RESUMEN
PURPOSE: Optimal postoperative radiation therapy (PORT) dose is unclear in penile squamous cell carcinoma (PeSCC). Herein, we characterized the radiosensitivity index (RSI) and genomic-adjusted radiation dose (GARD) profiles in a cohort of patients with PeSCC, and assessed the application of GARD to personalize PORT. METHODS: A total of 25 PeSCC samples were identified for transcriptomic profiling. The RSI score and GARD were derived for each sample. A cohort of 34 patients was reviewed for clinical correlation. RESULTS: The median RSI for PeSCC was 0.482 (range 0.215-0.682). The majority (n = 21; 84%) of cases were classified as radioresistant. PeSCC GARD ranged from 9.56 to 38.39 (median 18.25), suggesting variable therapeutic effects from PORT. We further determined the optimal GARD-based RT doses to improve locoregional control. We found that therapeutic benefit was only achieved in 52% of PeSCC lesions with PORT of 50 Gy, in contrast to 84% benefit from GARD-modeled PORT of 66 Gy. In the clinical cohort, the majority of patients presented with pathological N2 or N3 disease (n = 31; 91%) and was treated with adjuvant concurrent platinum-based chemoradiotherapy (CRT, n = 30; 88%). Fourteen of the 34 patients (41%) had locoregional recurrence (LRR), of which half had LRR within six months of completion of PORT. CONCLUSIONS: The majority of PeSCC are intrinsically radioresistant with a low GARD-based therapeutic effect from PORT dose of 50 Gy, consistent with the observed high rate of LRR in the clinical cohort. A GARD-based strategy will allow personalizing PORT dose prescription to individual tumor biology and improve outcomes.
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Male veterans with unilateral primary inguinal hernia, classified intraoperatively as Gilbert Type III or IV, were randomized to subaponeurotic (Lichtenstein, n=126) or preperitoneal (Read-Rives, n=121) repair under general or spinal anesthesia. The two groups of patients were comparable in age, body weight index, comorbidities, and size and type of hernia. Of the 247 patients enrolled, 224 were followed for at least 2 years (median 82 months, range 24-110 months), 16 were lost to follow-up, and seven died from causes unrelated to the surgery. The average operative time of the Read-Rives repair was 9 min longer than that of the Lichtenstein repair. There were no wound infections, and the frequencies of other short- and long-term complications were low and similar in the two groups. Six patients developed hernia recurrence, five in the Lichtenstein group (4.3%), and one in the Read-Rives group (<1%), ( P=0.21). Both anterior repairs are associated with low postoperative morbidity and recurrence rates. The Lichtenstein repair is technically easier and less time consuming. There is no statistically significant difference in the recurrence rate between the two repairs.
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Hernia Inguinal/cirugía , Mallas Quirúrgicas , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias , RecurrenciaRESUMEN
Vibrational circular dichroism (VCD) has been shown to be a useful technique for characterization of the qualitative secondary structure type for linear polypeptides and oligopeptides. A brief review of characteristic spectral responses and applications is given. Since VCD is dependent on relatively short range interactions, it detects residual structure in such oligomers even if long range order is lost. VCD studies presented here for Lys oligomers as well as Lys and Glu polymers as a function of length, salt added and temperature, confirm residual local order in these 'random coils'. Comparison to results with Pro oligomers, supports an interpretation that these extended structures have a left handed twist conformation. The 'coil' VCD is shown to be significantly reduced in intensity by temperature increase and by decrease in peptide length. By contrast, for partially alpha-helical Ac-(AAKAA)3GY-NH2 oligomers, the spectrum changes to the high temperature Lys(n) shape on heating, first losing then gaining intensity, indicating an equilibrium shift between structured states, from helix to coil (locally ordered) forms. VCD is shown to be a useful technique for monitoring local order in otherwise random coil structures.
