Differential effects of sulindac on renal hemodynamics and function in the rat

Renal hemodynamics were studied using an electromagnetic perivascular flow sensor in anesthetized rats injected i.v. with vehicle, 5 or 10 mg/kg body weight (b.w.) sulindac. No hemodynamic changes occurred with vehicle (n=6), but mean arterial pressure was significantly decreased (by 15 mmHg) with sulindac (n=12). In the 5 mg/kg b.w. sulindac group (n=7), renal blood flow progressively and significantly increased from 7.88±0.36 to 8.98±0.58 ml/min, except during concomitant intrarenal infusion of 3 mg/kg b.w. per h proadifen (n=7). The pressure limits for efficient and no renal blood flow autoregulation remained unchanged (approx. 100 and 80 mmHg, respectively). In the 10 mg/kg b.w. sulindac group (n=5), renal blood flow did not change but autoregulatory pressure limits were lowered by 10 mmHg 2 h after treatment (P<0.025). Also, Na⁺ retention was marked. Prostanoid excretion in urine was significantly reduced with either dose but basal plasma renin activity was not (about 8 ng/ml per h; n=15). When plasma renin activity was enhanced after a reduction in renal perfusion pressure (n=21), it was decreased from 11.5±1.2 to 7.4±0.2 ng/ml per h only by 10 mg/kg b.w. sulindac (P<0.05; n=6). In conclusion, differential effects of sulindac on renal hemodynamics, Na⁺ excretion and plasma renin activity were demonstrated. Renal hemodynamic changes could be related in part to the cytochrome P-450 arachidonic acid pathway.     

Opticochiasmatic apoplexy

A 26-year-old patient presented with acute chiasmal syndrome. Computerized Tomography and Magnetic Resonance Imaging demonstrated an intrachiasmal hematoma which was evacuated via a right subfrontal approach. Histological examination revealed an arteriovenous malformation. In 21 similar cases in the literature, surgery generally resulted in the improvement of ophthalmological signs. In 3/4 of the cases, histology identified a subjacent lesion (arteriovenous malformation, cavernoma, venous angioma, glioma).     

Hormone formation in the isolated fragment 1-171 of human thyroglobulin involves the couple tyrosine 5 and tyrosine 130.

The 22 kDa fragment (Asn1-Met171) purified from iodine-poor human thyroglobulin (hTg) is capable by itself to synthesize thyroxine at Tyr5, the preferential hormonogenic acceptor site of the protein, after iodination in vitro. To identify the corresponding donor site in this model we studied the fate of the six Tyr residues present in the 22 kDa peptide after in vitro hormone synthesis. Structural studies of the tyrosyl peptides showed that Tyr5 was the only thyroxine-forming site, the other tyrosines (29, 89, 97 and 107) were noniodinated and Tyr130 was recovered in alanine form after CNBH4 treatment of the Tyr130-containing peptide. Taking into account that alanine could arise from aminoreduced pyruvate species, these results showed that in the 22 kDa fragment (1) hormone formation involves the couple Tyr5 (acceptor)-Tyr130 (donor), and (2) dehydroalanine, the resultant product of donor tyrosine after hormone synthesis, has evolved in pyruvoyl form. To test whether Tyr130 could also act as donor in hTg hormone synthesis, the 22 kDa peptide was isolated from hTg iodinated under conditions leading to iodotyrosine formation followed or not by hormone formation and the tyrosyl peptides were analyzed. After hTg iodination and before coupling (i.e. hormone synthesis) only Tyr5 and Tyr130 were recovered in iodotyrosine form; after coupling thyroxine was found at Tyr5 whereas Tyr130 disappeared. Taken together these results, correlated with the previously reported cleavage of hTg chain at Tyr130 occurring during in vivo hormone synthesis, support the theory that the couple Tyr5 (acceptor)-Tyr130 (donor) would be the preferential hormonogenic site in human Tg.     

Mitochondrial DNA variability detected in a single wheat regenerant involves a rare recombination event across a short repeat

The mitochondrial genome of the selfed progeny of a plant regenerated from long-term somatic tissue culture displays specific structural rearrangements characterized by the appearance of novel restriction fragments. A mitochondrial DNA library was constructed from this selfed progeny in the SalI site of cosmid pHC79 and the novel fragments were subsequently studied. They were shown to arise from reciprocal recombination events involving DNA sequences present in the parental plant. The regions of recombination were sequenced and the nucleotide sequences were aligned with those of the presumptive parental fragments. We characterized an imperfect short repeated DNA sequence, 242 bp long, within which a 7-bb DNA repeat could act as a region of recombination. The use of PCR technology allowed us to show that these fragments were present in both parental plants and tissue cultures as low-abundance sequence arrangements.     

