Nivolumab for locally advanced and metastatic cutaneous squamous cell carcinoma (NIVOSQUACS study)-Phase II data covering impact of concomitant haematological malignancies.

BACKGROUND: Monoclonal antibodies, such as cemiplimab and pembrolizumab, against the programmed death receptor (PD)-1 have become the current standard of care and first-line treatment of advanced cutaneous squamous cell carcinoma (cSCC), proving remarkable clinical benefit and acceptable safety. OBJECTIVES: To assess efficacy and safety of the anti-PD-1 antibody nivolumab in patients with locally advanced and metastatic cSCC. METHODS: Patients received open-label nivolumab 240 mg intravenously every 2 weeks for up to 24 months. Patients with concomitant haematological malignancies (CHMs), either non-progressing or stable under active therapy, were eligible for inclusion. RESULTS: Of 31 patients with a median age of 80 years, 22.6% of patients achieved an investigator assessed complete response, resulting in an objective response rate (ORR) of 61.3% and a disease control rate (DCR) of 64.5%. Progression-free survival (PFS) was 11.1 months, and the median overall survival (OS) was not reached after 24 weeks of therapy. Median follow-up was 23.82 months. Subgroup analysis of the CHM cohort (n = 11; 35%) revealed an ORR of 45.5%, a DCR of 54.5%, a median PFS of 10.9 months, and median OS of 20.7 months. Treatment related adverse events were reported in 58.1% of all patients (19.4% grade 3, the remaining grade 1 or 2). PD-L1 expression and CD-8+ T-cell infiltration did not significantly correlate with clinical response, although a trend towards a shorter PFS of 5.6 months was observed with PD-L1 negativity and low CD8+ intratumoral infiltration. CONCLUSION: This study demonstrated robust clinical efficacy of nivolumab in patients with locally advanced and metastatic cSCCs and a tolerability comparable to data of other anti-PD-1 antibodies. Favourable outcomes were obtained despite involving the oldest hitherto reported study cohort for anti-PD-1 antibodies and a significant proportion of CHM patients prone to high risk tumours and an aggressive course otherwise typically excluded from clinical trials.

Composition optimization of scintillating rare-earth nanocrystals in oxide glass-ceramics for radiation spectroscopy.

Glass-ceramic nanocomposites comprising GdBr3/CeBr3 loaded sodium-aluminosilicate glasses in which scintillating crystallites are precipitated in situ from a host glass matrix were studied. This materials system shows promise as an alternative to single-crystal scintillators, with potential to be fabricated into a wide variety of sizes, shapes, and compositions. Batch compositions containing 15-18 mol. % GdBr3 and 3-4 mol. % CeBr3 were prepared and analyzed for photoluminescent light yield. Light yield peaked with rare-earth content of 15 mol. % GdBr3 and 4 mol. % CeBr3. Preliminary ceramization studies on this composition found that the precipitated phase more closely matched a Gd2O3-CeO2 mixture rather than the GdBr3(Ce) that was targeted.

Evaluating a novel patient pathway to manage symptomatic breast referrals (the blue flag clinic): a longitudinal observational study.

INTRODUCTION: A novel referral pathway for exhibited breast symptom (EBS) referrals to manage increasing referrals of urgent suspected cancer (USC) was implemented in our trust. We report on the safety and effect on compliance with the 2-week-wait rule (2WW). METHODS: A single-centre longitudinal observational study included all patients referred to a UK breast unit during 13 May 2019 to 27 March 2020 (period 1) and 8 February 2021 to 31 January 2022 (period 2). USC referrals were assessed in a one-stop clinic (red flag clinic [RFC]); EBS referrals were assessed in a new clinic in which clinical evaluation was performed and imaging occurred subsequently (blue flag clinic [BFC]). Patients were followed up to determine the symptomatic interval cancer rate. RESULTS: There were 9,695 referrals; 1,655 referrals (17%) were assessed in the BFC after 63 exclusions. Some 95.9% of patients had a benign clinical examination (P1/P2), 80.1% had imaging (mammogram or ultrasound) and 4% had a tissue biopsy. In total, 16/1,655 (0.97%) BFC patients and 510/7,977 (8.2%) RFC patients were diagnosed with breast cancer (breast cancer detection rate). Some 1,631 patients (with 1,639 referrals) were discharged and followed up for a median of 17 months (interquartile range 12-32) with one subsequent cancer diagnosis (symptomatic interval cancer rate, 0.06%). Implementation of the BFC pathway increased 3-month average trust performance of USC referrals with 2WW standard from 8.5% to 98.7% (period 1) and from 30% to 66% (period 2). CONCLUSIONS: The BFC pathway for EBS patients is safe and implementation led to improvement against the 2WW target for USC referrals, ensuring resources are prioritised to patients with the highest likelihood of breast cancer.

