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.

In vitro reversal of the fasting state of liver metabolism in the rat. Reevaluation of the roles of insulin and glucose.

Studies were conducted to determine whether the direction of hepatic carbohydrate and lipid metabolism in the rat could be switched simultaneously from a "fasted" to a "fed" profile in vitro. When incubated for 2 h under appropriate conditions hepatocytes from fasted animals could be induced to synthesize glycogen at in vivo rates. There was concomitant marked elevation of the tissue malonyl-coenzyme A level, acceleration of fatty acid synthesis, and suppression of fatty acid oxidation and ketogenesis. In agreement with reports from some laboratories, but contrary to popular belief, glucose was not taken up efficiently by the cells and was thus a poor substrate for eigher glycogen synthesis or lipogenesis. The best precursor for glycogen formation was fructose, whereas lactate (pyruvate) was most efficient in lipogenesis. In both case the addition of glucose to the gluconeogenic substrates was stimulatory, the highest rates being obtained with the further inclusion of glutamine. Insulin was neither necessary for, nor did it stimulate, glycogen deposition or fatty acid synthesis under favorable substrate conditions. Glucagon at physiological concentrations inhibited both glycogen formation and fatty acid synthesis. Insulin readily reversed the effects of glucagon in the submaximal range of its concentration curve. The following conclusions were drawn. First, the fasted-to-fed transition of hepatic carbohydrate and lipid metabolism can be accomplished in vitro over a time frame similar to that operative in vivo. Second, reversal appears to be a substrate-driven phenomenon, in that insulin is not required. Third, unless an unidentified factor (present in protal blood during feeding) facilitates the uptake of glucose by liver it seems unlikely that glucose is the immediate precursor for liver glycogen or fat synthesis in vivo. A likely candidate for the primary substrate in both processes is lactate, which is rapidly formed from glucose by the small intestine and peripheral tissues. Fructose and amino acids may also contribute. Fourth, the requirement for insulin in the reversal of the fasting state of liver metabolism in vivo can best be explained by its ability to offset the catabolic actions of glucagon.

Inhibition of intestinal carcinogenesis in rats: effect of difluoromethylornithine with piroxicam or fish oil.

An inhibitor of ornithine decarboxylase, difluoromethylornithine (DFMO), and two inhibitors of prostaglandin biosynthesis, piroxicam and menhaden fish oil, were examined for their effect on intestinal tumorigenesis in male Sprague-Dawley rats fed a 5% fat semisynthetic diet. Each agent was given individually in one of two doses as follows: DFMO, 0.05% and 0.1% in the drinking water; piroxicam, 65 mg/kg diet and 130 mg/kg diet; and menhaden fish oil, 1.25% and 2.50% of the diet. Additional animal groups were given combinations of the lower dose of DFMO and the lower dose of either piroxicam or fish oil. Intestinal tumors were induced by sc injections of azoxymethane (AOM; CAS: 25843-45-2) at 8 mg/kg (body wt) weekly for 8 weeks. Test diets were started 1 week prior to the first dose of AOM, and the rats were sacrificed 26 weeks later. Rats that received either dose of DFMO or the high dose of piroxicam developed significantly fewer intestinal tumors compared to controls. The low dose of piroxicam and the fish oil given at either dose level had no effect. The combination of the low dose of DFMO and the low dose of piroxicam reduced tumor formation more than either dose of DFMO alone, whereas the low dose of DFMO and fish oil together was no more effective than either dose of DFMO alone. These results show that a combination of a small amount of DFMO and piroxicam, each acting through a different mechanism, exerts an additive inhibitory effect on intestinal tumor formation in rats.

Importance of the duration of inhibition on intestinal carcinogenesis by difluoromethylornithine in rats.

The effect of the duration and sequence of inhibition of intestinal tumor formation in rats was studied to determine whether part time inhibition has any value. Four groups of male Sprague-Dawley rats were given 8 weekly s.c. injections of azoxymethane (AOM) 8 mg/rat. Three groups were given the inhibitor, difluoromethylornithine (DFMO) in the drinking water; one for the entire 26 weeks of the study, one for the first 13 weeks only, and one for the last 13 weeks. A control group was not given the inhibitor. While the continuous treatment group developed the least number of tumors per rat (1.5 vs. 5 for controls), still both groups given the inhibitor for just 13 weeks also developed fewer tumors than controls 5 vs. 3.2 (early treatment) and 5 vs. 2.8 (late treatment). These results show that part time inhibition, including its late application, does reduce intestinal tumor formation in rats.

Fetal macrosomia: prediction, risks, proposed management.

