The unique potency of Cowpea mosaic virus (CPMV) in situ cancer vaccine.

The immunosuppressive tumor microenvironment enables cancer to resist immunotherapies. We have established that intratumoral administration of plant-derived Cowpea mosaic virus (CPMV) nanoparticles as an in situ vaccine overcomes the local immunosuppression and stimulates a potent anti-tumor response in several mouse cancer models and canine patients. CPMV does not infect mammalian cells but acts as a danger signal that leads to the recruitment and activation of innate and subsequently, adaptive immune cells. In the present study we addressed whether other icosahedral viruses or virus-like particles (VLPs) of plant, bacteriophage and mammalian origin can be similarly employed as intratumoral immunotherapy. Our results indicate that CPMV in situ vaccine outperforms Cowpea chlorotic mottle virus (CCMV), Physalis mosaic virus (PhMV), Sesbania mosaic virus (SeMV), bacteriophage Qß VLPs, or Hepatitis B virus capsids (HBVc). Furthermore, ex vivo and in vitro assays reveal unique features of CPMV that makes it an inherently stronger immune stimulant.

Comparison between surgical techniques in gallstone ileus and outcomes.

INTRODUCTION: Gallstone ileus is a rare cause of mechanical bowel obstruction, generally found in elderly patients who often have other significant medical conditions. OBJECTIVE: The objective of the study was to determine the prevalence of gallstone ileus and the number of postsurgical complications and outcomes depending on what type of surgical management is performed. METHOD: Cohort, retrospective, observational, and comparative study was conducted, which included 31 patients undergoing surgery for gallstone ileus. Three groups were integrated according to the type of surgical procedure: Group 1: enterotomy and stone extraction alone,. Group 2: enterotomy and cholecystectomy with fistula closure, and Group 3: bowel resection alone. RESULTS: A total of 31 patients were analyzed. Gallstone ileus represented the 1.44% of all cases of bowel obstruction. Complication rates were similar between three groups. Mortality rate was lower in Group A, especially when compared to Group B, with a statistically significant difference (p < 0.05). CONCLUSIONS: Surgery is the pillar in treatment of gallstone ileus. Enterotomy with stone extraction alone appears to be associated with a lower mortality rate and better outcomes when compared to more extensive techniques.

ANTECEDENTES: El íleo biliar es una causa rara de obstrucción intestinal mecánica, que se presenta generalmente en pacientes ancianos que a menudo tienen otras afecciones médicas importantes. OBJETIVO: Determinar la prevalencia del íleo biliar, el número de complicaciones y los resultados según el tipo de tratamiento quirúrgico que se realice. MÉTODO: Estudio de cohorte, retrospectivo, observacional y comparativo, que incluyó 31 pacientes sometidos a cirugía por íleo biliar. Se integraron tres grupos según el tipo de procedimiento quirúrgico: grupo 1, enterotomía y extracción de cálculos únicamente; grupo 2, enterotomía y colecistectomía con cierre de fístula; y grupo 3, resección intestinal únicamente. RESULTADOS: Se analizaron 31 pacientes. El íleo biliar representó el 1.44% de todos los casos de obstrucción intestinal. Las tasas de complicaciones fueron similares en los tres grupos. La tasa de mortalidad fue menor en el grupo 1, en especial cuando se comparó con el grupo 2, con una diferencia estadísticamente significativa (p < 0.05). CONCLUSIONES: La cirugía es el pilar en el tratamiento del íleo biliar. La enterotomía con extracción de cálculos parece asociarse con una menor tasa de mortalidad y mejores resultados en comparación con técnicas más extensas.

Wilkie's syndrome as a cause of bowel obstruction in adults: A case report.

BACKGROUND: The superior mesenteric artery (SMA) syndrome, also known as Wilkie's syndrome, is one of the rarest causes of small bowel obstruction. CLINICAL CASE: A 36-year-old female patient, with a medical history of diabetes mellitus type 2, arrived at the emergency department with upper intestinal obstruction; a study protocol is made, integrating the diagnosis of Wilkie's syndrome. We performed a laparoscopic duodenojejunostomy, the patient did well in the post-operative period. CONCLUSIONS: Laparoscopic duodenojejunostomy is a practical option to treat Wilkie's syndrome. It provides definitive treatment with the advantages and benefits of minimally invasive surgery.