Time to go wireless? A 15-year single institution experience of radioisotope occult lesion localisation (ROLL) for impalpable breast lesions.

INTRODUCTION: Wire guided localisation (WGL) is the standard localisation technique for impalpable breast lesions. Radio-guided occult lesion localisation (ROLL) has been proposed as an alternative. We have been performing ROLL for therapeutic wide local excisions (WLE) and diagnostic excision biopsies (DEB) for the last 15 years. We present the largest reported consecutive series of ROLL excisions to date. PATIENTS AND METHODS: One thousand thirty nine consecutive patients who underwent ROLL for impalpable breast lesions were identified from a prospectively collected database. 673 patients underwent WLE and 366 patients underwent DEB. Data were analysed from proformas completed at the time of the procedure by the radiologist and operating surgeon. These data were supplemented with an analysis of patient electronic records including specimen radiograph and histopathology reports. RESULTS: 99.1% of ROLL WLE revealed histological diagnoses of invasive cancer or DCIS. 98.7% of radiological abnormalities were identified on WLE post-excision radiographs (97.5% following DEB). Complete excision was recorded in 79.0% of the WLE patients following histological evaluation. 31.7% of DEB cases were pathologically upgraded to a malignant diagnosis. The presence of microcalcification, preoperative underestimation of the lesion size and symptomatic referral predisposed to incomplete excision status. DISCUSSION: ROLL is a safe and effective technique to localise impalpable breast lesions. In addition ROLL has potential technical and logistic advantages over WGL.

Hyperthermic modulation of respiratory inhibition factor- and iron releasing factor-dependent macrophage murine tumor cytotoxicity.

Hyperthermia modulated the cytotoxic activities of murine macrophages cocultured with EMT-6 tumor cells, altered the production of the monokines RIF (respiratory inhibition factor) and FeRF (iron-releasing factor) by these effector cells, and perturbed the activities of these monokines against EMT-6 cells. Cytotoxic activities of heated murine macrophages activated by Bacillus Calmette-Guérin were inhibited by heat doses of 40.5 degrees C for greater than or equal to 1 h if heating preceded triggering by the endotoxin lipopolysaccharide; however, cytotoxic activities were better retained if triggering preceded heating by 2 h. Treatment-sequence dependencies were also found in the secretion of some monokines that participate in these macrophage cytotoxic effects. Secretion of both RIF and FeRF by macrophages was slightly augmented or at least better retained if triggering of macrophages occurred several hours before heating for 1 h at 40.5-43 degrees C or for 24 h at 39-40.5 degrees C. If heating was nearly simultaneous with triggering or preceded it by several hours, there was a dose-dependent decrease in monokine secretion. The sensitivity of tumor cell targets to these monokines was also modified by the treatment sequence. When EMT-6 cells were treated with RIF- or FeRF-containing macrophage conditioned supernatants 1 h before heating at 40.5-43 degrees C, the RIF-treated cells became sensitized and the FeRF-treated cells retained better cytotoxic response than if cells had been treated 1 h after heating. Chronic heating for 24 h at 39-40.5 degrees C showed less dependence of tumor cell response on treatment sequence. Similar observations have recently been made in our laboratory for the interaction of tumor necrosis factor cytotoxic pathways with hyperthermia (Klostergaard et al., J. Biol. Response Modif., in press, 1989; Tomasovic et al., Int. J. Hyperthermia, in press, 1989). Those results and the present observations with the monokines RIF and FeRF support our hypothesis that the cytotoxic actions of macrophages and the cytotoxicity of endogenously added monokines can be augmented by appropriately constructed sequences combining hyperthermia with either macrophage priming/triggering or monokine treatment of tumor cells.

