Mejorando la respuesta patológica completa con tres esquemas diferentes de antraciclinas en densidad de dosis como primera línea en el tratamiento preoperatorio del cáncer de mama localmente avanzado / Improving the complete pathological response with three different schemes anthracyclines dose density as the first line in the preoperative treatment locally advanced breast cancer

Es un estudio prospectivo multiinstitucional que conlleva, a su vez, tres subestudios y luego se hace el metaanalisis de estos estudios piloto en pacientes con cáncer de mama localmente avanzado que reciben quimioterapia preoperatoria con antraciclinas en densidad de dosis seguido de tres esquemas diferentes, teniendo como objetivo llegar a la respuesta patológica completa (pCR). MATERIAL Y METODOS. Participaron 150 pacientes, 28 pacientes en el primer grupo (4AC+4AT), 57 pacientes en el segundo grupo (4AC+4CptT) y 65 pacientes en el tercer grupo (4AC+ 12 TXe), todos de inicio cánceres inoperables no metastásicos. RESULTADOS. En el primer grupo la RPC fue de 28 %, en el segundo grupo 20 % y en el tercer grupo 24 %, que se incrementó a 35 %, 19 %y 30 %, respectivamente, cuando solo se tabulo los datos de las pacientes que culminaron todo el tratamiento y que no presentaron progresión de enfermedad. CONCLUSIONES. En pacientes con tumores gigantes y en mds de 90 % EC III, las respuestas obtenidas son muy significativas solo con uso de quimioterapia, además de un ahorro económico importante al no usar biológicos. Con esto no se pretende ignorar la gran ayuda de los biológicos, simplemente que, para la realidad peruana, se proponen nuevas alternativas...

Is a prospective multi-institutional study involved three substudies in turn and then the meta-analysis of these pilot studies in patients with breast cancer with locally advanced receiving preoperative chemotherapy with anthracycline dose density followed by 3 different schemes, taking aim to reach the pCR. MATERIAL AND PATIENTS METHODS. 150 patients, 28 patients in the first group (4AC + 4AT), 57 patients in the second group (4CptT 4AC +) and 65 patients in the third group (4AC + I2TXe), all of them with inoperable cancers with nonmetastatic disease. RESULTS. The pCR In the first group was 28 %, in the second group 20% and in the third group 24 %, which increased to 35 %, 19 % and 30 % respectively when only the data of the patients culminating all treatment and no progression of disease was tabulated. CONCLUSIONS. Whereas these patients with giant tumors and in 90 % EC III responses obtained are significant only with use of chemotherapy, in addition to significant cost savings by not using biological agents. We not pretended ignore the evidence that the biological products help in excellent manner, but for our country this is an alternative good way...

The major exoglucanase secreted by Saccharomyces cerevisiae as a model to study protein glycosylation.

The major yeast exoglucanase (ExgIb) consists of a 408 amino acid polypeptide carrying two short N-linked oligosaccharides attached to asparagines 165 (Asn(165)) and 325 (Asn(325)). These oligosaccharides are very similar, in both length and composition, to those present in the vacuolar protease carboxypeptidase Y. Minor glycoforms of exoglucanase arise by underglycosylation of the protein precursor (Exg(165) and Exg(325)) or by elongation of the second oligosaccharide (ExgIa). The fact that these glycoforms can be readily separated and identified by HPLC and/or Western blots converts ExgI in an excellent model to study the role of the several components or branches of the precursor oligosaccharide in the efficiency and selectivity of the oligosaccharidyl transferase in vivo. We have found that the presence of a single glucose attached to Dol-PP-GlcNAc(2)-Man(9) increases the efficiency of transfer of that oligosaccharide to the protein acceptor. Also, the glucotriose unit appears to be involved in the selection of the sequons to be occupied, in such a way that its absence results in a bias towards the glycosylation of a particular sequon. Finally, we have shown the transfer of GlcNAc(2) from Dol-PP-GlcNAc(2) to exoglucanase, an indication that this intermediate is able to translocate from the cytoplasmic to the lumenal face of the endoplasmic reticulum membrane.

