EPD, milk EPD, and total maternal EPD were greater than zero (P < 0.01) (0.76, 0.65, and 0.89, respectively). Daughters of sires with high-milk EPD produced more milk at each age and weaned heavier calves than daughters of sires with low-milk EPD. These results confirm the value of milk EPD for improvement of weaning weights in beef cattle and also validate age of dam effects on milk yield and the associated effects on weaning weights.

Evaluation of maternal performance of daughters from high and low milk EPD sires.

Angus bulls (n = 24) were selected for either high or low milk EPD, but with similar growth EPD and mated within location (n = 6) at random to Angus cows. Daughters from these matings were bred to calve first at 2 yr of age to common reference sires across locations. Lactation records for 192 daughters were used to evaluate 12-h milk yield, percentage of milk fat and protein, and weaning weight of offspring. Milk production was measured four times during the lactation at regular intervals within location. Dams were separated from their calves the night before milking and milked with a portable milking machine the next morning to estimate 12-h milk yield. A sample of the milk was collected from each cow and analyzed for percentages of milk fat and protein. Data were analyzed as repeated records of the dam. Fixed effects were location, genetic line of sire, gender of calf within location, and milking period, with postpartum interval used as a covariate. Fixed effects and the random effects of sire of dam nested within line, sire of calf, and year were estimated by REML. Genetic line was an important source of variation for milk yield (P < 0.01) and percentage of milk fat (P = 0.03) but not for percentage of milk protein (P = 0.49). Location was significant for all three milk variables (P < 0.01), but the interactions between line and location were not significant. Gender of calf was significant for milk yield (P = 0.04) but not for percentage of milk fat or protein. Line (P = 0.02), location (P = 0.01), calf gender (P = 0.01), and age at weaning (P = 0.01) were significant sources of variation for weaning weight but the interaction of line and location was not (P = 0.69). The correlation coefficient between the sire's milk EPD and 12-h milk yield was significantly different from zero (r = 0.56). The difference between the least squares means for high and low lines for milk yield was 0.66 kg/12 h and the difference was 15.3 kg for weaning weight. The results indicate that there was not evidence for a genotype by environment interaction in milk production for daughters from divergent sires selected for high or low milk EPD.

Obstetric admissions to the intensive care unit.

OBJECTIVE: To determine whether obstetric admissions to the intensive care unit (ICU) are useful quality-assurance indicators. METHODS: We analyzed retrospectively obstetric ICU admissions at two tertiary care centers from 1991 to 1997. RESULTS: The 131 obstetric admissions represented 0.3% of all deliveries. The majority (78%) of women were admitted to the ICU postpartum. Obstetric hemorrhage (26%) and hypertension (21%) were the two most common reasons for admission. Together with cardiac disease, respiratory disorders, and infection, they accounted for more than 80% of all admissions. Preexisting medical conditions were present in 38% of all admissions. The median Acute Physiology and Chronic Health Evaluation II score was 8.5. The predicted mortality rate for the group was 10.0%, and the actual mortality rate was 2.3%. CONCLUSION: The most common precipitants of ICU admission were obstetric hemorrhage and uncontrolled hypertension. Improved management strategies for these problems may significantly reduce major maternal morbidity.

The risks and benefits of hormone replacement therapy.

The short-term benefits of hormone replacement therapy (HRT) for the relief of acute menopausal symptoms are beyond dispute. It is equally clear that premenopausal women who have undergone surgical menopause need HRT to prevent the otherwise rapid development of coronary heart disease and osteoporosis. There is epidemiologic evidence that women who have undergone a natural menopause receive similar relief with HRT. Yet patient compliance with long-term HRT is poor. This is due to unacceptable uterine bleeding and the largely unfounded fear that HRT promotes breast cancer.

Influence of calf genotype on colostral immunoglobulins in Bos taurus and Bos indicus cows and serum immunoglobulins in their calves.