[Laparoscopic diagnosis and treatment of organic hyperinsulinism--our first experience]. / Laparoskopická diagnostika a lécba organického hyperinzulinismu--nase první zkusenosti.

Laparoscopic pancreatic procedures are still at the stage of evaluation with regard to their indications and the technical variation used. Laparoscopic pancreatic surgery is currently used for staging malignant pancreatic tumours, for the resection of benign pancreatic tumours and for the occasional management of inflammatory disorders of the pancreas. Insulinomas are rare tumours with incidence per year of 0.1-0.4 per 100,000. Ist Surgical clinic, IIIrd Internal clinic and Radiological clinic are cooperating since 1971. On the list of IIIrd Internal clinic are 80 patients with insulinoma. Since 1971 at Ist Surgical Clinic 66 patients have been operated. In our article are diagnostic and therapeutic problems discussed. Laparoscopic pancreatic procedures are still at an evaluation stage regard to their indications and techniques. Authors give report about first experience with successful laparoscopic enucleation of insulinoma in case 83 year old woman (Fig. 3, 4). The operative time was 90 min. Drainage is necessary. CT guided drain in cavity of seroma is shown (Fig. 5).

Neutral red uptake and clonogenic survival assays of the hyperthermic sensitization of tumor cells to tumor necrosis factor.

Vital dye uptake and postfixation dye assays have recently been used to examine the interaction between short-term (24-48 h) exposures to the monokine, tumor necrosis factor (TNF), and hyperthermic treatments with the finding that synergistic increases in cytotoxicity occurred. However, survival measured by these short-term dye assays is not necessarily closely related to eventual loss of clonogenic capacity. Treatment-induced growth delays, delayed cytotoxic effects, or perturbations of vital dye sequestration mechanisms could result in a different measurement of surviving fraction than given by a clonogenic assay. In this study we directly compared the neutral red vital dye uptake and clonogenic survival assays and confirmed in both assays that TNF-sensitive (L-929) and TNF-resistant (EMT-6) phenotypes show greatly reduced survival when treated with combined recombinant human TNF (1.0-0.0005 micrograms/ml) and hyperthermia (1-2 h at 43 degrees C). Moreover, we confirmed that sensitization of the TNF-resistant EMT-6 cells was largely dependent on monokine treatment before hyperthermia and was reduced by the reverse sequence. The greatest sensitization of TNF-responsive L-929 cells also occurred when TNF treatment preceded heating. These results for clonogenic survival are consistent with the hypothesis that hyperthermia used in combination with TNF in vivo is more cytotoxic than TNF or hyperthermia separately.

The ecological effects of trichloroacetic acid in the environment.

Trichloroacetic acid (TCAA) is a member of the family of compounds known as chloroacetic acids, which includes mono-, di- and trichloroacetic acid. The significant property these compounds share is that they are all phytotoxic. TCAA once was widely used as a potent herbicide. However, long after TCAA's use as a herbicide was discontinued, its presence is still detected in the environment in various compartments. Methods for quantifying TCAA in aqueous and solid samples are summarized. Concentrations in various environmental compartments are presented, with a discussion of the possible formation of TCAA through natural processes. Concentrations of TCAA found to be toxic to aquatic and terrestrial organisms in laboratory and field studies were compiled and used to estimate risk quotients for soil and surface waters. TCAA levels in most water bodies not directly affected by point sources appear to be well below toxicity levels for the most sensitive aquatic organisms. Given the phytotoxicity of TCAA, aquatic plants and phytoplankton would be the aquatic species to monitor for potential effects. Given the concentrations of TCAA measured in various soils, there appears to be a risk to terrestrial organisms. Soil uptake of TCAA by plants has been shown to be rapid. Also, combined uptake of TCAA from soil and directly from the atmosphere has been shown. Therefore, risk quotients derived from soil exposure may underestimate the risk TCAA poses to plants. Moreover, TCE and TCA have been shown to be taken up by plants and converted to TCAA, thus leading to an additional exposure route. Mono- and di-chloroacetic acids can co-occur with TCAA in the atmosphere and soil and are more phytotoxic than TCAA. The cumulative effects of TCAA and compounds with similar toxic effects found in air and soil must be considered in subsequent terrestrial ecosystem risk assessments.