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Dicroismo Circular , Oligopéptidos/química , Conformación Proteica , Secuencia de Aminoácidos , Datos de Secuencia Molecular , Estructura Secundaria de Proteína , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
Vibrational circular dichroism (VCD) and Fourier transform IR (FTIR) were measured for a series of short alanine-based peptides having the general formula Ac-(AAKAA)n-GY-NH2 (n = 1-4) from 5 to 50 degrees C in D2O and at room temperature in both TFE and H2O. In both of these latter solvents, the dominant structural form at the lowest temperature for the longest oligomers is alpha-helical. The same is true for the n = 4 peptide in D2O, but under these more dilute aqueous conditions, the shorter (n = 3) peptides have mixed helix-coil structures and the n = 1 and 2 peptides are random coils. The VCD data do not support the 310-helix as a dominant contributor to the conformation of these oligomers in any of these solvents. These vibrational spectral data are consistent with lower-concentration electronic CD results and additionally indicate increased helical stability at higher concentrations. VCD amide I data for the 22mer (n = 4) in D2O indicate that the peptide undergoes a transition from a highly helical conformation at 5 degrees C to a dominant random coil structure at approximately 45 degrees C with a Tm of approximately 25 degrees C (effective midpoint). Factor analysis of the thermal data showed that three principal components were required to describe both the VCD and FTIR data for the n = 4 peptide in D2O. The transition is characterized by a gradual loss of contribution from a spectral component representing the alpha-helical fraction. The third component is evidence of an optically detected intermediate conformation best viewed as a mixed coil-helix structure resulting from end fraying of the helical peptide as the temperature is increased. The nature of the junction between the interior helix and frayed ends is not determined by these data and could involve local (phi and psi) angles mimicking a 310-helix that would provide consistency with ESR and NMR results from Millhauser and co-workers.
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Alanina/análisis , Dicroismo Circular , Proteínas/química , Análisis Factorial , Calor , Desnaturalización Proteica , Espectroscopía Infrarroja por Transformada de Fourier , VibraciónRESUMEN
A novel descriptor for protein structure is examined here that goes beyond predictions of the average fractional components (FC) of a few conformational types and represents the number and interconnection of segments of continuous, well-defined secondary structural elements such as alpha-helices and beta-sheets. This matrix descriptor can be predicted from optical spectra using neural network methods. The new matrix plus traditional FC descriptors can be quickly and generally obtained to provide a level of detail not previously derived from optical spectra and a discrimination between proteins that might otherwise be viewed as being very similar using just the FC descriptor. As an example of its potential utilization, this matrix descriptor approach was applied to an analysis of both the native state and the reversible thermal denaturation of ribonuclease T1 in H2O. Analyses of the FTIR spectral data indicate initial loss of the major helical segment at 50-55 degrees C but with little accompanying change in the number of sheet segments or the sheet FC values. Circular dichroism (CD) and vibrational CD data are also used to support this interpretation based on FC changes with temperature. Parallel analysis of the corresponding data for this protein in D2O demonstrates that the method is sensitive to the match between the degree of H-D exchange used to prepare samples for the unknown and the reference data set.
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Conformación Proteica , Pliegue de Proteína , Ribonucleasa T1/química , Dicroismo Circular , Óxido de Deuterio , Modelos Moleculares , Redes Neurales de la Computación , Desnaturalización Proteica , Estructura Secundaria de Proteína , Ribonucleasa Pancreática/química , Espectroscopía Infrarroja por Transformada de Fourier , TemperaturaRESUMEN
Vibrational CD (VCD) spectra of a series of blocked linear, alternating D- and L-proline containing oligopeptides, dissolved in D2O and in CDCl3, are reported. For the Boc-LDL-Pro3 to Boc-DLDLDLDL-Pro8 oligomers, the VCD spectra in the amide I band is a positive couplet, opposite in sense to that obtained for (L-Pro)n oligomers. While this admits the possibility of their favoring a right-handed helical chain conformation, the amide I ir spectra for these DL oligomers in D2O indicate a mixed, apparently alternate, cis-trans conformation that prevents a simple conclusion. Their VCD in D2O evidence no narrowing and has a progressive loss in intensity (measured as delta A/A) with an increase in chain length. In CDCl3 a similar pattern of positive VCD couplets decreasing in intensity with length was seen, but the ir spectra are narrower. Their electronic CD (ECD), in the uv, also indicates a loss in intensity with increasing length. Oligomers with odd or even numbers of Pro residues have different ECD patterns, indicating that those spectra are strongly influenced by local contributions arising in the N-terminal groups. The VCD arises from dipolar and vibrational coupling of the amides in the helical structure. All the spectra are consistent with the chiral end groups leading to formation of an excess of one helical handedness. With an increase in length, the influence of this selectiveness is less and the overall CD measured decreases.