Purebred Bos indicus calves are documented to have lower survival rates than Bos taurus calves. Thus, this study was designed to investigate the possibility that this decreased survival rate may be attributed to dam colostral immunoglobulin (Ig) concentrations and subsequent calf serum Ig concentrations. The specific objective was to determine the effect of breed type of calf on colostrum production, immunoglobulin concentrations in colostrum and calf serum, and availability and absorption efficiency of Ig. Brahman (B) and Angus (A) cattle were reciprocally mated to produce calves of the following types: A x A (n = 8), A x B (n = 9), B x B (n = 11), and B x A (n = 11). At birth, calves were separated from their dams and a blood sample was collected before feeding pooled colostrum (30 mL/kg birth weight) at 1 and 6 h of age. From 6 to 12 h of age, each calf was placed in a box that allowed interaction with the dam but prevented suckling. At 12 h of age, each calf was fed its dam's colostrum and placed with the dam. Additional blood samples were collected at 12, 24, and 48 h after birth. Serum and colostrum samples were analyzed for IgG, IgG1, IgG2, IgM, and IgA using single radial immunodiffusion (RID) assay techniques. The cows were hand-milked after induction of milk letdown with oxytocin at 1 and 12 h after calving. Colostrum volume was recorded, and samples were collected. Brahman cows produced more (P < .001) colostrum at 1 and 12 h than A cows. Total Ig concentrations were obtained by summing IgG, IgG1, IgG2, IgM, and IgA concentrations. Total Ig (P < .02), IgG (P < .005), and IgA (P < .01) concentrations in colostrum were greater in cows producing crossbred calves. Total Ig (P < .006), IgG (P < .02), IgG1 (P < .004), and IgG2 (P < .02) available in colostrum were affected by B x B and A x B breed types of calf. Brahman cows had more Ig available at 1 and 12 h than A cows due to increased production of colostrum. Breed type influenced colostral Ig in cattle. Serum concentrations of total Ig, IgG, IgG1, IgG2, IgM, and IgA in the calf and efficiency of absorption at 6 and 12 h were not affected by breed type, sex of calf, or any interaction.

Comparison of transdermal and oral sequential gestagen in combination with transdermal estradiol: effects on bleeding patterns and endometrial histology.

OBJECTIVE: To assess prospectively the effect on bleeding patterns, transformation of the endometrium, and rate of endometrial hyperplasia of transdermal norethisterone acetate when administered sequentially in combination with transdermal estradiol (E2), and to compare it to a regimen using oral medroxyprogesterone acetate. METHODS: Two hundred eighteen women were randomized to receive either transdermal E2 0.05 mg/day for 14 days followed by transdermal E2 0.05 mg/day plus transdermal norethisterone acetate 0.25 mg/day for 14 days, or transdermal E2 0.05 mg/day for 25 days with the addition of oral medroxyprogesterone acetate 10 mg/day on days 16-25, followed by a 3-day treatment-free period. Treatment was planned for 13 cycles of 28 days. The subjects kept daily bleeding diaries, and endometrial biopsies were taken before and at the end of treatment. RESULTS: The mean duration of bleeding (regular) induced by the gestagen was 7.33 days in the transdermal gestagen-treated group, which was 1.54 days longer than in the oral gestagen-treated group (P = .0001). The mean cycle day of onset was 25.74. Bleeding was spotting or light in the transdermal group in 77% of the days in which bleeding occurred. When comparing the two groups, there were no differences in the overall mean cycle day of onset or in the intensity of gestagen-induced bleeding. Breakthrough (irregular) bleeding episodes occurred in 42% of the transdermal subjects, lasted a mean of 4.18 days, and were spotting or light in 87% of the days when they occurred. There were no differences between the treatment groups. There was only one case (1.3%) of confirmed simple hyperplasia and five cases of failure of gestagenic transformation of the endometrium in 77 women treated for a mean of 367 days with transdermal gestagen. CONCLUSION: A transdermal system delivering a combination of E2 and norethisterone acetate for 14 days in sequence with E2 delivered transdermally for 14 days produced bleeding patterns that are clinically acceptable and comparable to those produced by oral medroxyprogesterone acetate given in sequence with E2 delivered transdermally for 25 days. The use of the combination system was not associated with a significant risk of endometrial hyperplasia.

The morbidity of abdominal hysterectomy.