Sequencing of a 4.3 kbp region of chromosome 2 of Candida albicans reveals the presence of homologues of SHE9 from Saccharomyces cerevisiae and of bacterial phosphatidylinositol-phospholipase C.

The nucleotide sequence of a 4.3 kb fragment downstream of the LIG4 gene of Candida albicans has been determined. This fragment contains two entire ORFs (ORF1 and ORF2) and a truncated one (ORF3). ORF1 (1029 bp; EMBL databank, Accession No. AJ277539) encodes a putative protein of 343 amino acids with a high degree of similarity to phosphatidylinositol-specific phospholipases C (PI-PLC) of bacterial origin and, to a lesser degree, to similar proteins from trypanosome, fly and human. Isolated ORF1 confers PI-PLC activity to Escherichia coli transformants. ORF2 (1572 bp; EMBL databank, Accession No. AJ277538) predicts a protein of 524 amino acids with high similarity along most of the entire length to Ydr393w from Saccharomyces cerevisiae. This protein carries a domain with significant similarity to several cytoskeleton proteins of different origins. YDR393w (SHE9) is an orphan gene whose overexpression compromises cell growth. ORF3 appears to encode the homologue of the well-conserved proteasomal 26S regulatory subunit.

Leiomyoma of the nasal septum.

Leiomyoma is a benign myogenic tumor that may develop wherever smooth muscle is present. It occurs commonly in the uterus, skin, and gastrointestinal tract and is rare within the nasal cavity. Only three of twenty-four reported cases of sinonasal leiomyoma have been found to originate from the nasal septum. Treatment of choice for these neoplasms is surgical excision. We present two cases of nasal septal leiomyoma. Unique features discussed include recurrence of one neoplasm and the technique used to endoscopically repair a cerebrospinal fluid leak resulting from resection of the neoplasm.

Disruption and phenotypic analysis of six open reading frames from the left arm of Saccharomyces cerevisiae chromosome VII.

Six open reading frames (ORFs) from Saccharomyces cerevisiae chromosome VII were deleted using the kanMX4 module and the long-flanking homology-PCR replacement strategy in at least two different backgrounds. Among these ORFs, two of them (YGL100w and YGL094c) are now known genes which encode well-characterized proteins (Seh1p, a nuclear pore protein, and Pan2p, a component of Pab1p-stimulated poly(A) ribonuclease, respectively). The other four ORFs (YGL101w, YGL099w, YGL098w and YGL096w) code for proteins of unknown function, although the protein encoded by YGL101w has a strong similarity to the hypothetical protein Ybr242p. Gene disruptions were performed in diploid cells using the KanMX4 cassette, and the geneticin (G418)-resistant transformants were checked by PCR. Tetrad analysis of heterozygous deletant strains revealed that YGL098w is an essential gene for vegetative growth in three backgrounds, whereas the other five genes are non-essential, although we have found some phenotypes in one of them. YGL099wDelta strain did not grow at all at 15 degrees C and showed a highly impaired sporulation and a significantly lower mating efficiency. The other three deletants did not reveal any significant differences with respect to their parental strains in our basic phenotypic tests.

Areolar temporalis fascia: a reliable graft for tympanoplasty.

OBJECTIVE: This study examines the success rate of areolar temporalis fascia (fool's fascia) as a graft material for tympanoplasty. DESIGN: This study is a retrospective review of surgical cases. SETTING: This study was conducted at Kaiser Permanente Medical Center, San Diego, a tertiary referral center for otologic surgery within Southern California Permanente Medical Group. PATIENTS: Four hundred six patients having undergone tympanoplasty (with and without mastoidectomy) from September 1992 to December 1997 were observed. Medial graft (underlay) techniques were used in all cases, including total drum replacement procedures. Sixty-three percent (256/406) of the cases were revision surgeries. Seventy-three percent (296/406) of the cases were for total drum replacement. In 342 (84%) cases, areolar temporalis fascia was used as the graft material. OUTCOME MEASURE: Successful tympanic membrane healing. Failure of a graft was considered to be reperforation during the entire period of follow-up (range 6 months-5 years). RESULTS: Tympanic membrane healing was successful in 98.54% (337/342) of the cases in which areolar temporalis fascia was used as the graft material. Graft failure for other graft materials was slightly higher. Overall success rate for all 406 cases was 97.5%. CONCLUSIONS: Areolar temporalis fascia is an effective and reliable graft material for primary and revision tympanoplasty. Areolar fascia is readily found in most revision surgeries. Revision tympanoplasty achieved a success rate better than 95%.