The outcome of delivery of infants weighing more than 4000 g born during two time periods 15 years apart was studied retrospectively. The increased use of cesarean section and other obstetric advances did not reduce the risk of fetal asphyxia and trauma associated with large fetal size. Maternal factors were identified for risk categorization of fetal macrosomia during pregnancy. Macrosomia was rare at 37 weeks and increasingly common thereafter. Fetal size assessment by ultrasound at 36 to 38 weeks' gestation would permit induction of labor for the macrosomic infant before the size became excessive or would make the accoucheur aware of the dangers that may arise during delivery.

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 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.

Failed forceps.

Among 53 cases of failed forceps occurring in 6524 uncomplicated primiparous deliveries, depression at birth and encephalopathy occurred with similar frequency as when cesarean section was done for failure to progress in the second stage, and birth trauma was no more common than that with successful midforceps delivery. Factors predisposing to or associated with midforceps deliveries or second stage cesarean sections were short mothers, heavy babies, induced or prolonged labors, and fetal distress or meconium release in labor.

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.

Prolonged amenorrhea and oral contraceptives.

Of 106 consecutive women referred for secondary amenorrhea of more than 1 year's duration, 65 were diagnosed as having functional amenorrhea. Of these 65, 29 had amenorrhea directly following discontinuation of oral contraceptives (OC group) and 36 had never used oral contraceptives (NOC group). There was no difference in the incidence of prior menstrual irregularity in either group. Similarly, there was no difference in the resting serum estrone, estradiol, luteinizing hormone, follicle-stimulating hormone, and prolactin levels between the OC and NOC groups. Nor was there a difference between the OC and NOC groups in response to medroxyprogesterone acetate, clomiphene citrate, or luteinizing hormone-releasing factor. Of 106 patients, 17 were proven to have prolactinomas. Eight patients had a prior history of OC use, whereas nine did not. With the exception of elevated serum prolactin levels, there were no significant differences in biochemical tests or history of oral contraceptive use between the prolactinoma group and patients with prolonged "functional" amenorrhea (OC plus NOC groups). The lack of historical or biochemical difference between the OC and NOC subjects indicates homogeneity between groups, and does not support the existence of a "postpill" syndrome.

PIP: 65 of 106 consecutive women referred for secondary amenorrhea of more than 1 year's duration were diagnosed as having functional amenorrhea. 29 of the 65 women had amenorrhea directly following discontinuation of oral contraceptives (OC group) and 36 had never used OCs (NOC group). There was no difference in the incidence of prior menstrual irregularity in either group, and there was no difference in the resting serum estrone, estradiol, luteinizing hormone, follicle-stimulating hormone, and prolactin levels between the 2 groups. There was no difference between the groups in response to medroxyprogesterone acetate, clomiphene citrate, or luteinizing hormone-releasing factor. 17 of the 106 patients were proven to have prolactinomas; 8 of these had a prior history of OC use and 9 did not. Except for elevated serum prolactin levels, there was no significant differences in biochemical tests or history of OC use between the prolactinoma group and patients with prolonged "functional" amenorrhea (OC plus NOC groups). The lack of historical or biochemical difference between the OC and NOC subjects suggests homogeneity between groups and fails to support the existence of a "postpill" syndrome.

Reproductive performance of postpartum beef cows after short-term calf separation and dietary energy and protein supplementation.

Beef cows (n = 294) calving between November and April in six states were used to evaluate the effects of postpartum diet and calf separation on body weight, body condition score (BCS), reproductive performance, and weaning weight of calves. In each state, half of the 48 cows that calved during 60 d were group fed an additional 4.5 kg of a 20% crude protein supplement daily for 28 d starting an average of 30 d post partum (flush). Calves were separated from half of the flush and half of the nonflush cows for 48 h at 14 and 28 d after the beginning of flush. Progesterone was quantified in plasma samples obtained weekly during a 56-d breeding period to assess ovarian luteal activity. The breeding period started at the first calf separation. BCS ranged from 3.3 to 5.6 among states (on a scale of 1 to 9) at the start of the flush but was similar for treatments within a state. There was a state x flush (P < 0.008) effect on body weight at the end of the flush period. Weaning weights were influenced by state x separation x flush (P < 0.06) and were greatest for flush nonseparated calves in five of six states. There were state x flush (P < 0.08) and separation (P < 0.04) effects on ovarian luteal activity at the start of the breeding period. Flush and separation tended to increase ovarian luteal activity. During the breeding period, ovarian luteal activity was influenced only by state but there was a state x separation x flush effect (P < 0.001) on the number of weeks post partum to onset of ovarian luteal activity. Conception rate and days postpartum to conception were not influenced by either separation or flush but were affected by state (P < 0.001). These data indicate that flushing may increase weaning weights of calves and calf separation may hasten the onset of postpartum ovarian luteal activity, but conception rate and days postpartum to conception for cows in thin to moderate body condition were not influenced by the calf separation or flushing treatments.