Upper and lower limb disarticulation in soft tissue and bone sarcomas

The authors have reviewed 23 patients with proximal disarticulations with the aim of assessing the therapeutic value in sarcoma, taking into account previous radio- and chemotherapy. The following criteria were especially examined: recurrences, survival, and quality of life. There were 14 soft tissue sarcomas, and 9 bone sarcomas. In 11 cases, the tumor was primary and treated for the first time while, in 12 cases, it was recurrent. Eighteen patients had been previously treated by nonradical surgery, 11 by radiotherapy, and 10 by chemotherapy. For upper limb tumors, 6 patients underwent an interscapulothoracic disarticulation, and 3 an interscapulothoracic resection according to Tikhoff-Linberg. For lower limb tumors, 8 patients were submitted to interilioabdominal disarticulation, 3 to coxofemoral disarticulation, and 1 to internal hemipelvectomy according to Eilber. The mean disease-free interval has been 34 months, and the mean survival, 38.5 months. Three (15%) of 20 evaluable patients recurred locally, although most of them benefited from second surgery. Quality of life has been excellent, in general, despite the fact that only 8 patients accepted to wear a prosthesis. The Karnofsky index ranged from 60 to 100%. No significant difference was seen, whether or not previous radio- and/or chemotherapy had been administered.

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Resumen Los autores han revisado 23 pacientes con desarticulaciónes proximales con el propósito de determinar el valor terapéutico en el sarcoma, habida consideración a radioterapia y quimioterapia previas. Los siguientes criterios fueron específicamente analizados: recurrencia, supervivencia, y calidad de la vida. La serie incluyó 14 sarcomas de tejidos blandos, y 9 sarcomas óseos. En 11 casos el tumor era primario y aparecía tratado por primera vez, y en 12 casos el tumor era recurrente. Diez y ocho pacientes habían sido previamente tratados con cirugía no radical, 11 con radioterapia, y 10 con quimioterapia. En cuanto a los tumores del miembro superior, 6 pacientes fueron sometidos a desarticulación interescápulotorácica, y 3 a resección interescapulotorácica según Tikhoff-Linberg. En cuanto a los tumores del miembro inferior, 8 pacientes fueron sometidos a desarticulación interilioabdominal, 3 a desarticulación coxofemoral, y 1 a hemipelvectomía interna según Eilber. El promedio de estado libre de enfermedad ha sido 34 meses, y el promedio de supervivencia, 38.5 meses. Tres (15%) de 20 pacientes valorables presentaron recurrencia aunque la mayoría de ellos se benefició con una segunda operación. En general, la calidad de la vida ha sido excelente a pesar de que solamente 8 pacientes aceptaron usar prótesis. El índice de Karnofsky osciló entre 60 y 100%. No se observó diferencia entre los pacientes que habían recibido radioterapia y/o quimioterapia y los que no la recibieron.

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Résumé Les auteurs ont étudié 23 cas de désarticulations proximales pour sarcome en ayant pour but d'apprécier la valeur de l'intervention, la désarticulation étant précédée de radiothérapie et de chimiothérapie. Les critères retenus furent: l'existence de récidives, la survie et la qualité de la vie. La série a concerné 14 sarcomes des parties molles, 9 sarcomes des os. Dans 11 cas il s'agissait d'une tumeur primitive, dans 13 cas de récidives tumorales. Sur ce groupe de malades, 18 avaient été traités par une intervention limitée, 11 par radiothérapie, et 10 par chimiothérapie. En ce qui concerne le membre supérieur, 6 ont été traités par désarticulations inter-scapulo-thoraciques, et 3 par une résection inter-scapulo-thoracique selon la technique de Tikhoff-Linberg. En ce qui concerne le membre inférieur, 8 malades ont été soumis à une désarticulation interilio-abdominale, 3 à une désarticulation ilio-coxo-fémorale, et 1 à une hémipelvectomie interne selon la technique de Eilber. La moyenne de durée de vie normale a été de 34 mois et la moyenne de la durée de la survie de 38.5 mois. Trois (15%) des 20 malades qui ont été revus ont présenté une récidive locale mais la majorité d'entre eux ont pu bénéficier d'une réintervention. La qualité de la vie a été excellente en général bien que 8 opérés seulement aient accepté le port d'une prothèse. L'index de Karnofsky a varié de 60 à 100%. Aucune différence significative n'a été observée que le malade ait été soumis ou non à la radiothérapie et/ou à la chimiothérapie.

     

Hyperthermic isolation perfusion of the limbs with cytostatics after surgical excision of sarcomas

In order to prevent recurrence, isolation perfusion was applied in 15 patients after resection of sarcomas of the limbs. There were 6 liposarcomas, 4 synoviosarcomas, 2 malignant fibrohistiocytomas, 1 malignant mesenchynoma, 1 Kaposi, and 1 osteosarcoma (the only bone sarcoma). Eight sarcomas were recurrent after narrow surgery and/or radiotherapy. The treatment schedule was conducted in 2 steps: (a) removal of the tumor with safety margins at least outside the tumor capsule, followed 3–8 weeks later by (b) isolation perfusion with melphalan with or without actinomycin D under moderate hyperthermia at 39–41°C for 1 hour. Median follow-up time has been 30 months. Four of the 8 recurrent sarcomas recurred again and developed distal metastases. In contrast, none of the previously untreated patients recurred and 1 disseminated in the form of multicentric liposarcoma. Eleven are still alive with survival ranging from 8 to 103 months. It is concluded that isolation perfusion with melphalan with or without actinomycin D may be considered as an adjunct to surgery.