Luteal function of induced corpora lutea in the bitch.

Nineteen anestrous bitches with a mean of 22 kg body weight and ranging from 2 to 4 years of age were induced to exhibit estrus and ovulate using PMSG and HCG. Twelve days after the first day of estrus, bitches were assigned to four treatment groups. Group (A) consisted of six bitches, Group (B) of five bitches and Groups (C) and (D) of four bitches each. At this time, bitches in Groups (A), (B) and (C) were laparotomized and those assigned to Groups (A) and (B) were bilaterally hysterectomized leaving the cervix and oviducts intact. Although bitches in Group (C) were laparotomized, they were not hysterectomized. Group (D) bitches were not subjected to any surgical procedures. Homologous uterine extract was prepared from each bitch in Group (A) and administered intramuscularly beginning on day 25 (day 0=first day of estrus) and continued every other day for 61 days post-estrus. Bitches in Group (B) were similarly injected with equal volumes of 0.9% saline. Blood samples, obtained prior to laparotomy and every other day for 85 days thereafter, were assayed for plasma progesterone concentrations using radioimmunoassay. One bitch in each of Groups (A) and (D) did not form luteal tissue following treatment with PMSG and HCG although both bitches exhibited estrus following treatment. All other bitches showed an increase in progesterone levels (4 to 19 ng/ml) between the first day of estrus and 10 days post-estrus. Thereafter, progesterone levels progressively declined in all groups with levels below 1 ng/ml between 38 to 40 days post-estrus. Results of this study suggested that CL formed in the bitch following PMSG and HCG treatment have a reduced function compared to non-induced CL of a normal, non-fertile estrous cycle. Such premature CL regression appears to be independent of the presence or absence of the uterus.

Progesterone secretion by induced corpora lutea (CL) of anestrous bitches after administration of gonadotropin-releasing hormone (GnRH) and human chorionic gonadotropin (HOG).

Sixteen bitches were treated with pregnant mare serum gonadotropin (PMSG; 44 IU/kg bwt) intramuscularly (i.m.) for nine consecutive days and each was given 500 IU HOG i.m. on the tenth day or on the first day of induced estrus (Day 0). On Day 12, each bitch was randomly assigned to three groups and treated as follows: Group 1-six bitches, each given 10 mcg GnRH i.m.once every 24 hr; Group 2-six bitches, each given 500 IU HOG i.m. once every 24 hr; and Group 3-four bitches, each given 5 ml 0.9% saline i.m. once every 24 hr. Treatments were continued until Day 55. Blood samples were obtained prior to treatment and every other day until Day 55. Plasma progesterone concentrations were determined by radioimmunoassay (RIA) and data arranged using a split-plot design, with treatment as the main plot and days of sampling as subplots. Analysis of data was by Duncan's Multiple Range Test and treatment-by-day interaction determined by the least-squares method. After treatment, progesterone concentrations from Group 2 were higher (P<0.05) than those of the other groups. A significant effect was seen on Day 20 (P<0.01), while on Day 50 the difference approached significance. These findings suggest that HOG is capable of stimulating the production of progesterone by induced CL in the bitch. However, neither HOG nor GnRH prevented premature regression of these induced CL. Results of this study suggest that premature luteolysis of induced CL is probably not due to lack of gonadotrophic support from either the hypothalamus or the anterior pituitary gland.

Comparative investigation on the effect of T-2 mycotoxin on lipid peroxidation and antioxidant status in different poultry species.

The effect of low dose T-2 toxin was investigated in chicken, duck and goose. The purpose of the present study was to investigate the effect of T-2 toxin on the lipid peroxidation and on the activity of glutathione redox system (amount of reduced and oxidised glutathione and the activity of glutathione peroxidase) in blood and liver. The treatment lasted days and two samples were taken, first at the time of lowest feed intake and second when the intake was the same as the control. It was found, that lipid per oxidation as detected by the amount of malondialdehyde increased in all of the species and tissues but the changes varied by species. The most sensitive species was goose followed by duck and chicken, and the most sensitive tissue was the liver followed by blood plasma and red blood cells.

Transoral hypophysectomy with mandibular symphysiotomy in the dog.

