Chemoradiotherapy plus induction or consolidation chemotherapy as total neoadjuvant therapy for locally advanced rectal cancer: Pooled analysis of the CAO/ARO/AIO-12 and the OPRA randomized phase 2 trials.

BACKGROUND: Total neoadjuvant therapy (TNT) has been used for patients with locally advanced rectal cancer. The optimal sequence of chemoradiotherapy (CRT) and chemotherapy (CT) is a matter of debate. METHODS: We performed a pooled analysis of the CAO/ARO/AIO-12 and OPRA multicenter, randomized phase 2 trials to identify patient subsets that could benefit from one TNT sequence over the other regarding disease-free survival (DFS). Patients with stage II/III rectal cancer were randomized to CRT (50.4-54 Gy) with either induction (INCT-CRT) or consolidation CT (CRT-CNCT) with fluorouracil, leucovorin, oxaliplatin (CAO/ARO/AIO-12 and OPRA) or capecitabine and oxaliplatin (OPRA) followed by mandatory total mesorectal excision (TME) (CAO/ARO/AIO-12) or selective watch-and-wait surveillance (OPRA). 311 and 324 patients were recruited from June 15, 2015 to January 31, 2018; and from April 12, 2014 to March 30, 2020 in the two trials, respectively. Pretreatment clinical and tumor characteristics included were age, sex, ECOG, cT-category, cN-category, clinical UICC stage, location from anal verge, and tumor grade. FINDINGS: In total, 628 eligible patients were included in the pooled analysis (CAO/ARO/AIO-12, n = 304; OPRA, n = 324). Of those, 313 were randomly assigned to the INCT-CRT group, and 315 to the CRT-CNCT group. Median follow-up was 43 months (IQR, 35-49) months in the CAO/ARO/AIO-12 trial and 61,2 months (IQR, 42-68,4) in the OPRA trial. Pooled analysis of baseline clinical and tumor characteristics did not identify any subgroups of patients that would benefit by the one TNT sequence over the other with regard to DFS. INTERPRETATION: To our knowledge, this is the first pooled analysis of two randomized trials after direct head-to-head comparison of both TNT sequences. Both trials reported higher rates of complete response with CRT-CNCT, and this should be considered the preferred TNT sequence if organ preservation is a priority.

Internal mammary lymphoscintigraphy in breast carcinoma--a surgeon's perspective.

Internal mammary lymphoscintigraphy (IML) should now be considered a standard staging procedure in the present state of the art of the management of the patient with breast carcinoma. It provides clues for assessing the extent of disease and helps one to select individualized therapy. The interpretation is reliable enough in expert hands, to rule out the necessity of internal mammary node histopathologic diagnosis. In view of the significance of nodal invasion in relation to distant spread of the disease, one would be entitled to use this test as an indication for complementary systemic therapy when positive. On the other hand, if systemic therapy is to be employed without selection according to the multitude of relevant criteria, there may be no need to carry out this staging procedure prior to a management decision. The authors have reviewed their experience with more than 1000 examinations and have shown some of the practical implications of IML as a staging procedure as well as a guide to therapy.

Radiosterilization of albuminated polyester prostheses.

The study reported here is concerned with the radio-sterilization of Dacron vascular prostheses coated with crosslinked albumin. gamma-Radiations have no effect on the mechanical properties of the polyester fibres or on their crystallinity, whether irradiated in a dry state or immersed in saline. Special attention has been paid to the release of the albumin, or protein fragments from the reticulum using 125I-labelled albumin as a radiotracer. The albumin leakage depends upon the type of Dacron fabrics considered but the values derived from radioactivity measurements are always greater than those directly measured, which indicates a radio-induced break of the bond between iodine and albumin; this has nothing to do with the break of the association between albumin and Dacron. Moreover no cytotoxicity of the irradiated immersion medium has been observed using a test based on organotypic culture in liquid medium. Thus radio-sterilization of an albuminated polyester vascular prosthesis immersed in saline appears to be a suitable procedure.

Degradability of crosslinked albumin as an arterial polyester prosthesis coating in in vitro and in vivo rat studies.

