Targeting the PD-1/PD-L1 axis for the treatment of non-small-cell lung cancer.

Lung cancer is the leading cause of cancer-specific death among Canadians, with non-small-cell lung cancer (nsclc) being the most common histologic variant. Despite advances in the understanding of the molecular biology of nsclc, the survival rate for this malignancy is still poor. It is now understood that, to evade detection and immune clearance, nsclc tumours overexpress the immunosuppressive checkpoint protein programmed death ligand 1 (PD-L1). Inhibiting the PD-1/PD-L1 axis with monoclonal antibodies has significantly changed the treatment landscape in nsclc during the last 5 years. Despite evidence of clinical response in some patients, only approximately 20% of patients obtain any durable benefit, and many of the patients who do respond ultimately relapse with drug-resistant disease. The identification of patients who are most likely to benefit from such therapy is therefore important. In the present review, we cover the basics of the PD-1/PD-L1 axis and its clinical significance in nsclc, biomarkers that are predictive of treatment response, relevant clinical trials of PD-1/PD-L1 blockade completed to date, and proposed mechanisms of acquired therapeutic resistance.

Reovirus as a successful ex vivo purging modality for multiple myeloma.

Autologous stem cell rescue (ASCT) following high-dose myeloablative chemotherapy is considered to be a therapeutic option for many multiple myeloma (MM) patients; however relapse post ASCT presents a major challenge. The oncolytic potential of reovirus has been previously demonstrated and is currently undergoing phase I monotherapy clinical trials for MM and phase II/III clinical trials for solid tumors. Here we tested the hypothesis that reovirus can successfully purge MM in a murine model that partially recapitulates human MM. RPMI 8226, MM1S, H929 and U266 human myeloma cell lines were exposed to reovirus and oncolysis was assessed. Apheresis product admixed with MM cells was purged with live reovirus (LV) or dead virus (DV) and purging efficacy was monitored via flow cytometry, reverse transcribed-PCR (RT-PCR) and disease relapse in non obese diabetic/severe combined immune deficient (NOD/SCID) mice. Significant LV purging was seen with MM1S, H929 and U266 and the complete ex vivo purging achieved with RPMI 8226 was confirmed by flow cytometry, RT-PCR and absence of disease relapse in vivo. Mice that received LV-purged autografts exhibited 100% survival in comparison to mice that received DV-purged controls. Reovirus's unique ability to kill MM while sparing hematopoietic stem cells places it as an attractive purging agent for MM during ASCT.

Embryo death in cattle: an update.

For heifers, beef and moderate-yielding dairy cows, fertilisation generally exceeds 90%. In high-producing dairy cows, it may be lower and possibly more variable. The major component of embryo loss occurs before Day 16 following breeding, with emerging evidence of greater losses before Day 8 in high-producing dairy cows. Late embryo loss causes serious economic losses because it is often recognised too late to rebreed females. Systemic concentrations of progesterone during the cycles both preceding and following insemination affect embryo survival; too-high or too-low a concentration has been shown to be negatively associated with survival rate. Energy balance and dry matter intake during the 4 weeks after calving are critically important in determining conception rate when cows are inseminated 70 to 100 days after calving. More balanced breeding strategies with greater emphasis on fertility, feed intake and energy must be developed. Genetic variability for fertility traits can be exploited; genomic technology will not only provide scientists with an improved understanding of the underlying biological processes involved in fertilisation and the establishment of pregnancy, but could identify genes responsible for improved embryo survival. Their incorporation into breeding objectives would increase the rate of genetic progress for embryo survival. There is a range of easily adoptable management factors, under producer control, that can either directly increase embryo survival or ameliorate the consequences of low embryo survival rates. The correction of minor deficits in several areas can have a substantial overall effect on herd reproductive performance.

Negative energy balance and hepatic gene expression patterns in high-yielding dairy cows during the early postpartum period: a global approach.