A surgical approach that offered direct visualization and removal of the hypophysis was evaluated in 17 dogs. Ten of the dogs were euthanatized and used to identify reliable landmarks for the drill site in the basisphenoid bone to expose the hypophysis. The intersphenoidal suture was an accurate landmark in that 1 cm caudal to the intersphenoidal suture was determined to be the precise point for the center of the drill hole. The remaining 7 dogs were hypophysectomized, using this approach. The landmarks were accurate, the surgery had a high degree of safety, and all hypophyses were removed.

Clinical and laboratory characterization of Basenjis with immunoproliferative small intestinal disease.

Eleven adult Basenji dogs with immunoproliferative small intestinal disease (IPSID) were studied. Two items of history related to the digestive tract were characteristic: (i) chronic intractable diarrhea in most dogs, and (ii) progressive emaciation. Anorexia was intermittent in only a few dogs. In addition, skin lesions of various degrees of severity were observed, including alopecia of pinnae and ventrum, hyperpigmentation and hyperkeratosis of pinnae, and necrosis and ulcerations of margins of pinnae. The cause of the skin lesions was not determined; however, hypothyroidism did not appear to contribute to the skin changes. Standard hematologic and serum chemical values were not consistently abnormal. However, a poorly regenerative anemia, mild neutrophilia, and increased aspartate aminotransferase and alanine aminotransferase activities were generally observed in severely affected dogs. The Pelger-Huet anomaly was identified in dog 3. Maldigestion and malabsorption as determined by the N-benzoyl-L-tyrosyl-p-aminobenzoic acid and d-xylose test was documented to varying degrees in dogs with IPSID. Maldigestion was correlated with functional pancreatic exocrine insufficiency. Severe malabsorption was documented in only 3 dogs. Serum gastrin values were evaluated in these dogs because of a prior observation of parietal cell hyperplasia and gastric ulceration. Hypergastrinemia was documented in 3 dogs. Additional studies will be necessary to determine whether an acid hypersecretory state contributes to the pathogenesis of IPSID in Basenjis.

[Collection of sperm from foxes using electroejaculation under halothane anesthesia]. / Získavanie spermy od lisiakov metódou elektroejakulácie v halotanovej narkóze.

A method has been developed for the collection of ejaculate from anaesthesized dog foxes. General anaesthesia was produced by inhaling 3 to 5% narcotan mixed with oxygen, the inhalation rate being two litres per minute. An electroejaculator with a bipolar electrode, introduced in the rectum, was used for the electrostimulation of ejaculation. The voltage needed to produce the ejaculation effect and the number of impulses depended on the individuality of the foxes. The average amount of ejaculate per one collection was 0.86 ml, the sperm motility percentage was 74.80% sperm concentration was 270.62 x 10(3) spermatozoa per mm3, and the average pH value was 6.87.

[Detection of estrus and determination of the optimal time for insemination in polar foxes (Alopex lagopus)]. / Detekcia ruje a urcenie optimálneho casu inseminácie polárnych lísok (Alopex lagopus).

Oestrus cycles were investigated in seven polar foxes: the investigation consisted of evaluation of clinical symptoms of heat (vulva enlargement), measurement of vaginal mucus electrical resistance and determination of progesterone concentrations in the blood plasma of foxes; the objective was to determine optimum insemination time. The females were inseminated with fresh semen intravaginally by means of a pseudopenis, a day following the record of maximum electrical resistance of vaginal mucus and at the minimum progesterone concentration in blood plasma of 30 ng.ml-1. The females were reinseminated on the following day. The insemination dose had a volume of 1 ml with sperm concentrations of 150.10(6). Clinical symptoms of heat were observed in six out of the seven test foxes. Heat detection by means of measuring vaginal mucus electrical resistance was successful also in six females. Progesterone test enabled to detect heat in five females. Out of six inseminated females, five foxes became pregnant (83.3%) and a total of 33 cubs were born; this is 5.5 cubs per female.

[Fertilizing capacity of the ejaculate of nutria (Myocastor coypus) after the removal of the seminal vesicles as evaluated by the penetration test and natural mating]. / Fertilizacná kapacita ejakulátu nutrií (Myocastor coypus) po exstirpácii semenných vackov zistená testom penetrácie a prirodzeným párením.