ANTECEDENTES: El síndrome de la arteria mesentérica superior o síndrome de Wilkie es una de las causas más raras de obstrucción del intestino Delgado. CASO CLÍNICO: Mujer de 36 años, con antecedente de diabetes mellitus tipo 2, que llegó al servicio de urgencias con un cuadro de oclusión intestinal alta. Se realizó protocolo de estudio, integrando el diagnóstico de síndrome de Wilkie. Se realizó anastomosis duodenoyeyunal laparoscópica y la paciente cursó con adecuada evolución posquirúrgica. CONCLUSIONES: La anastomosis duodenoyeyunal laparoscópica es una opción práctica en el tratamiento del síndrome de Wilkie, con las ventajas y beneficios de la cirugía de mínima invasión.

In Situ Vaccination of Tumors Using Plant Viral Nanoparticles.

Viral nanoparticles are self-assembling units that are being developed and applied for a variety of applications. While most clinical uses involve animal viruses, a plant-derived virus, cowpea mosaic virus (CPMV) has been shown to have antitumor properties in mice when applied as in situ vaccine. Here we describe the production and characterization of CPMV and its use as in situ vaccines in the context of cancer. Subsequent analyses to obtain efficacy or mechanistic data are also detailed.

Abundance and microhabitat use by the frog Platymantis hazelae (Anura: Ceratobatrachidae)

Introduction: Forest frogs that undergo direct development (no tadpole stage) rely heavily on moist microhabitats for their survival. Objective: To describe the abundance and microhabitat use and some aspects of the breeding behaviour of the threatened forest frog Platymantis hazelae at Twin Lakes Balinsasayao Natural Park, Negros Island, Philippines. Methods: From September 2016 to February 2017, we surveyed Platymantis hazelae using 27 (400 m2) plots in Twin Lakes Balinsasayao-Danao Natural Park in Negros Oriental, Philippines. Results: After a total of six months survey P. hazelae was found abundant in the montane zone with mean density ranging from 30.56±6.94 to 86.11±15.65 ind./ha. Fourteen environmental variables were measured and subjected to multivariate principal component analysis (PCA). PCA revealed that rainfall, altitude, relative humidity, and air temperature influenced the density of P. hazelae. Screwpines (Pandanus) leaf axils and leaves (51.56 %) and palm leaves (14 %) were the preferred microhabitats for the species. Details of physical characters of embryos and froglets are also described. Conclusions: P. hazelae was found abundant in higher elevations (sub-montane and montane zones) where ambient temperature was generally lower, higher rainfall and relative humidity and microhabitats (e.g. screwpines) remain intact and abundant.

Introducción: las ranas de bosque que se desarrollan directamente (sin etapa de renacuajo) dependen en gran medida de los microhábitats húmedos para sobrevivir. Objetivo: describir la abundancia y el uso de microhábitats y algunos aspectos del comportamiento reproductivo ante la amenaza de la rana del bosque Platymantis hazelae en el Parque Natural Twin Lakes Balinsasayao, Isla Negros, Filipinas. Métodos: de septiembre 2016 a febrero 2017, examinamos Platymantis hazelae utilizando 27 parcelas (400 m2) en el Parque Natural Twin Lakes Balinsasayao-Danao en Negros Oriental, Filipinas. Resultados: Después de un muestreo total de seis meses, se encontró que P. hazelae era abundante en la zona montañosa, con una densidad media que oscila entre 30.56±6.94 y 86.11±15.65 ind./ha. Catorce variables ambientales se midieron y se sometieron a un análisis de componentes principales multivariantes (PCA). El PCA reveló que la lluvia, la altitud, la humedad relativa y la temperatura del aire influyeron en la densidad de P. hazelae. Los microhábitats preferidos para la especie fueron las axilas foliares y hojas (51.56 %) y las hojas de palma (14 %). También se describen los detalles de los caracteres físicos de embriones y ranas. Conclusiones: P. hazelae se encontró abundante en elevaciones más altas (zonas sub-montanas y montanas) donde la temperatura ambiente fue generalmente más baja, las precipitaciones y la humedad relativa más altas y los microhábitats (por ejemplo, screwpines) permanecen intactos y abundantes.

In Situ Vaccination with Cowpea vs Tobacco Mosaic Virus against Melanoma.