In high-yielding dairy cows the liver undergoes extensive physiological and biochemical changes during the early postpartum period in an effort to re-establish metabolic homeostasis and to counteract the adverse effects of negative energy balance (NEB). These adaptations are likely to be mediated by significant alterations in hepatic gene expression. To gain new insights into these events an energy balance model was created using differential feeding and milking regimes to produce two groups of cows with either a mild (MNEB) or severe NEB (SNEB) status. Cows were slaughtered and liver tissues collected on days 6-7 of the first follicular wave postpartum. Using an Affymetrix 23k oligonucleotide bovine array to determine global gene expression in hepatic tissue of these cows, we found a total of 416 genes (189 up- and 227 downregulated) to be altered by SNEB. Network analysis using Ingenuity Pathway Analysis revealed that SNEB was associated with widespread changes in gene expression classified into 36 gene networks including those associated with lipid metabolism, connective tissue development and function, cell signaling, cell cycle, and metabolic diseases, the three most significant of which are discussed in detail. SNEB cows displayed reduced expression of transcription activators and signal transducers that regulate the expression of genes and gene networks associated with cell signaling and tissue repair. These alterations are linked with increased expression of abnormal cell cycle and cellular proliferation associated pathways. This study provides new information and insights on the effect of SNEB on gene expression in high-yielding Holstein Friesian dairy cows in the early postpartum period.

Effects of changes in the concentration of systemic progesterone on ions, amino acids and energy substrates in cattle oviduct and uterine fluid and blood.

Early embryo loss is a major factor affecting the conception rate in cattle. Up to 40% of cattle embryos die within 3 weeks of fertilisation while they are nutritionally dependent on oviduct and uterine fluids for their survival. Inadequate systemic progesterone is one of the factors contributing to this loss. We have characterised the effects of changes in systemic progesterone on amino acid, ion and energy substrate composition of oviduct and uterine fluids on Days 3 and 6, respectively, of the oestrus cycle in cattle. Oviduct and uterine fluids were collected in situ following infusion of progesterone. There was no effect of progesterone on oviduct fluid secretion rate; however, uterine fluid secretion rate was lowered. Progesterone increased uterine glucose, decreased oviduct sulfate and, to a lesser degree, oviduct sodium, but had no effect on any of the ions in the uterus. The most marked effect of progesterone was on oviducal amino acid concentrations, with a twofold increase in glycine, whereas in the uterus only valine was increased. These results provide novel information on the maternal environment of the early cattle embryo and provide further evidence of progesterone regulation of oviduct amino acid concentrations in cattle.

Differences in the expression of genes involved in the somatotropic axis in divergent strains of Holstein-Friesian dairy cows during early and mid lactation.

Differences in genetic selection criteria for dairy cows internationally have led to divergence in the Holstein-Friesian breed. The objective of this study was to compare hepatic expression of genes of the somatotropic axis in the North American Holstein-Friesian and the New Zealand Holstein-Friesian strains of dairy cow at early and mid lactation. Mature cows of both the North American Holstein-Friesian (n = 10) and New Zealand Holstein-Friesian (n = 10) strains were selected. Liver tissue was collected by percutaneous punch biopsy from all cows at 35 and 140 d postpartum, representing early and mid lactation, respectively. Total RNA was extracted and the hepatic expression of genes involved in the control of the somatotropic axis was examined. Abundance of insulin-like growth factor (IGF)-1 mRNA was greater in the New Zealand strain, concomitant with a tendency for increased expression of acid-labile subunit mRNA. Across strains, mRNA abundance of IGF-binding protein-1, IGF-binding protein-2, and growth hormone receptor 1A decreased from d 35 to 140 postpartum, whereas expression of IGF-1 and acid-labile subunit tended to increase. Abundance of suppressor of cytokine signaling-3 mRNA was increased at d 140 postpartum. Both the strain of Holstein-Friesian cow and the stage of lactation influenced expression of genes controlling the somatotropic axis in hepatic tissue.