The fertility of male coypu sperm following seminal vesicle extirpation was investigated using the penetration test into the egg of Syrian golden hamster (Mesocricetus auratus). Ejaculates were obtained from five males by means of electro-ejaculation under halothane narcosis. The results of the zona-free hamster eggs (ZFHE) penetration test showed that the ejaculates of all the surgically treated coypu males were fertile and that ZFHE value fluctuated from 54 to 76.6%. The results obtained in experiments with natural mating revealed that the extirpation of male coypu seminal vesicles did not affect their fertility. In total 47 foetuses were found post mortem in ten coypu females covered by surgically treated males, which on average represented 4.7 foetuses per female.

[Fluctuations in the level of progesterone in the peripheral blood of nutria during pregnancy]. / Kolísanie hladiny progesterónu v periférnej krvi nutrií pocas gravidity.

The fluctuations in the concentrations of progesterone in peripheral blood of three intact coypus and three coypus after natural mating were investigated for the period of four months. Immediately after mating the concentrations of progesterone are low (1.5-2.4 ng.ml-1), the maximum values reach the peak between the 14th and 15th week of gravidity (12.50-20.72 ng.ml-1), whilst there is almost no change in the intact females. On the last days of gravidity the values of progesterone decrease rapidly and they are very low on the day of parturition (1.0-2.5 ng.ml-1). The concentration of progesterone in the blood plasma of intact females in the test period is low (0.09-3.18 ng.ml-1).

Effect of lipid peroxide loading on lipid peroxidation and on the glutathione and cytochrome systems in rabbits.

New Zealand White rabbits (6 males and 6 females) were fed a diet of high lipid peroxide content (peroxide value: 249.05 meq/kg fat) for 21 days. Twelve rabbits served as controls (peroxide value: 40.3 meq/kg fat). The lipid peroxide loading did not cause clinical signs. The rate of lipid peroxidation, as measured on the basis of thiobarbituric acid reactive substances (TBARS), was significantly (P < 0.05) higher in all of the investigated tissues, in the following order: liver > red blood cells (RBC) > blood plasma. Reduced and oxidised glutathione content was higher in the blood plasma (P < 0.01) and liver (P < 0.001) of rabbits exposed to the peroxide load. Lipid peroxide loading decreased the activity of glutathione peroxidase in the blood plasma, RBC haemolysate and liver and that of glutathione reductase in the liver. The amount of cytochrome P450 (both CO- and metyrapone-reduced) and the activity of cytochrome c (P450) oxidoreductase in the microsomal fraction of the liver homogenate were also lower in the group exposed to lipid peroxide load. Subchronic alimentary lipid peroxide loading in the presence of sufficiently high levels of antioxidants in the complete feed was found to increase the rate of lipid peroxidation and markedly lower the activities of both the glutathione and xenobiotic transforming enzyme systems without causing any clinical signs of toxicity.

[CT-guided interventions in diseases of the small pelvis following rectal resection]. / CT vezérelt beavatkozások a rectum resectióját követö kismedencei elváltozásokban.

60% of relapses of rectal cancer after abdominoperineal resection occurs at the site of the surgical intervention. Early detection of these recurrent tumours is vital. Among the up-to-date imaging systems CT is the most sensitive method in diagnosis of pelvic tumours. Despite the accurate imaging diagnosis the nature of lesions remains sometimes ambiguous. 11 CT guided biopsies and 2 punctures were performed because of suspected local recurrence or abscess. As a result of biopsies, local recurrence was histologically proven in 6 cases, fibrosis in 4, inflammatory disease in 1. Both punctures revealed the cytological diagnosis of abscess. There were no complications. The interventions were carried out in prone position through the greater sciatic foramen. In the knowledge of the exact anatomy of this region, the procedure can be performed safely by CT guidance and a correct diagnosis can be achieved.

[Ultrasonic examination of the brain (through an opening in the skull)]. / Az agy postoperativ ultrahang vizsgálata (csonthiányon át).

Post-operative neurosonography - through calvarial defect. 9 patients were examined by post-operative high resolution real-time ultrasound, using an operative calvarial defect. The findings of 2 patients are analysed in details. The authors have found good agreement with computed tomography, with other imaging methods and pathology as well. They suggest sonographic examination as a first step in the follow-up control of the pathological processes in patients with burr holes.