Cancer immunotherapy approaches have emerged as novel treatment regimens against cancer. A particularly interesting avenue is the concept of in situ vaccination, where immunostimulatory agents are introduced into an identified tumor to overcome local immunosuppression and, if successful, mount systemic antitumor immunity. We had previously shown that nanoparticles from cowpea mosaic virus (CPMV) are highly potent in inducing long-lasting antitumor immunity when used as an in situ vaccine in various tumor mouse models. Here we asked whether the nanoparticles from tobacco mosaic virus (TMV) could also be applied as an in situ vaccine and, if so, whether efficacy or mechanism of immune-activation would be affected by the nanoparticle size (300 × 18 nm native TMV vs 50 × 18 nm short TMV nanorods), shape (nanorods vs spherical TMV, termed SNP), or state of assembly (assembled TMV rod vs free coat protein, CP). Our studies indicate that CPMV, but less so TMV, elicits potent antitumor immunity after intratumoral treatment of dermal melanoma (B16F10 using C57BL/6 mice). TMV and TMVshort slowed tumor growth and increased survival time, however, at significantly lower potency compared to that of CPMV. There were no apparent differences between TMV, TMVshort, or the SNP indicating that the aspect ratio does not necessarily play a role in plant viral in situ vaccines. The free CPs did not elicit an antitumor response or immunostimulation, which may indicate that a multivalent assembly is required to trigger an innate immune recognition and activation. Differential potency of CPMV vs TMV can be explained with differences in immune-activation: data indicate that CPMV stimulates an antitumor response through recruitment of monocytes into the tumor microenvironment (TME), establishing signaling through the IFN-γ pathway, which also leads to recruitment of tumor-infiltrated neutrophils (TINs) and natural killer (NK) cells. Furthermore, the priming of the innate immune system also mounts an adaptive response with CD4+ and CD8+ T cell recruitment and establishment of effector memory cells. While the TMV treatment also lead to the recruitment of innate immune cells as well as T cells (although to a lesser degree), key differences were noted in cyto/chemokine profiling with TMV inducing a potent immune response early on characterized by strong pro-inflammatory cytokines, primarily IL-6. Together, data indicate that some plant viral nanotechnology platforms are more suitable for application as in situ vaccines than others; understanding the intricate differences and underlying mechanism of immune-activation may set the stage for clinical development of these technologies.

Combination of Plant Virus Nanoparticle-Based in Situ Vaccination with Chemotherapy Potentiates Antitumor Response.

Immunotherapeutics are gaining more traction in the armamentarium used to combat cancer. Specifically, in situ vaccination strategies have gained interest because of their ability to alter the tumor microenvironment to an antitumor state. Herein, we investigate whether flexuous plant virus-based nanoparticles formed by the potato virus X (PVX) can be used as an immunotherapeutic for in situ vaccine monotherapy. We further developed dual chemo-immunotherapeutics by incorporating doxorubicin (DOX) into PVX yielding a dual-functional nanoparticle (PVX-DOX) or by coadministration of the two therapeutic regimes, PVX immunotherapy and DOX chemotherapy (PVX+DOX). In the context of B16F10 melanoma, PVX was able to elicit delayed tumor progression when administered as an intratumoral in situ vaccine. Furthermore, the coadministration of DOX via PVX+DOX enhanced the response of the PVX monotherapy through increased survival, which was also represented in the enhanced antitumor cytokine/chemokine profile stimulated by PVX+DOX when compared to PVX or DOX alone. Importantly, coadministered PVX+DOX was better for in situ vaccination than PVX loaded with DOX (PVX-DOX). Whereas the nanomedicine field strives to design multifunctional nanoparticles that integrate several functions and therapeutic regimens into a single nanoparticle, our data suggest a paradigm shift; some therapeutics may need to be administered separately to synergize and achieve the most potent therapeutic outcome. Altogether, our studies show that development of plant viral nanoparticles for in situ vaccines for treatment is a possibility, and dual mechanistic therapeutics can increase efficacy. Nonetheless, combining immunotherapeutics with cytolytic chemotherapy requires detailed investigation to inform optimal integration of cytolytic and immunotherapies and maximize synergy and efficacy.