Pleiotropic effects of negative energy balance in the postpartum dairy cow on splenic gene expression: repercussions for innate and adaptive immunity.

Increased energy demands to support lactation, coupled with lowered feed intake capacity results in negative energy balance (NEB) and is typically characterized by extensive mobilization of body energy reserves in the early postpartum dairy cow. The catabolism of stored lipid leads to an increase in the systemic concentrations of nonesterified fatty acids (NEFA) and beta-hydroxy butyrate (BHB). Oxidation of NEFA in the liver result in the increased production of reactive oxygen species and the onset of oxidative stress and can lead to disruption of normal metabolism and physiology. The immune system is depressed in the peripartum period and early lactation and dairy cows are therefore more vulnerable to bacterial infections causing mastitis and or endometritis at this time. A bovine Affymetrix oligonucleotide array was used to determine global gene expression in the spleen of dairy cows in the early postpartum period. Spleen tissue was removed post mortem from five severe NEB (SNEB) and five medium NEB (MNEB) cows 15 days postpartum. SNEB increased systemic concentrations of NEFA and BHB, and white blood cell and lymphocyte numbers were decreased in SNEB animals. A total of 545 genes were altered by SNEB. Network analysis using Ingenuity Pathway Analysis revealed that SNEB was associated with NRF2-mediated oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, natural killer cell signaling, p53 signaling, downregulation of IL-15, BCL-2, and IFN-gamma; upregulation of BAX and CHOP and increased apoptosis with a potential negative impact on innate and adaptive immunity.

Granulomatous bronchiolitis of Crohn's disease successfully treated with inhaled budesonide.

A 39-year-old white woman with longstanding Crohn's disease presented with the rare complication of granulomatous bronchiolitis. Rapid resolution after inhaled budesonide is highlighted, as this is the first case described in the literature successfully treated without the need for systemic therapy. This less toxic approach to therapy is warranted in granulomatous bronchiolitis of Crohn's disease to avoid unwanted side effects of steroids and infliximab.

Embryonic and early foetal losses in cattle and other ruminants.

Embryo survival is a major factor affecting production and economic efficiency in all systems of ruminant milk and meat production. For heifers, beef and moderate yielding dairy cows, does and camelids it appears that fertilization generally lies between 90% and 100%. In high-producing dairy cows there is a less substantive body of literature, but it would appear that it is somewhat lower and perhaps more variable. In cattle, the major component of embryo loss occurs before day 16 following breeding with some evidence of greater losses before day 8 in high-producing dairy cows. In cattle late embryo loss, while numerically much smaller than early embryo mortality loss, nevertheless, causes serious economic losses to producers because it is often too late to rebreed females when they repeat. In multiple ovulating small ruminants, the loss rate is positively related to ovulation rate. Systemic concentrations of progesterone, during both the cycle preceding and following insemination, affect embryo survival rate with evidence that too high or indeed too low a concentration being negatively associated with survival rate. Uterine expression of mRNA for progesterone receptor, oestradiol receptor and retinol-binding protein appears to be sensitive to changes in peripheral concentrations of progesterone during the first week after artificial insemination. Energy balance and dry matter intake during 4 weeks after calving are critically important in determining conception rate when cows are inseminated at 70-100 days post-calving. Concentrate supplementation of cows at pasture during the breeding period has minimal effects on conception rates though sudden reductions in dietary intake should be avoided. For all systems of milk production, more balanced breeding strategies with greater emphasis on fertility and feed intake and/or energy balance must be developed. There is sufficient genetic variability within the Holstein breed for fertility traits. Alternative dairy breeds such as the Jersey or Norwegian Red could also be utilized. Genomic technology will not only provide scientists with an improved understanding of the underlying biological processes involved in fertilization and the establishment of pregnancy, but also, in the future, identify genes responsible for improved embryo survival. Its incorporation into breeding objectives would increase the rate of genetic progress for embryo survival.