N-glycosylation by transfer of GlcNAc2 from dolichol-PP-GlcNAc2 to the protein moiety of the major yeast exoglucanase.

Transfer of truncated oligosaccharides to yeast exoglucanase (Exg) in Saccharomyces cerevisiae alg1 has been investigated. When incubated at the non-permissive temperature, alg1 cells secreted into the culture medium, in addition to the exoglucanase glycoforms secreted by wild type, underglycosylated forms as well as material with ionic properties of the non-glycosylated enzyme. As expected, none of the latter had affinity towards concanavalin A, but part of it bound to wheat germ agglutinin (WGA), suggesting that it contained, in addition to non-glycosylated Exg, glycoforms carrying non-reducing terminal GlcNAc. Only the WGA-bound material could be labelled with galactosyltransferase; furthermore, the label could be released by treatment with peptide-N4-N-acetyl-beta-glucosamine asparagine amidase. These results unambiguously demonstrate that GlcNAc2 can be transferred from dolichol-PP-GlcNAc2 to one or both sequons of yeast Exg. Accordingly, they support previous observations suggesting that this early intermediate is able to translocate in vivo in order to make its sugar portion accessible to the oligosaccharyltransferase in the lumen of the endoplasmic reticulum.

Direct cochlear nerve monitoring: first report on a new atraumatic, self-retaining electrode.

OBJECTIVE: To assess the efficacy and safety of a new atraumatic, self-retaining cranial nerve electrode for direct cochlear nerve monitoring during cerebellopontine angle surgery. STUDY DESIGN: Prospective clinical investigation. SETTING: The Skull Base Surgery Center at Kaiser Permanente, San Diego, a tertiary referral center for neurotologic and skull-base surgery within Southern California Permanente Medical Group. PATIENTS: Eighteen patients, with aidable preoperative hearing, underwent direct cochlear nerve monitoring with this new electrode during cerebellopontine angle surgery for a variety of diagnoses. METHODS: Intraoperative observations of cochlear nerve action potential amplitude and latency were recorded. Preoperative and 1-month postoperative audiograms were compared to assess the degree of hearing preservation. Postoperative facial nerve function was assessed using the House-Brackmann method. RESULTS: Good auditory function was preserved in four of eight acoustic tumors, with poor hearing preserved in two additional patients. Good auditory function was preserved in the remaining ten patients. Cochlear nerve action potential amplitudes between 5 and 70 microV were recorded. Postoperative facial nerve function was House-Brackmann class I-II in all 18 patients. CONCLUSION: The authors find this new electrode to be safe and effective for monitoring cochlear nerve function during cerebellopontine angle surgery.

Advantages of a new, atraumatic, self-retaining electrode for direct cochlear nerve monitoring.

Direct cochlear nerve monitoring during posterior fossa surgery offers the surgeon real-time information concerning auditory stams. However, routine utilization of this monitoring technique has been hampered by electrode designs that have not allowed the maintenance of a consistent contact between the nerve and electrode. We report on our experience with a new electrode designed to maintain consistent, atraumatic contact with the cochlear nerve and discuss the advantages of this electrode over existing wick and ball type electrodes.The utilization of this electrode during 18 posterior fossa surgeries, performed at Kaiser Permanenie Hospital, San Diego, including 8 vestibular schwannoma resections, allowed for consistent recording of high amplitude cochlear compound action potentials. Long-term exposure to pulsating cerebrospinal fluid (CSF) did not displace the electrode. Minimal cochlear nerve action potential amplitude change was noted with the electrode imrnersed in CSF. The electrode caused no trauma to the nerve, even in cases where it was accidentally dislodged from the nerve. It is hoped that by overcoming the problems previously associated with direct cochlear nerve monitoring, this electrode will allow for increased use of this advantageous monitoring technique. As a by product of the real-time data provided to the surgeon, we anticipate increased rates of hearing preservation during cerebellopontine angle surgery.