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.

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.

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.

Myomectomy.

If fibroids require treatment, hysterectomy is usually the therapy of choice. Myomectomy is best reserved for women who wish to preserve their uterus and have a single large fibroid tumour; it is not normally recommended for either abnormal uterine bleeding or infertility. The blood supply of leiomyomas is from the periphery and is such that degeneration frequently ensues. Degeneration, in particular the acute degeneration that may occur in pregnancy, is rarely an indication for operation. Myomectomy has been associated with considerable blood loss intraoperatively and prolonged morbidity postoperatively. The former can be avoided by limiting the uterine circulation during surgery with a uterine tourniquet and vascular clamps. Atraumatic intracapsular removal of the tumour and perfect hemostasis will minimize the latter.

Dysfunctional uterine bleeding.

Dysfunctional uterine bleeding is defined as abnormal uterine bleeding in the absence of organic disease. It is the result of anovulation or the abnormal local production of prostaglandins, and in each case the primary fault is inappropriate hormone formation. There are two approaches to diagnosis. The traditional one is primarily concerned with the exclusion of cancer of the endometrium; this concern results in the frequent resort to uterine curettage. The second approach is to limit curettage to patients whose symptoms are not ameliorated by medical therapy. The aim of medical treatment is either to produce secretory change in the endometrium or to decrease the formation of uterine prostaglandins. Intermittent progesterone treatment is used to cause secretory changes in the endometrium. Decreased production of the prostaglandins is achieved indirectly by causing atrophy of the endometrium or directly through the use of prostaglandin synthetase inhibitors. Surgery in the form of dilatation and curettage has no long-term therapeutic effect; hysterectomy is definitive therapy.

PIP: Dysfunctional uterine bleeding is defined as abnormal uterine bleeding in the absence of organic disease. It is the result of anovulation or the abnormal local production of prostaglandins (PGs), and in each case, the primary fault is inappropriate hormone formation. There are 2 approaches to diagnosis. The traditional one is primarily concerned with the exclusion of cancer of the endometrium; this concern results in the frequent resort to uterine curettage. The 2nd approach is to limit curettage to patients whose symptoms are not ameliorated by medical therapy. The aim of the medical treatment is either to produce secretory change in the endometrium or to decrease the formation of uterine PGs. Intermittent progesterone treatment is used to cause secretory changes in the endometrium. Decreased production of the PGs is achieved indirectly by causing strophy of the endometrium or directly through the use of PG synthetase inhibitors. Surgery in the form of dilatation and curettage has no longterm therapeutic effect; hysterectomy is definitive therapy. (author's)

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.

Pelvic inflammatory disease and the general surgeon.

New causal agents of pelvic inflammatory disease that have recently been determined are Chlamydia trachomatis, anaerobic bacteria and penicillinase-producing gonococci. It is also recognized that the pelvic infection is normally polybacterial. The symptoms produced by these organisms are so indefinite that diagnosis based on clinical findings alone is often difficult. The diagnosis of pelvic inflammatory disease should therefore be established by laparoscopy in these cases. Antibiotics capable of eradicating most pelvic infections are now available. As a result of their use, the primary therapy has become medical. The indication for surgery is, in essence, failed medical therapy. Ablative surgery should generally be delayed until adequate antibiotic therapy has been tried and found inadequate. Furthermore, the surgery should be conservative because the disease is often unilateral. Total abdominal hysterectomy and bilateral salpingo-oophorectomy as a treatment for pelvic inflammatory disease should be the exception rather than the rule.

Ovarian cancer.

The behaviour of epithelial cancer of the ovary differs from that of other epithelial tumours that the general surgeon normally contends with for the following reasons: first, it often responds well to incomplete surgery as it is frequently sensitive to chemotherapy and, second, its method of spread is unique. Proper treatment of this lesion must take these characteristics into account. Immediate therapy is excision of the tumour mass and its principal metastases. This normally includes removing the uterus and its adnexae plus the omentum. Only when the remaining tumour masses are small will postoperative chemotherapy be effective. Moreover, the chemotherapy can only be given rationally if the extent of dissemination of the disease is carefully defined. The spread of this malignant tumour is most often by way of free-floating cells in the peritoneal cavity. The tumour cells subsequently deposit in "watersheds" throughout the peritoneal cavity and accumulate on the undersurface of the diaphragm and in the omentum. Staging, which describes this process and its variations, is therefore of great importance and is described in this paper in detail.