Energy substrates in bovine oviduct and uterine fluid and blood plasma during the oestrous cycle.

Up to 40 percent of cattle embryos die within 3 weeks of fertilization but there is little or no published information on the composition of the oviduct and uterine fluids essential for their survival during this time. We have measured the concentrations of the energy substrates, glucose, lactate, and pyruvate in cattle oviduct fluid on Days 0, 2, 4, and 6 and uterine fluid on Days 6, 8, and 14 of the oestrous cycle and corresponding blood samples. Oviduct and uterine fluids were collected in situ. Glucose concentrations in oviduct and uterine fluids were similar on all days and lower than in plasma (P < 0.05). Oviduct lactate concentration was up to eightfold higher than uterine or plasma concentration (P < 0.01). Oviduct pyruvate concentrations were similar on all days and lower than plasma concentrations on Days 0 and 2 (P < 0.005). Pyruvate concentrations were similar in the uterus and in plasma except on Day 14 when the concentration in plasma was higher (P < 0.05). There were no associations between systemic progesterone or oestradiol and glucose, lactate or pyruvate. There was a linear positive relationship (P < 0.001) between oviduct fluid secretion rate and oviduct glucose concentration and a linear negative relationship (P < 0.001) between oviduct fluid secretion rate and oviduct lactate, but no association between uterine fluid secretion rate and energy substrates. The different concentrations and associations between the energy substrates in oviduct and uterine fluids and blood plasma indicate a differential regulation of the secretion of these energy substrates by the oviduct and uterine epithelium.

Ion concentrations in oviduct and uterine fluid and blood serum during the estrous cycle in the bovine.

In the bovine up to 40% of embryos die before implantation but despite the importance of ions in oviduct and uterine fluid formation and in gamete, zygote and early embryo development there is very little published information on the ion concentrations of oviduct or uterine fluid. The free anions chloride, phosphate and sulphate and the free cations sodium, calcium, magnesium and potassium were measured in oviduct fluid on days 0, 2, 4 and 6 and in uterine fluid on days 6, 8 and 14 and in corresponding blood samples. Oviduct and uterine fluids were collected in situ. Sodium was 25-fold higher than potassium and 80-fold higher than the other ions and chloride was 10-fold higher than potassium and 40-fold higher than the other ions in oviduct and uterine fluid. Phosphate, sulphate, magnesium, potassium and calcium were at lower concentrations in all fluids. Oviduct calcium and sodium were higher on day 0 than other days. The most striking uterine differences were the higher potassium and lower chloride, sodium and magnesium on day 14 than other days. There were significant positive associations between oviduct and blood chloride, sulphate, magnesium and calcium while only uterine sulphate was positively related to its blood concentration. There was no relationship between fluid secretion rate and no association between the concentrations of systemic progesterone or oestradiol and any ion in oviduct or uterine fluid. The different concentrations and associations between ions in the oviduct, uterus and blood suggest a differential regulation of ion secretion by the oviduct and uterine epithelia.

Influence of negative energy balance on cyclicity and fertility in the high producing dairy cow.

The peripartum period is of critical importance to subsequent health and fertility. Most cows enter a state of negative energy balance (NEB) associated with many metabolic changes which have carry over effects on the resumption and normality of estrous cyclicity and the success of subsequent inseminations. A dataset on 500 lactations explored the relationships between metabolic traits measured before and after calving with fertility. Stepwise multiple regression analysis showed that longer calving to conception intervals were associated with altered profiles of IGF-I, urea and body condition score. These relationships between metabolic profiles and fertility differed between first lactation cows (which are still growing but produce less milk) and mature animals. Early postpartum the liver undergoes extensive biochemical and morphological modifications to adapt to NEB, the uterus is extensively remodeled and must clear bacterial infections, and the ovary must resume ovulatory cycles. RNA isolated from liver and uterine tissues harvested 2 weeks postpartum from cows in mild (MNEB) and severe (SNEB) energy balance was used to screen the Affymetrix 23K bovine microarray. In liver, SNEB resulted in differential expression of key genes involved in lipid catabolism, gluconeogenesis, and the synthesis and stability of IGF-I. This was accompanied by reduced systemic concentrations of IGF-I which is likely to impact on ovarian function and early embryo development. Within endometrium, cows in SNEB showed histological evidence for higher levels of inflammation and the microarray analysis identified groups of differentially expressed genes involved in tissue remodeling and immune response. This may delay uterine repair after calving, likely contributing to the observed reduction in fertility.