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Péptidos/química , Conformación Proteica , Secuencia de Aminoácidos , Dicroismo Circular , Ésteres del Ácido Fórmico/química , Datos de Secuencia Molecular , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
Terminally blocked (L-Pro-Aib)n and Aib-(L-Pro-Aib)n sequential oligopeptides are known to form right-handed beta-bend ribbon spirals under a variety of experimental conditions. Here we describe the results of a complete CD and ir characterization of this subtype of 3(10)-helical structure. The electronic CD spectra were obtained in solvents of different polarity in the 260-180 nm region. The vibrational CD and Fourier transform ir (FTIR) spectra were measured in deuterochloroform solution in the amide I and amide II (1750-1500 cm-1) regions. The critical chain length for full development of the beta-bend ribbon spiral structure is found to be five to six residues. Spectral effects related to concentration-induced stabilization of the structures of the longer peptides were seen in the resolution-enhanced FTIR spectra. Comparison to previous studies of (Aib)n and (Pro)n oligomers indicate that the low frequency of the amide I mode is due to the interaction of secondary and tertiary amide bonds and not to a strong difference in conformation from a regular 3(10)-helix.
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Oligopéptidos/química , Estructura Secundaria de Proteína , Secuencia de Aminoácidos , Ácidos Aminoisobutíricos , Dicroismo Circular , Modelos Moleculares , Datos de Secuencia Molecular , Oligopéptidos/síntesis química , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
The operative technique presented here, placement of polypropylene mesh in the properitoneal (deep) position through an inguinal approach, has yielded very satisfactory results with few recurrences and with postoperative morbidity rates comparable to those of standard techniques that do not involve prosthetic material. The main advantage of this method over other operations that utilize prosthetic material lies in the combination of the greater flexibility in the choice of operative technique afforded by the inguinal approach and the potential benefit of low recurrence rates after properitoneal placement of the mesh. There is an urgent need for a controlled randomized trial addressing the potential benefit (or lack thereof) of hernia repairs with prosthetic material in general, as well as the issue of optimal placement of the prosthesis.
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Hernia Femoral/cirugía , Hernia Inguinal/cirugía , Mallas Quirúrgicas , Adulto , Anciano , Anciano de 80 o más Años , Humanos , Masculino , Métodos , Persona de Mediana Edad , Complicaciones Posoperatorias , RecurrenciaRESUMEN
Ozone measurements (daily maximum values) from the Aerometric Information Retrieval System database are analyzed for selected sites, during 1980 to 1988, in southeastern USA. Frequency distributions, for most sites during most years, show a typical bell-shaped curve with the higher frequency around the yearly daily maximum ozone mean of about 100 to about 110 microg m(-3) (50-55 ppbv). Abnormal years in ozone concentration may skew the distribution as the mean shifts. A correlation of daily maximum ozone concentrations above 140 microg m(-3) (70 ppbv) between sites shows a division between the sites in the northern protion of the region and those in the southern portion of the region. Variations in ozone levels are well correlated over distances of several hundred kilometers, suggesting that high values are associated with synoptic scale episodes. An ozone exposure analysis also shows higher ozone exposures (250-300 ppm days) in the northerly sites as compared to the southerly sites (150-170 ppm days).