Pineapple and citrus silage as potential feed for small ruminant diets: fermentation characteristics, intake, nutrient digestibility, and aerobic stability / Ensilaje de piña y cítricos como posible fuente de alimento en dietas de pequeños rumiantes: características de fermentación, consumo, digestibilidad de nutrientes, y estabilidad aeróbica / Ensilagem de abacaxi e cítricos como possível fonte de alimento em dietas para pequenos ruminantes: características de fermentação, o consumo, a digestibilidade de nutrientes e estabilidade aeróbia

Background: fruit by-products represent a feed resource for ruminants. However, preservation is needed to increase its life span. Objectives: to evaluate the fermentative characteristics, intake, digestibility and aerobic stability of fruit by-products. Methods: pineapple and citrus residues were fermented for 0, 4, 7, 11, 29 and 65 days (d). Samples from each by-product and fermentation period were analyzed for pH, microbial succession, chemical composition, and fermentation products. Crossbred rams were used to determine dry matter (DM) and crude protein (CP) intake and digestibility. Dietary treatments consisted of 100% tropical grass hay (TGH) and 20% substitution of TGH with pineapple (PS) or citrus silage (CS). Aerobic stability of PS and CS after 29 or 65 d of fermentation was determined during 5 d. Results: final pH at 65 d was 3.21 and 3.32 for PS and CS, respectively. During the entire fermentation for both silages, population of enterobacteriaceae was not detected, while lactic acid producing bacteria, yeast and molds showed typical microbial growth. After 65 d fermentation, lactic acid was the main product associated with the fermentation process (1.0 and 1.7 g/kg for PS and CS respectively). Concentrations of acetic acid were 0.38 in PS and 0.36 g/kg in CS. Rams consumed 98 and 85% of the DM offered as PS or CS, respectively. The DM and CP intakes and digestibility were similar among treatments. Both fermented fruit by-products were unstable upon aerobic exposure, PS after 1 d when fermented 29 d and CS after 3 d when fermented 65 d. Conclusions: results indicate that pineapple and citrus by-products could be preserved as silage and included in sheep diets at 20% substitution of TGH without adverse results; however, they are susceptible to aerobic deterioration.

Antecedentes: los subproductos de fruta representan una fuente de alimento para los rumiantes, sin embargo su preservación es necesaria para aumentar su vida útil. Objetivos: evaluar las características fermentativas, consumo, digestibilidad y estabilidad aeróbica de subproductos de frutas. Métodos: residuos de piña y cítricos se fermentaron durante 0, 4, 7, 11, 29 y 65 días (d). Muestras de cada subproducto y período de fermentación se analizaron para determinar pH, sucesión microbiana, composición química, y productos de fermentación. Carneros mestizos se utilizaron para determinar el consumo y digestibilidad de materia seca (MS) y proteína bruta (PB). Los tratamientos consistieron en: 100% heno de gramínea tropical (HGT); 20% sustitución de HGT con ensilaje de piña (EP) o ensilaje de cítricos (EC). La estabilidad aeróbica del EP y EC después de 29 o 65 días de fermentación se determinó durante 5 d. Resultados: el pH final al día 65 fue de 3,21 y 3,32 para EP y EC, respectivamente. Durante toda la fermentación y para ambos ensilajes, no se detectaron poblaciones de enterobacteriaceae, mientras que las bacterias productoras de ácido láctico, levaduras y hongos mostraron un crecimiento microbiano típico. Después de 65 d de fermentación, el ácido láctico era el producto principal asociado con el proceso de fermentación (1,0 y 1,7 g/kg para EP y EC, respectivamente). Las concentraciones de ácido acético fueron 0,38 g/kg en EP y 0,36 g/kg en EC. Los carneros consumieron 98 y 85% de la MS ofrecida como EP o EC, respectivamente. El consumo y la digestibilidad de MS y PB fueron similares entre los tratamientos. Ambos subproductos de fruta fermentados fueron inestables a la exposición aeróbica, el EP después del primer día cuando se fermenta 29 d y el EC después de 3 d cuando se fermenta 65 d. Conclusiones: los resultados indican que los subproductos de piña y cítricos podrían ser preservados como ensilaje y que podrían ser incluidos en las dietas de ovejas a 20% de sustitución de HGT sin resultados adversos, sin embargo, son susceptibles al deterioro aeróbico.