In order to avoid the preclotting procedure in knitted polyester arterial prostheses and in woven models, compound polyester grafts have been proposed, containing preadsorbed collagen or albumin. Since we are currently investigating grafts impregnated with crosslinked albumin, it was decided to establish the degradation rate of this coating after stabilization with either glutaraldehyde (GA) or carbodiimide (CDI). Tests were performed in vitro by incubation in either PBS, plasma or pancreatin and in vivo by implantation in the abdominal cavity of rats. In PBS or plasma in vitro, the coatings were very stable (2% degradation after 144 h incubation), however, in pancreatin the CDI crosslinked albumin degraded much faster than the GA crosslinked albumin (more than 50% degradation in 12 h compared to less than 30% in 48 h). In vivo the degradation rates of the two types of crosslinked albumin were similar (almost all of the albumin having been lost after 4 weeks) but the cellular response was very different: a mild tissue reaction was observed with the CDI crosslinked coating whereas many foreign body giant cells were present on the GA crosslinked material.

Scintiphotographic evaluation of LeVeen peritoneo-venous shunt patency using intraperitoneal Tc-99m-MAA.

A simple method is described for assessing the patency of LeVeen peritoneo-venous shunts. Following the intraperitoneal injection of 5 mCi of Tc-99m-MAA pulmonary radioactivity is monitored using a gamma scintillation camera. Lung visualization indicates shunt patency, while lack of lung uptake implies shunt obstruction.

Physiological effect of cholecystokinin on gastric emptying of liquid in functional dyspepsia.

OBJECTIVE: Early satiety and postprandial epigastric fullness are common symptoms in functional dyspepsia. Cholecystokinin (CCK), a mediator of satiety in humans, may be responsible for these symptoms through an increased effect on delaying gastric emptying. METHODS: In five normal subjects and in five patients, gastric emptying of inert liquid mixed with technetium (Tc99m) was studied during i.v. perfusion of normal saline and of physiological concentrations of CCK octapeptide. RESULTS: Administration of CCK significantly delayed emptying of inert liquid in patients and in normal subjects, and the effect was of similar magnitude in the two groups: residual gastric volumes at 90 min increased from 9.9 +/- 6.1 to 32.1 +/- 6.2% (p < 0.025) in controls and from 9.8 +/- 4.4 to 32.2 +/- 4.7% (p < 0.005) in patients during saline infusion in comparison with CCK infusion; also, prolongation of half emptying time was not different between the two groups (19.4 +/- 1.9 min to 39.4 +/- 15.2 min in controls and 19.5 +/- 3.0 min to 31.4 +/- 7.9 min in patients). CONCLUSIONS: We conclude that CCK at physiological concentrations acts similarly in normal subjects and in patients with functional dyspepsia; this suggests that, if this hormone is normally released after a meal, a peripheral action of CCK through delayed gastric emptying is not responsible for increased postprandial satiety in functional dyspepsia.

Metabolism of 5-hydroxylysine in Pseudomonas fluorescens.

Hydroxylysine is metabolized via two routes by a Pseudomonas fluorescens strain as shown by the oxidation of selected intermediates. Hydroxy-L-lysine is oxidized via a pathway analogous to the monooxygenase pathway for L-lysine, and data suggest that at least some of tthe enzymes are those involved in the metabolism of L-lysine. Hydroxy-L-lysine is also converted by a racemase to allohydroxy-D-lysine, which is then degraded via a pathway analogous to, but different from, that described for D-lysine, involving hydroxy-L-pipecolate, 2-amino-5-hydroxyadipate, and 2-hydroxyglutarate. Data obtained with mutants unable to oxidize L-pipecolate suggest that the enzymes for the metabolism of hydroxy-L-pipecolate are distinct from those for L-pipecolate. Studies on D- and L-lysine degradation have shown that the previously described pathways for these compounds are present in this soil pseudomonad.

Effect of hydroxylysine on the biosynthesis of lysine in Streptococcus faecalis.