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Resumen Con miras a la prevención de recurrencias, se aplicó perfusión aislada en 15 pacientes después de resección de sarcomas de las extremidades. El grupo incluyó 6 liposarcomas, 4 sinoviosarcomas, 2 fibrohistiocitomas malignos, 1 mesenquimoma maligno, 1 Kaposi, y 1 osteosarcoma (el único sarcoma óseo). Ocho sarcomas representaron recurrencia después de cirugía limitada y/o radioterapia.El programa terapéutico fue conducido en 2 etapas: (a) remoción del tumor con márgenes de seguridad por lo menos por fuera de la cápsula tumoral, seguida 3–8 semanas después de (b) perfusión aislada con melfalán con o sin actinomicina D bajo hipertermia moderada a 39–41°C por 1 hora.El promedio de seguimiento ha sido de 30 meses. Cuatro de los 8 sarcomas recurrentes presentaron la recurrencia de nuevo y desarrollaron metástasis distales. En contraste, ninguno de los pacientes que no habían recibido tratamiento previo presentó recurrencia y en uno se diseminó en la forma de un liposarcoma multicéntrico. Once permanecen vivos con supervivencia entre 8 y 103 meses.Nuestra conclusión es que la perfusión aislada con melfalán con o sin actinomicina D puede ser considerada como una terapia adyuvante de la cirugía.

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Résumé Pour prévenir la récidive des sarcomes, la perfusion isolée a été employée après résection de 15 sarcomes des membres. Elle a concerné 6 liposarcomes, 4 sarcomes synoviaux, 2 fibrohistiocytomes malins, 1 sarcome de Kaposi, et 1 ostéosarcome (le seul cas de sarcome osseux).Le protocole thérapeutique a compris 2 étapes: (a) ablation de la tumeur avec une marge de sécurité suffisante passant à l' exterieur de la capsule tumorale, (b) puis après 3 à 8 semaines circulation extracorporelle pendant une heure de melphalan associé ou non à de 1 'actinomycine D sous hyperthermie modérée à 39–41°C.La médiane du temps de suivi a été de 30 mois. Quatre sur huit des récidives sarcomateuses ont récidivé à nouveau et ont vu se développer des métastases. Par contre, aucun malade qui n 'avait pas été traité préalablement n'a récidivé et un a présenté une dissémination tumorale sous la forme d'un liposarcome à foyers multiples. Onze sont encore en vie, la durée de la survie étant comprise entre 8 et 103 mois.Les auteurs concluent de ces faits que la circulation extracorporelle avec du melphalan associé ou non à de l'actinomycine D peut être considérée comme un traitement complémentaire du traitement chirurgical.

     

Regional Administration of Recombinant Tumour Necrosis Factor-α in Cancer, with Special Reference to Melanoma

Recombinant tumour necrosis factor-alpha (rTNFalpha) possesses the unique property of activating and selectively destroying the tumour-associated microvasculature. Systemic application of rTNFalpha has shown that the maximum tolerated dose (MTD) is 10 times lower than the efficient dose in animals. The main toxicity corresponds to the systemic inflammatory response syndrome (SIRS), with a decrease of vascular resistance and hypotension. We found that it is possible to administer rTNFalpha at 10 times the MTD in an isolated limb perfusion system, using a heart-lung machine, for advanced melanoma and sarcoma of the limbs. Our results, using the combination of high dose rTNFalpha, interferon-gamma and melphalan (TIM), produced an overall objective response rate of 100% in 2 successive studies on melanoma, with 90% and 78% complete response, respectively. In sarcoma, there was an overall response rate of 64%, with 36% complete response. Angiographic and immunohistological studies demonstrated selective and early damage of the tumour-associated microvasculature, preceded by upregulation of adhesion molecules and intratumoural leak of von Willebrand factor. Tumour invasion by platelets and, in some cases, by polymorphonuclear cells, appeared within hours after the application of rTNFalpha, long before the lysis of the tumour. Systemic changes after rTNFalpha treatment included the production of soluble TNFalpha receptors and of interleukin-6. A typical acute phase reaction was observed within 3 days, with increase of C-reactive protein parallelled by an increase of tenascin-C. A selective effect on intratumoural endothelial cells seems to be involved in the mechanism of the impressive antitumour effect of rTNFalpha, but the role of acute phase protein production is not fully understood. In selected cases of melanoma, specific cytotoxic T lymphocytes were increased after perfusion.