Antecedentes: os subprodutos da agroindústria de frutas são uma fonte de alimento para os ruminantes, mas sua preservação é necessária para aumentar a vida útil. Objetivos: avaliar as características fermentativas, consumo, digestibilidade e estabilidade aeróbia dos subprodutos de frutas. Métodos: resíduos de abacaxi e frutas cítricas foram fermentados durante 0, 4, 7, 11, 29 e 65 dias (d). Amostras de cada subproduto e os períodos de fermentação foram analisadas para: pH, sucessão microbiana, composição química, e produtos de fermentação. Um quadrado latino 3 x 3, com nove carneiros mestiços foi usado para determinação de consumo e digestibilidade da matéria seca (MS) e proteína bruta (PB). Os tratamentos dietéticos utilizados foram: 100% feno de capim tropical (FCT) e 20% de substituição do FCT com silagem de abacaxi (SA) ou silagem de cítricos (SC). A estabilidade aeróbia de SA e SC depois de 29 ou 65 d de fermentação foi determinada durante 5 d. Resultados: o pH final (65 d) foi de 3,21 e 3,32 para o SA e SC, respectivamente. Durante a fermentação para as duas silagens, a população de enterobactérias não foi detectada. Enquanto a bactérias produtoras de ácido láctico, leveduras e fungos as silagens mostraram um crescimento microbiano típico. Depois de 65 d de fermentação, o ácido láctico era o produto principal associado com o processo de fermentação (1,0 e 1,7 g / kg para SA e SC, respectivamente). As concentrações de ácido acético foram 0,38 g / kg em SA e 0,36 g / kg em SC. Os carneiros consumiram 98 e 85% da MS oferecida como SA ou SC, respectivamente. O consumo e a digestibilidade da MS e PB foram semelhantes entre os tratamentos. Os dois subprodutos de frutas fermentados foram instáveis após a exposição aeróbia, a SA depois de 1 d, quando foi fermentada 29 d e a SC depois de 3 d, quando foi fermentada 65 d. Conclusões: os resultados indicam que os subprodutos de abacaxi e cítricos poderiam ser preservados como silagem e serem incluídos em dietas de ovinos em 20% de substituição do FCT sem resultados adversos, ainda que, tem que ter cuidado porque as silagens são susceptíveis à deterioração aeróbia.

Defining a dose-response relationship with radiotherapy for prostate cancer: is more really better?

PURPOSE: Data were reviewed addressing the association between radiation therapy (RT) dose and treatment outcome for localized prostate cancer to help clarify the existence of a potential dose-response relationship. METHODS AND MATERIALS: Articles were identified through the MEDLINE database, CancerLit database, and reference lists of relevant articles. Studies were categorized into four groups based upon the endpoint analyzed, including biochemical control (BC), local control (LC), pathologic control (PC), and cause-specific survival (CSS). The impact of increasing RT dose with each endpoint was recorded. RESULTS: Twenty-two trials involving a total of 11,297 patients were identified. Of the 11 trials addressing the association of RT dose with LC, 9 showed statistically significant improvements. Of the 12 trials that reported BC with RT dose, all showed statistically significant improvements. Two out of 4 studies analyzing PC with increasing dose showed a positive correlation. Finally, 3 out of 9 studies addressing RT dose with CSS showed statistically significant improvements. Despite inconclusive results, patients with poor risk features (e.g., prostate-specific antigen [PSA] > or = 10, Gleason score [GS] > or = 7, or tumor stage > or = T2b) were most likely to benefit from increasing dose with respect to each endpoint. However, the optimal RT dose and the magnitude of benefit of dose escalation could not be identified. CONCLUSIONS: Although RT dose appears to correlate with various measures of treatment outcome, objective, high-quality data addressing this critical issue are still lacking. At the present time, the absolute improvement in outcome due to dose escalation, the subset of patients benefitting most, and the optimal dose remain to be defined.

Outcome at 8 years after breast-conserving surgery and radiation therapy for invasive breast cancer: influence of margin status and systemic therapy on local recurrence.

PURPOSE: To examine the relationship between pathologic margin status and outcome at 8 years after breast-conserving surgery and radiation therapy. PATIENTS AND METHODS: The study population comprised 533 patients with International Union Against Cancer/American Joint Committee on Cancer clinical stage I or II breast cancer who had assessable margins, who received at least 60 Gy to the primary tumor bed, and who had more than 8 years of potential follow-up. Each margin was scored (according to the presence of invasive or in situ disease that touched the inked surgical margin) as one of the following: negative, close, focally positive, or extensively positive. Outcome at 8 years was calculated using crude rates of first site of failure. A polychotomous logistic regression analysis was performed. Median follow-up time was 127 months. RESULTS: At 8 years, patients with close margins and those with negative margins both had a rate of local recurrence (LR) of 7%. Patients with extensively positive margins had an LR rate of 27%, whereas patients with focally positive margins had an intermediate rate of LR of 14%. In the polychotomous logistic regression model, margin status and the use of systemic therapy were the only two variables that had significant effects on the risk ratio of LR to remaining alive and free of disease. Among the 45 patients with focally positive margins who received systemic therapy, the crude LR rate was 7% at 8 years (95% confidence interval, 1% to 20%). CONCLUSION: Pathologic margin status and the use of adjuvant systemic therapy are the most important factors associated with LR among patients treated with breast-conserving surgery and radiation therapy.