Pain subsequent to resection of acoustic neuromas via suboccipital and translabyrinthine approaches.

Prolonged headache subsequent to excision of acoustic neuromas via a suboccipital approach has been cited as a significant complication of this procedure. However, few studies have sought to compare the incidence of postoperative headaches in patients undergoing either translabyrinthine or suboccipital approaches with surgical techniques designed to minimize this complication. We performed a retrospective survey of 52 patients having undergone either a suboccipital or translabyrinthine resection of acoustic neuromas. Cranioplasties were performed on all patients having undergone resections via a suboccipital approach. The survey asked patients to categorize headache severity based on a numeric scale at 1 month, 6 months, and 1 year after surgery. Medications required to control headaches were also recorded. At 1 and 6 months after surgery, headache severity was significantly less in patients having undergone a translabyrinthine resection (p < 0.05). However, by 1 year after surgery, headache severity in the two groups of patients was essentially equivalent (p = 0.6). Data concerning the strength of analgesics required to control postoperative headaches paralleled these results. These results indicate that within the first postoperative year, patients undergoing suboccipital craniotomies have significantly more postoperative pain than do those patients having undergone translabyrinthine resections, despite the performance of a cranioplasty. However, by 1 year after surgery, these differences are no longer significant. Thus the complication of long-term postoperative headache is no more prevalent in patients undergoing a suboccipital resection than in those having undergone translabyrinthine surgery. These results are important to both the surgeon and the patient during preoperative counseling regarding the choice of surgical approach for acoustic neuroma excision.

Preferential transfer to truncated oligosaccharides to the first sequon of yeast exoglucanase in Saccharomyces cerevisiae alg3 cells.

In addition to the exoglucanases (Exg) secreted into the culture medium by wild type cells, ExgIa and ExgIb, which have oligosaccharides attached to both potential N-glycosylation sites, Saccharomyces cerevisiae alg3 mutant secreted substantial amounts (35--44%) of underglycosylated and unglycosylated forms. Quantification of these forms indicated that no more than 78% of the available N-sites were occupied. About 50% of the transferred oligosaccharides were endo H sensitive, indicating that the lipid-linked precursor had completed its synthesis to Glc3-Man9-GlcNAc2. The other 50% remained endo H-resistant and, accordingly, it should be derived from the precursor oligosaccharide Man5-GlcNAc2 synthesized by this mutant. A closer analysis of forms that have received two oligosaccharides (ExgIb) showed that the first sequon was enriched in truncated residues, whereas the second one was enriched in regular counterparts. Similarly, analysis of the individual underglycosylated glycoforms indicated that 38% of the oligosaccharides attached to the second site were regular. This percentage dropped to 20% for glycoforms carrying the oligosaccharide in the first sequon. The preferential transfer of truncated oligosaccharides to the first glycosylation site seems to be a consequence of (1) the low percentage of truncated lipid linked oligosaccharides that receives the glucotriose unit, and (2) the effect of the glucotriose unit on the selection of N-sites to be glycosylated.

A prospective study of ABR and MRI in the screening for vestibular schwannomas.

The advent of magnetic resonance imaging (MRI) has significantly increased the clinician's ability to detect small vestibular schwannomas. This had led to controversy in the evaluation of patients with asymmetric sensorineural hearing loss, as some recent studies have suggested that the auditory brainstem response (ABR) does not adequately detect small tumors of the internal auditory canal and cerebellopontine angle. As these studies evaluated ABR results in patients already diagnosed with vestibular schwannomas, they could not determine the epidemiologic accuracy (validity) of the ABR as a screening test for retrocochlear pathology. We report on the preliminary results of an ongoing prospective study on the evaluation of patients with asymmetric sensorineural hearing loss. All patients with asymmetry in two or more pure-tone thresholds of > or = 15 decibels or asymmetry in speech discrimination scores of > or 15% or both entered the study and underwent both an ABR examination and an enhanced MRI scan. Based on preliminary results obtained from the first 47 patients entered in this study, the ABR screening test for retrocochlear pathology was determined to have a sensitivity of 63%, a specificity of 64%, a positive predictive value of 26%, and a negative predictive value of 89%. All patients in whom ABR failed to diagnose a vestibular schwannoma had unilateral hearing los. These results bring into question the validity of ABR as a screening test for retrocochlear pathology, particularly in cases of unilateral hearing loss. Continued patient enrollment in this study will allow the confirmation of these results.