Viral purging of haematological autografts: should we sneeze on the graft?

High-dose cytotoxic chemotherapy followed by autologous haematopoietic stem cell transplantation (ASCT) is extensively used for the treatment of many haematopoietic, as well as several epithelial cancers. Disease relapse may be the result of tumour contamination within autograft as evidenced by gene marking studies. The multiple purging strategies that have been described to date have not proven effective in most ASCT settings. This review addresses the possibility of using oncolytic viruses as a novel purging strategy. DNA viruses such as genetically engineered adenoviral vectors have widely been used to deliver either a prodrug-activating enzyme or express wild-type p53 selectively in tumour cells in ex vivo purging protocols. In addition, conditionally replicating adenoviruses that selectively replicate in tumour cells and herpes simplex virus type 1 are other DNA viruses that have been tested as ex vivo purging agents under laboratory conditions. Vesicular stomatitis virus (VSV) and reovirus are naturally occurring RNA viruses that appear to hold promise as purging agents under ex vivo and in vivo settings. Preclinical data demonstrate reovirus's purging potential against breast, monocytic and myeloma cell lines as well as patient-derived tumours of diffuse large B-cell lymphoma, chronic lymphocytic leukaemia, Waldenstrom macroglobulinemia and small lymphocytic lymphoma. In addition, VSV has shown effective killing of leukaemic cell lines and multiple myeloma patient specimens. Given the increasing interest in the utilization of viruses as purging agents, the following review provides a timely summary of the potential and the challenges of oncolytic viruses as purging modalities during ASCT.

Effect of systemic progesterone concentration on the expression of progesterone-responsive genes in the bovine endometrium during the early luteal phase.

Increasing evidence indicates an association between the concentration of systemic progesterone during the early luteal phase of the oestrous cycle and embryo survival rate in cattle. We examined the relationship between the concentration of systemic progesterone on Days 4 to 8 post-ovulation and expression of progesterone receptor (PGR), oestrogen receptor +/- (ESR1) and retinol-binding protein (RBP) mRNA in the bovine endometrium. Heifers were blood sampled from the day of ovulation (Day 0) to Day 8 post-ovulation. On Day 4, animals were divided into low progesterone control (LC) and high progesterone control (HC) groups based on their plasma progesterone concentrations. Half of each group was supplemented with exogenous progesterone resulting in two further groups, low progesterone supplemented (LS) and high progesterone supplemented (HS). Endometrial tissues were recovered from all groups on Day 6 or Day 8 and gene expression was analysed following Northern blotting. Increasing progesterone concentrations were associated with decreased PGR and ESR1 expression. Duration-dependent effects of progesterone supplementation on ESR1 were evident and there was an effect of systemic progesterone concentrations between Day 0 and Day 4 on the expression of RBP at Days 6 and 8. Such progesterone-responsive changes in uterine gene expression are likely to affect embryo development.

Associations between milk progesterone concentration on different days and with embryo survival during the early luteal phase in dairy cows.