The relation between the presence and extent of lobular carcinoma in situ and the risk of local recurrence for patients with infiltrating carcinoma of the breast treated with conservative surgery and radiation therapy.

BACKGROUND: When found in an otherwise benign biopsy, lobular carcinoma in situ (LCIS) has been associated with an increased risk of development of a subsequent invasive breast carcinoma. However, the association between LCIS and the risk of subsequent local recurrence in patients with infiltrating carcinoma treated with conservative surgery and radiation therapy has received relatively little attention. METHODS: Between 1968 and 1986, 1625 patients with clinical Stage I-II invasive breast carcinoma were treated at the Joint Center for Radiation Therapy at Harvard Medical School with breast-conserving surgery (CS) and radiation therapy (RT) to a total dose to the primary site of > or =60 grays. Analysis was limited to 1181 patients with infiltrating ductal carcinoma, infiltrating lobular carcinoma, or infiltrating carcinoma with mixed ductal and lobular features who, on review of their histologic slides, had sufficient normal tissue adjacent to the tumor to evaluate for the presence of LCIS and also had a minimum potential follow-up time of 8 years. The median follow-up time was 161 months. RESULTS: One hundred thirty-seven patients (12%) had LCIS either within the tumor or in the macroscopically normal adjacent tissue. The 8-year crude risk of recurrence was not significantly increased for patients with LCIS associated with invasive ductal, invasive lobular, or mixed ductal and lobular carcinoma. Among the 119 patients with associated LCIS adjacent to the tumor, the 8-year rate of local recurrence was 13%, compared with 12% for the 1062 patients without associated LCIS. For the 70 patients with moderate or marked LCIS adjacent to the tumor, the 8-year rate of local recurrence was 13%. The extent of LCIS did not affect the risk of recurrence. The risks of contralateral disease and of distant failure were similarly not affected by the presence or extent of LCIS. CONCLUSIONS: Breast-conserving therapy involving limited surgery and radiation therapy is an appropriate method of treating patients with invasive breast carcinoma with or without associated LCIS. Neither the presence nor the extent of LCIS should influence management decisions regarding patients with invasive breast carcinoma. [See editorial counterpoint and reply to counterpoint on pages 978-81 and 982-3, this issue.]

No long-term increase in cardiac-related mortality after breast-conserving surgery and radiation therapy using modern techniques.

PURPOSE: To determine whether left-breast irradiation using modern techniques after breast-conserving surgery leads to an increased risk of cardiac-related mortality. METHODS: Between 1968 and 1986, 1,624 patients were treated for unilateral stage I or II breast cancer at the Joint Center for Radiation Therapy, Harvard Medical School, Boston, MA, with conservative surgery and breast irradiation. Seven hundred forty-five patients with a potential follow-up of at least 12 years were analyzed. Clinical, pathologic, and treatment characteristics were compared between the 365 patients (49%) who received left-sided irradiation and the 380 patients (51%) who received right-sided irradiation. The relationship between left-sided breast irradiation and the risk of nonbreast cancer- and cardiac-related mortality was examined. RESULTS: There was no significant difference in the distribution of clinical, pathologic, or treatment characteristics between the two groups, with the exception of a small difference in pathologic tumor size (medians, left, 2.0 cm, right, 1.5 cm; P = .007). At 12 years, a majority of patients still were alive. Slightly more patients with left-sided tumors had died of breast cancer (31% v 27%; P = NS). Equivalent proportions from each group died of nonbreast cancer causes (11%), including nine patients (2%) from each group who died from cardiac causes. The risk of cardiac mortality did not increase as time after treatment increased for patients who received left-sided irradiation compared with right-sided irradiation. A model that controlled for clinical, pathologic, and treatment differences showed no significant increase in any category of cause of death (breast, cardiac, or other) for patients who received left-sided irradiation. CONCLUSION: These results suggest that modern breast radiotherapy is not associated with an increased risk of cardiac-related mortality within at least the first 12 years after treatment.