In vivo processing of the precursor of the major exoglucanase by KEX2 endoprotease in the Saccharomyces cerevisiae secretory pathway.

We have established the main post-translational modification of the major exoglucanase of Saccharomyces cerevisiae as the enzyme progresses through the secretory pathway. The protein portion of the enzyme accumulated by sec18 cells was about 2 kDa larger than that of the secreted enzyme. This precursor (form A) was stable when maintained in the endoplasmic reticulum but was processed to the mature form (form B) before the block imposed by the sec7 mutation. Sec7 cells, when incubated at 37 degrees C, accumulated form B first, but upon prolonged incubation, form A was preferentially accumulated. When the supply of newly synthesized exoglucanase was prevented by the addition of cycloheximide, the accumulated A was transformed into B in the presence of altered Sec7p that still prevented secretion. Conversion of A into B was prevented in the double mutant sec7 kex2-1, indicating that Kex2p is central to the in vivo processing. Consistent with this, a KEX2 deletion mutant secreted form A exclusively. Conversion of A into B was also prevented in sec7 cells by the presence of dinitrophenol, a poison that depletes ATP levels, indicating that processing is dependent upon intracellular transport which involves ER --> Golgi and/or, at least, one intra-Golgi step(s). It follows that this transport step(s) is independent of functional Sec7p.

Transcriptional regulation of the yeast vacuolar aminopeptidase yscI encoding gene (APE1) by carbon sources.

Transcription of the vacuolar aminopeptidase yscI-encoding gene (APE1) is regulated by the carbon source used for yeast growth, responding to carbon catabolite repression. By Northern blot analyses, we determined the kinetics of glucose repression in growth-shift experiments. When added to induced cells, glucose leads to the disappearance of hybridizable aminopeptidase yscI RNA sequences within 30 min. However, the amount of inmunoreactive protein, once induced, is not affected by the addition of glucose. By deletion analysis of the fusion gene APE1-lacZ we have identified a number of strong regulatory regions in the APE1 promoter. Consensus sequences for the binding of yAP1 and the HAP2/HAP3/HAP4 complex are contained in those regions. Control of the APE1 gene expression is not mediated by the HXK2 regulatory gene, but a strain bearing a deletion in the CAT1 gene can not derepress APE1 transcription to wild-type levels.

Molecular biology of yeast exoglucanases.

Three exoglucanase (Exg) genes have been reported in Saccharomyces cerevisiae. Gene EXG1 encodes the major isoenzyme (ExgI). Differential glycosylation of the primary translation product throughout the secretory pathway results in the secretion of several glycoforms. The major glycoform (ExgIb) contains two short carboxypeptidase Y-like oligosaccharides attached to both potential glycosylation sites present in the molecule. A minor glycoform (ExgIa) arises from the former by elongation of the second oligosaccharide. The protein portion is processed in the secretory pathway by the Kex2 protease. Gene EXG2 encodes a 63 kDa polypeptide with 12 potential glycosylation sites. The predicted protein, ExgII, carries a signal peptide at the amino terminus and a glycosyl-phosphatidyl inositol anchoring motif at the carboxyl end. The latter appears responsible for the particulate nature of this isoenzyme, since its elimination results in the secretion of this activity into the culture medium. Gene SSG1 encodes a 52 kDa polypeptide which is specifically synthesized during sporulation of diploids. SSG1 expression is under control of both sexual (a1-alpha 2 element) and nutritional control. Although homozygous ssg1/ssg1 diploid strains are still able to complete sporulation, they exhibited a delay in the appearance of mature asci. Single or double disruption of EXG1 and EXG2 did not result in any relevant phenotype and the triple mutant behaved as ssg1/ssg1. A ExgI-related enzyme is secreted by Candida albicans. All these four enzymes share 8 highly conserved regions in the same relative positions, indicating that they derived from a common ancestor. However, no clear function has so far been demonstrated for them.