The relationships between the concentration of milk progesterone and early embryo survival on Days 4-8 inclusive and between the concentration of progesterone on different days from Days 0-8 inclusive following ovulation and insemination were examined in dairy cows. The relationships were examined following 77 randomly chosen artificial inseminations to cows in standing oestrus. There was a significant (P < 0.05) linear and quadratic relationship between the concentration of milk progesterone on each of Days 4-6 after ovulation and the probability of embryo survival. There was no association (P > 0.05) between milk progesterone concentration and probability of embryo survival on Days 7 and 8 after ovulation. There were no associations between milk progesterone concentration on Days 0-2 and the concentrations on Days 4-7, however, progesterone concentrations on Days 4 and 5 were highly predictive of the concentration on Days 6 and 7, respectively. Overall, the results indicate that suboptimal progesterone support during the early luteal phase is likely to deleteriously affect embryo viability and in addition, that it is possible to predict milk progesterone concentrations during the early luteal phase based on earlier stage concentrations and thus identify cows at risk of early embryo loss.

Post-insemination milk progesterone concentration and embryo survival in dairy cows.

Logistic regression analysis was used to evaluate the relationship between post-insemination milk progesterone concentration and embryo survival, and between milk yield and milk progesterone concentration. Milk samples were collected on Days 1, 4, 5, 6, and 7 (insemination=Day 0) following 871 inseminations in spring-calving dairy cows. Milk progesterone concentrations were measured by enzyme-immunoassay and pregnancy diagnosis was conducted with transrectal ultrasonography at approximately Day 30. There was a negative linear relationship (P<0.01) between milk progesterone concentration on Day 4 and embryo survival while, in contrast, there was a positive linear and quadratic relationship between milk progesterone concentration on Days 5, 6 and 7 (P<0.05) and also between the rate of change in progesterone concentrations between Days 4 and 7 inclusive and embryo survival (P<0.05). There was a weak negative linear relationship between average daily milk yield at the time of insemination and milk progesterone concentrations (P<0.001). There was no association between many production parameters, including liveweight and body condition score measured at various stages between calving and insemination, and milk progesterone concentration between Days 4 and 7 inclusive (P>0.05). In conclusion, low progesterone during Days 5-7 (after insemination) was associated with low fertility in dairy cows and there were indications of a range of progesterone concentrations within which embryo survival was maximal.

Enhanced protein kinase B/Akt signalling in pituitary tumours.

Pituitary tumours have previously been shown to harbour several abnormalities that cause deregulation of the cell cycle, particularly down-regulation of expression of the cyclin-dependent kinase inhibitor p27. However, it has been unclear whether these are the primary initiating events, or are secondary to other more proximate alterations in signalling pathways. In other cellular systems the Akt signalling pathway has been associated with downstream modulation of cell-cycle control. The aim of the present study was to test the hypothesis that Akt signalling is enhanced in pituitary tumours, and to see if changes in Akt expression are related to previous findings on low expression levels of the nuclear cell-cycle inhibitor p27 in pituitary tumours. We examined normal and adenomatous human pituitary tissue for mRNA and protein expression of Akt1, Akt2 and p27, and the activation of Akt, as well the phosphatase involved in the inactivation of Akt, phosphatase and tensin homologue deleted on chromosome 10 (PTEN). In pituitary adenomas Akt1 and Akt2 mRNA were found to be over-expressed compared with normal pituitary, while PTEN transcripts showed similar levels between the two tissue types. Immunohistochemical expression of phospho-Akt was found to be higher in the tumours than normal pituitaries, while the protein expression of nuclear p27 and PTEN was lower in the adenomas. However, the expression of p27 and Akt were not directly correlated. PTEN sequencing revealed no mutation in the coding region of the gene in pituitary adenomas, and thus we did not locate a cause for the increased phosphorylation of Akt. In summary, we have shown over-expression and activation of the Akt pathway in pituitary tumours, and we speculate that cell-cycle changes observed in such tumours are secondary to these more proximate alterations. Since Akt is a major downstream signalling molecule of growth factor-liganded tyrosine kinase receptors, our data are most compatible with an abnormality at this level as the primary driver of pituitary tumorigenesis.

Biological purging of breast cancer cell lines using a replication-competent oncolytic virus in human stem cell autografts.