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Two hundred forty-four veterans, with a mean age of 62.4 years, mainly asymptomatic (pulmonary), were admitted generally for other disease or pension evaluation and underwent lobectomy (131), segmentectomy (107), or wedge resection (6) for T1 N0 M0 lung cancer between 1966 and 1988. Conservative resection was preferred during the past decade. The average lesion diameter was 2 cm. Thirty-day mortality was 2.9%, similar for the three procedures. Absolute 5-year survival, 51%, was 78% if only deaths from the initial lesion are considered; 19% died of comorbidity, and 8% died of second lung cancers. Routine preoperative computed tomographic staging and intraoperative sampling of even normal-sized hilar and mediastinal nodes, conducted after 1982, improved survival (p less than 0.006). Patients with lesions less than 2 cm in diameter (146) did better (p less than 0.04), and those with squamous tumors improved similarly (p less than 0.02). Lesions that communicated with a bronchus (88) were more malignant than those (156) that did not (p less than 0.02), because from that locus undifferentiated nonsquamous tumors metastasized widely. These results suggest that the T1 N0 M0 category is not uniform. Histology, size, and location in the lung are significant variables. Results of conservative resection were similar or better than those of lobectomy. The latter was used more in deep-seated lesions, however, when major intersegmental planes were transgressed, and before modern preoperative and intraoperative staging. The T1 N0 M0 category should include lesions 2 cm or less in diameter as a discrete entity.
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Carcinoma de Pulmón de Células no Pequeñas/cirugía , Neoplasias Pulmonares/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Humanos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Ganglios Linfáticos/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neumonectomía/métodos , Neumonectomía/estadística & datos numéricos , Tasa de Supervivencia , Factores de TiempoRESUMEN
Cushing's group, operating on metastatic brain tumors in the 1920s, was the first to point out that lung cancer (usually adenocarcinoma in an upper lobe) was the most common primary tumor. Excision of a solitary metastasis could result in long-term survival. Magilligan and coworkers (J Thorac Cardiovasc Surg 1976;72:690) introduced the modern era of large series of combined lung-brain resection with low mortality (3%) and a 5-year outcome of 21%. Our results (92 patients) confirm their experience. Presenting symptoms were pulmonary (53), synchronous (28), or neurologic (11). Nonsquamous cell (48) predominated. Pulmonary resections (45) were pneumonectomy (five), lobectomy (27), segmentectomy (five), and wedge biopsy (eight). Craniotomy (68) and irradiation resulted in recurrence in seven patients. There was no operative mortality. The survival rate after curative lung and brain resection (27) was 52% at 1 year, 35% at 2 years, and 21% at 5 years. Median survival in noncurative combined resection (eight), craniotomy only (27), thoracotomy only (eight), or no surgery (22) groups, with or without irradiation or chemotherapy, averaged 6.4 months. Every effort should be made to give patients with this syndrome the benefit of combined surgery, which was not offered or agreed on in more than a third of our cases.
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Adenocarcinoma/cirugía , Neoplasias Encefálicas/cirugía , Carcinoma de Células Escamosas/cirugía , Neoplasias Pulmonares/cirugía , Análisis Actuarial , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adenocarcinoma/radioterapia , Adulto , Anciano , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/secundario , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/radioterapia , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/radioterapia , Masculino , Métodos , Persona de Mediana Edad , Estadificación de Neoplasias , Cuidados Paliativos , Pronóstico , Estudios RetrospectivosRESUMEN
There is a high incidence of risk factors for incisional herniation in hospitalized veterans. Almost half the defects appear more than 12 months after celiotomy. "Buttonholing" of the rectus sheath by a sawing motion of the continuous nonabsorbable suture may be responsible for this later herniation. Suturing with synthetic, slowly absorbed monofilament may reduce delayed herniation. The recurrence rate after primary repair was 24.8% (n = 206), and after a second repair the recurrence rate was 41.7% (n = 36). Plastic prostheses, used only in difficult cases (18% of the sample), were associated with a recurrence rate similar to that associated with sutures because of protrusion around the edge. The use of larger and better fixed ("sandwich") polypropylene mesh (Marlex) is indicated. Subxiphoid epigastric hernias following sternotomy do not require prosthetic herniorrhaphy.