Skin recurrences after breast-conserving therapy for early-stage breast cancer.

PURPOSE: To assess the frequency and prognosis of skin recurrences after breast-conserving therapy (BCT) compared with other breast recurrences. MATERIALS AND METHODS: From 1968 to 1986, 1,624 patients with unilateral stage I or II breast cancer treated with BCT at the Joint Center for Radiation Therapy (Boston, MA) underwent gross tumor excision and received a dose of > or = 60 Gy to the tumor bed. Skin recurrences (SR) were defined as breast recurrences without associated parenchymal disease. An invasive breast recurrence with any parenchymal disease noted clinically or radiographically was scored as an other breast recurrence (OBR). Median follow-up for survivors was 137 months. RESULTS: SR represented 8% (18 of 229) of all breast recurrences and occurred in 1.1% of all patients. The outcome after local recurrence was different for patients with SR and invasive OBR. Patients with SR more frequently had uncontrolled local failure (50%; 9 of 18) than did patients with OBR (14%; 26 of 188) (P = .0007). Forty-four percent (8 of 18) of patients with SR had distant metastasis simultaneously or within 2 months of the recurrence compared with 5% (9 of 188) of invasive OBR patients (P < .0001). For patients without distant metastasis at the time of recurrence, the 5-year actuarial rate of development of distant metastasis was 60% for SR patients compared with 39% for invasive OBR patients (P = .07), and the corresponding 5-year actuarial survival rates beyond the time of local failure were 51% and 79%, respectively (P = .06). CONCLUSION: In contrast to other types of invasive breast recurrence after breast-conserving therapy, skin recurrences are rare and are associated with a significantly higher rate of distant metastasis and uncontrolled local disease as well as a lower rate of survival.

Correlation of tumor size and axillary lymph node involvement with prognosis in patients with T1 breast carcinoma.

BACKGROUND: The prognosis of patients with T1 breast carcinoma remains controversial. Some studies have shown a low risk of lymph node metastasis and distant failure whereas others have not, possibly due to differences in the definition of tumor size. In this study, the authors assessed the relation between macroscopic tumor size, microscopic invasive tumor size, axillary lymph node involvement, and prognosis in a group of patients with clinically lymph node negative disease. METHODS: Between 1968 and 1986, 1865 women with American Joint Committee on Cancer clinical Stage I or II infiltrating carcinoma of the breast were treated at the Joint Center for Radiation Therapy with conservative surgery and radiation therapy. The study population was limited to 118 patients with clinically negative axillary lymph nodes for whom the macroscopic pathologic tumor size was identified unambiguously as being < or = 2.0 cm, who underwent an axillary lymph node dissection with at least 6 lymph nodes sampled, and for whom the microscopic size of the invasive component could be determined. The median follow-up time for surviving patients was 134 months (range, 90-208 months). No patients with pathologically negative axillary lymph nodes received systemic therapy. RESULTS: Macroscopic and microscopic tumor sizes differed by > 5 mm in 17 patients (14%), by 3-5 mm in 24 patients (20%), and by < or = 2 mm in 77 patients (65%). The macroscopic tumor size was smaller than the microscopic size in 37 patients (31%), larger in 55 patients (47%), and equal in 26 patients (22%). Pathologic axillary lymph node involvement was present in 21% of all patients. The risk of lymph node involvement was not significantly different for those patients with tumors < or = 1 cm compared with patients with tumors > or = 1.1 cm, regardless of whether tumor size was measured by macroscopic or microscopic examination. The 10-year actuarial rate of freedom from distant recurrence (FFDR) was 91% for lymph node negative patients with macroscopic tumors measuring < or = 1.0 cm compared with 77% for patients with macroscopic tumors measuring > or = 1.1 cm (P = 0.07). When measured microscopically, the rates were 96% and 72%, respectively (P = 0.001). CONCLUSIONS: There often is a discrepancy between microscopic tumor size and macroscopic tumor size. T1 tumors have a substantial risk of axillary lymph node metastasis whether measured macroscopically or microscopically. Among those patients with pathologic lymph node negative tumors who are not treated with systemic adjuvant therapy, microscopic invasive tumor size is a better predictor of 10-year FFDR than macroscopic tumor size. There is a substantial risk of distant failure for patients with tumors whose invasive component microscopically measure > or = 1.1 cm, whereas the prognosis for patients with tumors that microscopically measured < or = 1 cm is excellent. These results suggest that the microscopic size of the invasive component of breast carcinomas < or = 2.0 cm routinely should be reported.