Treatment of an acoustic neuroma in an only-hearing ear: case reports and considerations for the future.

Current options regarding the treatment of acoustic neuroma in an only-hearing ear include: observation, attempted hearing preservation surgery, and stereotactically guided radiation therapy. A patient who had a left labyrinthectomy for Menière's disease presented 15 years later with a large right acoustic neuroma. Due to anticipated profound deafness, he fit the criteria for cochlear implantation. Promontory stimulation of the left ear was positive. He underwent successful left cochlear implantation with the Nucleus 22-channel device and was successfully rehabilitated. He then underwent translabyrinthine removal of his right-sided 2.5-cm acoustic neuroma. This case is used to illustrate a new option available to those faced with treating a patient with acoustic neuroma in an only-hearing ear. How this approach may fit in with other available options will be discussed.

Electrical promontory stimulation in patients with intact cochlear nerve and anacusis following acoustic neuroma surgery.

Anacusis following hearing preservation surgery for acoustic neuroma removal in which the cochlear nerve was preserved has been explained on the basis of neural or vascular compromise. In the absence of pathologic evidence for either theory, a physiologic model was chosen. Electrical promontory stimulation with monitoring of subjective and electrically evoked auditory brainstem responses was undertaken. A positive response to stimulation suggests a vascular impairment of the cochlea sparing the cochlear nerve and spiral ganglion. The absence of response suggests loss of neural integrity at the level of the spiral ganglion or cochlear nerve. Six patients who suffered anacusis following hearing preservation surgery for acoustic neuroma were studied. Data regarding electrical promontory stimulation, auditory brainstem responses, and implications of the possible role of cochlear implantation are discussed.

Aminopeptidase I of Saccharomyces cerevisiae is localized to the vacuole independent of the secretory pathway.

The Saccharomyces cerevisiae APE1 gene product, aminopeptidase I (API), is a soluble hydrolase that has been shown to be localized to the vacuole. API lacks a standard signal sequence and contains an unusual amino-terminal propeptide. We have examined the biosynthesis of API in order to elucidate the mechanism of its delivery to the vacuole. API is synthesized as an inactive precursor that is matured in a PEP4-dependent manner. The half-time for processing is approximately 45 min. The API precursor remains in the cytoplasm after synthesis and does not enter the secretory pathway. The precursor does not receive glycosyl modifications, and removal of its propeptide occurs in a sec-independent manner. Neither the precursor nor mature form of API are secreted into the extracellular fraction in vps mutants or upon overproduction, two additional characteristics of soluble vacuolar proteins that transit through the secretory pathway. Overproduction of API results in both an increase in the half-time of processing and the stable accumulation of precursor protein. These results suggest that API enters the vacuole by a posttranslational process not used by most previously studied resident vacuolar proteins and will be a useful model protein to analyze this alternative mechanism of vacuolar localization.

Transcochlear transtentorial approach for removal of large cerebellopontine angle meningiomas.

Meningiomas of the cerebellopontine angle (CPA) most often arise from the posterior surface of the petrous pyramid and may extend along the dura to involve the tentorium. Petroclival meningiomas often involve Meckel's cavity and the tentorium. It is impossible to completely remove these large lesions with extension to the supratentorial region by conventional surgical approaches to the CPA such as the suboccipital, middle fossa, or translabyrinthine routes. If total tumor resection is not accomplished, recurrence inevitably follows. A transcochlear approach and actual excision of a large portion of the tentorium allows wide exposure to these large CPA and petroclival meningiomas with supratentorial extension. Thirty-three CPA meningiomas were reviewed from 1976 to 1991. Fourteen patients had tumor extension not only into Meckel's cavity but to the supratentorial region. Ten patients had complete tumor removal, whereas subtotal removal was associated with cavernous sinus invasion. The surgical technique is described in detail with accompanying illustrations. Preoperative symptoms, medical imaging scans, results, and complications are discussed.