OBJECTIVE: To determine the morbidity of abdominal hysterectomy. DESIGN: Descriptive. Physician billings to the Quebec Health Care Plan in the 1-month period after abdominal hysterectomy were examined. SETTING: Operations performed in 102 hospitals in the Province of Quebec between Jan. 1, 1989, and Mar. 31, 1989, were selected. PATIENTS: The study group included 3322 patients who had abdominal hysterectomy. Patients who had vaginal or abdominal hysterectomy for invasive cancer or pregnancy-related complications were excluded. A patient was considered to be morbid if the physician's intervention indicated concern for the patient's well-being. MAIN OUTCOME MEASURES: Multiple logistic regression analysis to determine the adjusted rate ratio for inclusion in a categorical list of morbid patients among different subsets of surgeons, hospitals and patients. RESULTS: Postoperative morbidity occurred in 646 patients (19.5%), who spent an average of 1.7 days longer in the hospital than patients with no postoperative morbidity. There were two postoperative deaths (0.1%). Forty-nine patients (1.5%) had postoperative surgical intervention. On 119 occasions (3.6%), patients were treated in the intensive care unit. A consultation was given by a medical specialist in 303 cases (9.1%). The rate ratio for postoperative morbidity was not significantly affected by years in practice or specialty of the surgeon but was increased for operations performed in mid-sized hospitals. The strongest predictor of postoperative morbidity was pre-existing medical disorder (RR). CONCLUSION: The major causes of morbidity in patients who undergo abdominal hysterectomies are medical rather than surgical.

The changing pattern of fetal death, 1961-1988.

The aim of this study was to assess any changes in cause-specific fetal death rates in the nonreferred population of a tertiary care unit. The fetal death rate (per 1000 births) among 88,651 births diminished from 11.5 in the 1960s to 5.1 in the 1980s. Fetal death due to intrapartum asphyxia and Rh isoimmunization has almost disappeared. Toxemia and diabetes continue to make similar and small contributions to fetal death rates. There has been a significant decline in unexplained antepartum fetal deaths and in those caused by fetal growth retardation, but no significant change in the death rate due to intrauterine infection or abruptio placentae. During the 1960s, the risk of fetal death was increased in women with hypertension, diabetes, or a history of stillbirth; during the 1980s, only women with a history of insulin-dependent diabetes were at risk. Improved application of current knowledge may help decrease the fetal death rate caused by fetal growth retardation. Reduction in deaths due to abruptio placentae, intrauterine infections, or lethal malformations, as well as unexplained antepartum deaths, appears to depend on better understanding of the etiology of these disorders.

Postterm infants: too big or too small?

Concern over the postterm pregnancy has shifted from that of the difficult delivery of an excessively large fetus to the current concern with death in utero of an undernourished, small-for-date fetus. Studies of postterm pregnancy before the availability of ultrasonography may have included a large proportion of erroneous menstrual dates. The present study of 7000 infants was undertaken to reassess fetal growth in postterm pregnancies in which the expected date of confinement from last normal menstrual period dating was confirmed (+/- 7 days) by early ultrasonography. Results show a gradual shift toward higher birth weight and greater crown-heel length and head circumference between 273 and 300 days of gestational age. No evidence of postterm weight loss or lower weight for length could be demonstrated. Concern in postterm pregnancy should be for fetal macrosomia, not for intrauterine growth retardation.

Spontaneous abortion.

As a result of improved investigation and treatment techniques, understanding of all aspects of spontaneous abortion has improved. The term "threatened abortion" is often a misnomer, for the fate of the pregnancy is decided when bleeding occurs. A dilated cervix indicates that abortion is inevitable. If the cervix is not dilated, pelvic ultrasonography will usually show the following: a live fetus, an anembryonic pregnancy, incomplete abortion or missed abortion. If fetal heart movement is seen, no further treatment is needed and the prognosis is excellent (98% fetal survival). In other cases, the uterus must be evacuated, with a Karman catheter if the uterus is small, with a suction curette if the uterus is large. Forceful dilation of the cervix is avoided through the use of Laminaria.

Endometrial cancer.

Abdominal hysterectomy will cure cancer of the endometrium confined to the body of the uterus. If the tumour has spread beyond the uterus, adjuvant therapy will be needed. The likelihood of such spread can be predicted from postoperative histologic examination of the uterus or discovered by surgical staging. Surgical staging does not appear to be curative or to reduce the need for adjuvant therapy. Prognosis depends on the grade and location of the tumour in the uterus and the extent of invasion into the myometrium or beyond the uterus, and not on the removal of occult metastases.

Dilatation and curettage.

The most important role of dilatation and curettage is in the evacuation of retained products of conception; its diagnostic value is mostly limited to the detection of cancer of the endometrium. The procedure is associated with a number of complications, the majority of which occur during dilatation of the cervix. Vabra curettage is suggested as an alternative to diagnostic dilatation and curettage; it is efficient, is associated with fewer complications and is less expensive. Hysteroscopy is a useful supplement to Vabra curettage, especially in diagnosing focal lesions.