We were able to show that two lysine-independent mutants of Streptococcus faecalis ATCC 8043 contained the enzymes for the usual bacterial pathway for lysine biosynthesis. Because of this synthetic capacity, one mutant, the Lys(+)OHLys(s) strain, could not grow in the presence of hydroxylysine without a lysine supplement. Both lysine and hydroxylysine inhibited the first enzyme of the pathway, aspartokinase. Unlike the Escherichia coli enzyme, S. faecalis dihydrodipicolinic acid synthetase was not inhibited by either lysine or hydroxylysine. Both amino acids caused the repression of dihydrodipicolinic acid synthetase and diaminopimelic acid decarboxylase. Failure of Lys(+)OHLys(s) strain to grow in hydroxylysine-supplemented medium was caused by the mimicking of lysine control by hydroxylysine. Because hydroxylysine could not completely substitute for lysine and lysine could not be synthesized, the organism did not grow. We tested three lysine analogues and found that they prevented lysine-depletion lysis in the Lsy(-)OHLys(s) strain, as did hydroxylysine. Each analogue seemed to support cell wall mucopeptide synthesis, although ornithine did not. Preliminary data indicated that these analogues like hydroxylysine, have growth-inhibitory action on the Lys(+)OHLys(s) strain, but not the Lys(+)OHLys(r) strain. The nature of the specificity of the lysine-adding enzyme for cell wall mucopeptide synthesis is discussed.

Transport of lysine and hydroxylysine in Streptococcus faecalis.

Data are presented which support the view that l-lysine is transported by two systems in Streptococcus faecalis. The system with the higher affinity for l-lysine appears to be specific for l-lysine among the common amino acids and to require an energy source. The second system transports both l-lysine and l-arginine and does not appear to require an energy source. Both of these systems will accept hydroxy-l-lysine as a substrate as shown by the energy requirement for hydroxy-l-lysine transport and by the inhibition of uptake by l-arginine as well as by l-lysine. The affinity of both systems appears to be considerably lower for hydroxy-l-lysine than for l-lysine. A mutant of S. faecalis which is resistant to the growth inhibitory action of hydroxy-l-lysine appears to differ from the parent strain by having a defective l-lysine-specific transport system. In this mutant, hydroxy-l-lysine is not readily transported via the l-lysine-specific system because of the mutation or via the second system because of the high concentration of l-arginine present in the growth medium. This overall lack of transport prevents hydroxy-l-lysine from reaching inhibitory levels within the cell.

Radioimmunodetection of human bladder tumor xenografts in nude mice with radiolabeled monoclonal antibodies.

The tumor targeting potential of two monoclonal antibodies (mAbs) reacting with growth-regulated surface glycoproteins of human bladder cancer was investigated. The mAb T16 reacts more intensely with stationary cells while the mAb T43 is preferentially reactive with exponentially growing cells. The test target was T24 human bladder cancer cells grown subcutaneously in 30 nude mice. Controls for tumor specificity were human lung cancer cells grown on the contralateral side. Purified mAb's T16 and T43, and Om5, a non-reactive control, were radiolabeled with 131-Iodine and injected intravenously in doses ranging from 50 to 300 microCi in tumor-bearing animals. Consistent images of the bladder cancer xenografts were obtained at 48 and 72 hours with tumors as small as 0.1 gm. High resolution tumor images were obtained only with the reactive antibodies and according to their in vitro specificity. These results demonstrate that the two mAbs T16 and T43 can specifically and sensitively localize human bladder cancer cells in vivo.

Maintained reduction of uterine leiomyoma following addition of hormonal replacement therapy to a monthly luteinizing hormone-releasing hormone agonist implant: a pilot study.

Ten pre-menopausal women with uterine leiomyoma were treated for 1 year with a monthly depot of luteinizing hormone-releasing hormone agonist (LHRA-a), goserelin, combined after the initial 3 months of treatment with conjugated oestrogens 0.3 mg (days 1-25) and medroxy-progesterone acetate 5 mg (days 16-25). Mean leiomyoma volume decreased by 49.3% during the first 3 months when goserelin alone was administered but did not change significantly during the 9 months of combination therapy. There were no significant changes in bone mass or high-density lipoprotein cholesterol during the study whereas hot flushes and menstrual blood loss were well controlled. These results indicate that ovarian suppression with a monthly depot of the LHRH-a, goserelin, combined after 3 months with low-dose hormonal replacement therapy reduced the size and the symptomatology of leiomyoma while preserving the bone mass.