Autologous hematological stem cell transplantation (ASCT) is used for the treatment of many hematological and several solid cancers. ASCT, however, has proven disappointing as a therapeutic strategy for breast cancer. Our group and others have previously shown that breast cancer micrometastases found in patients' apheresis products (APs) predict shorter progression-free and overall survival. The implications of this finding are twofold: (i) contaminating tumor cells (CTCs) in AP reflect a higher systemic disease burden and/or (ii) reinfused CTCs contribute to relapse/progressive disease. To date, purging strategies have been disappointing. We have previously demonstrated the oncolytic properties of reovirus in in vitro, in vivo and ex vivo systems. In the present study, we tested the hypothesis that reovirus purges CTCs in a breast cancer cell line purging model. Reovirus-infected human breast cancer cell lines (HTB 133, HTB 132, SKBR3 and MCF7) exhibited cell death within days. Admixtures of AP with cells from breast tumor cell lines, which were then exposed to reovirus, showed complete purging of CTCs (assessed via flow cytometry/tumor cell outgrowth analysis) without deleterious effect on CD34+ cells. Our results provide preclinical support for the ex vivo use of reovirus as a purging modality for breast cancer during ASCT.

Groin soft tissue tumors--a challenge for local control and reconstruction: a prospective cohort analysis.

BACKGROUND AND OBJECTIVES: Groin soft tissue tumors are associated with high local recurrence rates of 16-48% and postoperative complications in 40-68%. Neoadjuvant chemoradiation and aggressive reconstructive techniques were utilized to improve local control and complication rates in this challenging area. METHODS: Nine patients in this prospective series were treated with neoadjuvant chemoradiation (30 mg IV doxorubicin x 3d followed by 300 cGy/d x 10d) followed by surgery and two patients received radiation (5,000 cGy with tissue spacer) followed by surgery for tumors with a pelvic/retroperitoneal component. Surgery included resection plus reconstruction of the abdominal wall, myocutaneous flaps for large defects, and vascular reconstruction as necessary. RESULTS: The 11 consecutive patients presented with Stage I (30%), II (40%), or III (30%) disease. Four patients (36%) were operated on for possible incarcerated hernia prior to referral and two (18%) presented with recurrent tumors. Pathology included 10 sarcomas and 1 desmoid tumor; tumor grade was low (30%), moderate (40%), or high (30%). Local control (mean follow-up 55 months; minimum follow-up 36 months) and limb salvage rate was 100%. Minor wound complications not requiring re-operation occurred in three patients, lymphedema in two, and there were no postoperative hernias. CONCLUSIONS: Preoperative therapy provides excellent local control of groin soft tissue tumors. Current surgical techniques allow extensive resection with limb salvage, dependable primary wound healing and long-term integrity of the abdominal wall.

In situ oviduct and uterine pH in cattle.

Knowledge of oviduct and uterine pH in cattle is lacking mainly because of the difficulty of accessing these reproductive tissues, which for the oviduct at least necessitates anesthesia. Because halothane anesthesia is known to depress respiratory function and thus increase blood CO2 and decrease pH, oviduct and uterine pH was measured both in the presence and absence of halothane. Using short-term anesthesia with thiopentone only, oviduct pH was measured on days 2-4 of the estrous cycle and uterine pH on days 6 and 8; there was no significant effect of day of the cycle but oviduct pH ( 7.60+/-0.010 ) was greater ( P<0.001 ) than uterine pH ( 6.96+/-0.009 ). Oviduct pH was higher ( P<0.001 ) and uterine pH lower ( P<0.001 ) than venous blood pH ( 7.41+/-0.007 ). Using thiopentone/halothane anesthesia, oviduct pH was measured on days 0, 2, 3, 4 and 6, and uterine pH on days 6, 8 and 14; there was no effect of day of cycle but oviduct pH values were generally higher than uterine values and significantly so ( P<0.001 ) on day 6 where direct comparison was possible. To our knowledge these are the first published in situ measurements of oviduct pH in cattle.