The validity of gestational age estimation by menstrual dating in term, preterm, and postterm gestations.

Despite recognition that estimation of gestational age (GA) based on maternal recollection of the last normal menstrual period (LNMP) is fraught with error, it is not generally appreciated that the magnitude and direction of this error vary as a function of the LNMP estimate. Early second-trimester (16 to 18 weeks) ultrasound determinations of the fetal biparietal diameter were used as the "gold standard" to test the validity of LNMP-based GA estimates in 11,045 women. The large majority of deliveries occurring at or near term showed LNMP estimates that were valid within plus or minus seven days of the ultrasound estimate. As the LNMP GA deviated progressively toward earlier or later GAs, however, the discrepancies became quite marked, especially for postterm dates. The positive predictive values of the LNMP GA estimates decreased dramatically from term (.949) to preterm (.775) to postterm (.119) deliveries. These systematic errors in menstrual GA estimates have profound implications for unnecessary induction, dysfunctional labor and cesarean section, and resultant neonatal and maternal morbidity.

Obstetric consequences of postmaturity.

The obstetric management of 340 pregnancies delivered 2 or more weeks postterm and 1408 pregnancies delivered at 41 weeks is compared with that of 5915 pregnancies delivered at 39 to 40 weeks. In all patients menstrual dating was confirmed by early ultrasonographic examination. Postterm labor in primiparas resulted in a high cesarean section rate because of failure to progress; this increased rate was observed even after controlling for induction of labor and the size of the infant. We suggest that primiparas who go postterm often have increased uterine dysfunction. Uterine dysfunction accounts for the increase in the cesarean section rate and is a partial explanation for "failed" inductions.

Assessment of fetal risk in postdate pregnancies.

To assess postdate fetal risk, pregnancies in which menstrual history was confirmed by early ultrasound examination were reviewed; 5915 pregnancies within 1 week of term, 1408 1 to 2 weeks postdate, and 340 at least 2 weeks postdate. Fetal distress and meconium release were twice as frequent and meconium aspiration eight times as frequent postterm. Birth asphyxia was unrelated to gestational age. Fractures and palsies were more frequent because of primiparity and macrosomia. Only one antepartum fetal death occurred in 1748 postdate pregnancies. Review of 674 perinatal deaths at 37 plus weeks in Quebec showed no increase in deaths postterm. The increase in fetal distress and meconium aspiration postterm without an increase in birth asphyxia or fetal death may reflect greater responsiveness of the more mature fetus to mild asphyxic insults. Findings of this study could not justify increased fetal monitoring in postdate pregnancies.

Cesarean section.

Cesarean section has become a common operation, but its complexity should not be underestimated. Often it must be done as an emergency without skilled assistants; at the same time the surgeon must deal with the maternal disorder that prompted the cesarean section and ensure the well-being of the fetus. Of further concern is the operative blood loss, which can be massive, and the postoperative morbidity, which is often high. The operative technique has evolved from an intraperitoneal vertical incision on the body of the uterus (classical cesarean section) to a near-complete reliance on a retroperitoneal transverse incision (lower segment cesarean section). The historic reason for this change was the fear of peritonitis postoperatively. Present-day practice favours the lower segment operation and emphasizes the reduced operative blood loss and the more secure uterine scar as reasons for the choice. Operative complications (injury to the fetus, lacerations of the uterus and vagina) are the result of inadequate uterine incisions. The classical incision has the advantage of being easily extended and thus has a continued purpose. Postoperative febrile morbidity is attributed to endometritis; the mixed aerobic and anaerobic bacteria of the vagina are the causal organisms. Febrile morbidity can be prevented by antibiotics given prophylactically.

Care of the ureter in pelvic surgery.

Maintaining the integrity of the ureter is crucial in pelvic surgery. The ureter is best safeguarded by routine intraoperative exposure, which will also allow immediate recognition of injury to it. If doubts over possible injury persist, it is best to open the bladder. The flux of urine from the ureteric orifices or the retrograde passage of catheters will then confirm or deny clinical suspicions. If specialist help is unavailable, the pelvic surgeon must be able to perform simple ureteric repairs or temporize in a way that allows the safe delay of definitive surgery. End-to-end ureteric anastomosis and ureteroneocystostomy are straight-forward procedures that all pelvic surgeons should be familiar with. If they cannot be performed safely, the situation may be salvaged by draining the proximal ureter through the lateral abdominal wall; later, definitive surgery can be performed.