Neoadjuvant therapy for surgically staged IIIA N2 non-small cell lung cancer (NSCLC).

INTRODUCTION: Neoadjuvant therapy in patients with Stage IIIA NSCLC is associated with a 50-70% resection rate and a 3-5 year survival of 20-32%, but few trials have required meticulous staging of the mediastinum to ensure homogeneity of the study population. Continuous infusion cisplatin 25 mg/m2/day 1-5, 5-fluorouracil 800 mg/m2/day 2-5, and high-dose leukovorin 500 mg/m2/day 1-5 (PFL) given every 4 weeks achieved a 41% response rate in metastatic NSCLC (Lynch TJ, Kalish LA, Kass F, Strauss G, Elias A, Skarin A, Shulman L, Sugarbaker D, Frei E. Continuous infusion cisplatin, 5-fluorouracil, and leukovorin for advanced non-small cell lung cancer. Cancer 1994; 73: 1171-1176). The regimen was therefore evaluated in 34 patients with pathologic Stage IIIA N2 disease between 3/91 and 10/92. METHODS: Staging consisted of chest, liver, brain computerized tomography and bone scan, bronchoscopy and surgical mediastinal node mapping. Patients received PFL for 3 cycles, followed by thoracotomy and thoracic radiotherapy (TRT) to 54-60 Gy. RESULTS: Median age was 57 (42-68) years. Demographic factors included: male 56%; adenocarcinoma 59%, squamous cell carcinoma 24%; Stage T3N2 26%, T2N2 56%, and T1N2 18%. No treatment related deaths occurred. Radiographically defined response to PFL was 65% (6% complete). Thoracotomy was performed in 28 patients (82%) (6 had no attempt due to disease progression). Complete resection was achieved in 21 (75%) and seven were unresectable. Pathologic complete response was observed in five patients (15%) and an additional unresectable patient had fibrosis-only documented at thoracotomy for an overall clinicopathologic response rate of 76% (18% pathologic CR). Another ten patients had residual primary with or without hilar disease with resolution of previously documented mediastinal involvement. Six (18%) patients remain alive and disease-free with a median follow-up of 46 (33-50) months, four of whom had achieved pathologic complete response at time of surgery. CONCLUSIONS: Long-term event-free survival was associated with complete surgical resection which in turn was associated with clinical response to chemotherapy. There was a possible trend associating pathologic downstaging (absent residual disease in mediastinal nodes), particularly pathologic complete response observed in patients with non-bulky mediastinal disease, with improved event-free survival. Pathologic downstaging might therefore be a useful surrogate endpoint in trials evaluating the preoperative activity of new chemotherapy regimens. While radiographic response generally correlated with findings at surgery, response as determined by histologic examination of resected tissue was generally more extensive and may more accurately reflect the systemic impact of the chemotherapy regimen.

Thoracic and cranial radiotherapy for limited-stage small cell lung cancer.

Chemotherapy remains the mainstay of treatment for small cell lung cancer (SCLC). For patients with limited-stage disease, the addition of thoracic radiotherapy confers a moderate improvement in local control and a modest survival benefit, but these improvements come at the cost of increased toxic reactions. The optimal method for integrating chemotherapy and thoracic radiotherapy is unresolved. Concurrent and alternating strategies are appealing because they allow uninterrupted delivery of chemotherapy, but they have not been proven to be superior to conventional sequential approaches. Based on limited data, delivery of thoracic radiation early in the treatment course may be preferable to delivery later in the course. There is evidence of a radiation dose-response effect for SCLC, and, in standard regimens, thoracic radiation doses in the range of 50 to 60 Gy are recommended. The use of limited radiation fields (to postchemotherapy tumor volumes) appears reasonable. Results for alternative thoracic radiation fractionation schedules such as accelerated hyperfractionation are promising and worthy of further investigation. The role of prophylactic cranial irradiation (PCI) is controversial and should be individualized. It should be considered for the favorable subgroup of patients with limited-stage disease who achieve a complete response to chemotherapy and thoracic radiotherapy. If given, we recommend a total dose of 30 to 36 Gy in 2-Gy fractions; PCI should not be delivered concomitantly with chemotherapy.