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Spontaneous and isolated necrosis of the falciform ligament is a rare condition. A 55-year-old lady presented with sudden onset of epigastric pain, fever and vomiting. Laboratory studies revealed less than three-fold increase in serum amylase and lipase levels. Ultrasound examination and contrast enhanced computed tomography (CECT) revealed features suggestive of inflammation and necrosis of the falciform ligament involving ligamentum teres hepatis and extending to the lesser omentum with an adjacent minimal ill-defined collection. Then, conservative management was started. However, the symptoms did not resolve completely. Therefore, CECT scan was repeated 12 days later which showed findings similar to previous scan with expansion and organization of the collection anterior to lesser omentum with peripheral enhancement, suggestive of an abscess. A minimally invasive approach to treatment was adopted. Aspiration of the collection was performed under ultrasound guidance. This was followed by continuation of supportive management. The patient improved clinically and was discharged. This case study highlights the importance of imaging in the diagnosis of falciform ligament necrosis. An innovative minimally invasive approach to treatment in the form of ultrasound guided aspiration may be considered when a collection is present adjacent to the necrosed falciform ligament.
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Introduction and importance: Malignancy can lead to colo-enteric fistulas. A malignant fistula between the rectum and the jejunum is a rare occurrence. Case presentation: A 60-year-old female suffered from diarrhea, vomiting, and epigastric pain for 4 months. After demonstration of a dilated rectum with heterogeneous collection on ultrasonography, contrast-enhanced computed tomography (CECT) along with rectal contrast was done, which showed heterogeneously enhancing asymmetrical circumferential thickening of the proximal rectum, including rectosigmoid junction, collection in the rectum and two recto-jejunal fistulous tracts. Colonoscopy showed ulcero-proliferative growth in the rectum with two fistulous tracts communicating with the jejunum. Biopsy from the growth indicated a poorly differentiated adenocarcinoma. Conservative and palliative treatment was provided. Clinical discussion: Clinical features of colo-enteric fistulas can include abdominal pain, diarrhea, and weight loss. The patient may be asymptomatic in some cases. Options for diagnosis include barium studies, enteroscopy, colonoscopy, CECT, and computed tomography enterography (CTE). Malignant bowel fistula is associated with serious complications resulting in high morbidity and mortality rates. Surgical resection and fistula repair are the mainstay of curative treatment. Conclusion: Long-standing gastrointestinal symptoms like chronic diarrhea in the elderly should be investigated with imaging modalities like CECT. Early detection with imaging can reduce debilitating metabolic and nutritional deficiencies and improve patient's morbidity and mortality.
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Peripheral T cell lymphomas are typically aggressive with a poor prognosis. Unlike other hematologic malignancies, the lack of target antigens to discriminate healthy from malignant cells limits the efficacy of immunotherapeutic approaches. The T cell receptor expresses one of two highly homologous chains [T cell receptor ß-chain constant (TRBC) domains 1 and 2] in a mutually exclusive manner, making it a promising target. Here we demonstrate specificity redirection by rational design using structure-guided computational biology to generate a TRBC2-specific antibody (KFN), complementing the antibody previously described by our laboratory with unique TRBC1 specificity (Jovi-1) in targeting broader spectrum of T cell malignancies clonally expressing either of the two chains. This permits generation of paired reagents (chimeric antigen receptor-T cells) specific for TRBC1 and TRBC2, with preclinical evidence to support their efficacy in T cell malignancies.
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Neoplasias , Linfocitos T , Humanos , Inmunoterapia , Receptores de Antígenos de Linfocitos TRESUMEN
A versatile, safe, and effective small-molecule control system is highly desirable for clinical cell therapy applications. Therefore, we developed a two-component small-molecule control system based on the disruption of protein-protein interactions using minocycline, an FDA-approved antibiotic with wide availability, excellent biodistribution, and low toxicity. The system comprises an anti-minocycline single-domain antibody (sdAb) and a minocycline-displaceable cyclic peptide. Here, we show how this versatile system can be applied to OFF-switch split CAR systems (MinoCAR) and universal CAR adaptors (MinoUniCAR) with reversible, transient, and dose-dependent suppression; to a tunable T cell activation module based on MyD88/CD40 signaling; to a controllable cellular payload secretion system based on IL12 KDEL retention; and as a cell/cell inducible junction. This work represents an important step forward in the development of a remote-controlled system to precisely control the timing, intensity, and safety of therapeutic interventions.
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Comunicación Celular , Minociclina , Minociclina/farmacología , Distribución Tisular , Antibacterianos/farmacología , Transducción de SeñalRESUMEN
CAR T cells recognizing CD19 effectively treat relapsed and refractory B-ALL and DLBCL. However, CD19 loss is a frequent cause of relapse. Simultaneously targeting a second antigen, CD22, may decrease antigen escape, but is challenging: its density is approximately 10-fold less than CD19, and its large structure may hamper immune synapse formation. The characteristics of the optimal CD22 CAR are underexplored. We generated 12 distinct CD22 antibodies and tested CARs derived from them to identify a CAR based on the novel 9A8 antibody, which was sensitive to low CD22 density and lacked tonic signaling. We found no correlation between affinity or membrane proximity of recognition epitope within Ig domains 3-6 of CD22 with CART function. The optimal strategy for CD19/CD22 CART co-targeting is undetermined. Co-administration of CD19 and CD22 CARs is costly; single CARs targeting CD19 and CD22 are challenging to construct. The co-expression of two CARs has previously been achieved using bicistronic vectors. Here, we generated a dual CART product by co-transduction with 9A8-41BBζ and CAT-41BBζ (obe-cel), the previously described CD19 CAR. CAT/9A8 CART eliminated single- and double-positive target cells in vitro and eliminated CD19- tumors in vivo. CAT/9A8 CART is being tested in a phase I clinical study (NCT02443831).
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Linfoma de Burkitt , Receptores Quiméricos de Antígenos , Humanos , Receptores Quiméricos de Antígenos/metabolismo , Linfocitos T , Recurrencia Local de Neoplasia , Inmunoterapia Adoptiva , Proteínas Adaptadoras Transductoras de Señales , Antígenos CD19 , Anticuerpos , Lectina 2 Similar a Ig de Unión al Ácido SiálicoRESUMEN
Chimeric antigen receptor (CAR) T cells targeting CD19 or CD22 have shown remarkable activity in B cell acute lymphoblastic leukemia (B-ALL). The major cause of treatment failure is antigen downregulation or loss. Dual antigen targeting could potentially prevent this, but the clinical safety and efficacy of CAR T cells targeting both CD19 and CD22 remain unclear. We conducted a phase 1 trial in pediatric and young adult patients with relapsed or refractory B-ALL (n = 15) to test AUTO3, autologous transduced T cells expressing both anti-CD19 and anti-CD22 CARs (AMELIA trial, EUDRA CT 2016-004680-39). The primary endpoints were the incidence of grade 3-5 toxicity in the dose-limiting toxicity period and the frequency of dose-limiting toxicities. Secondary endpoints included the rate of morphological remission (complete response or complete response with incomplete bone marrow recovery) with minimal residual disease-negative response, as well as the frequency and severity of adverse events, expansion and persistence of AUTO3, duration of B cell aplasia, and overall and event-free survival. The study endpoints were met. AUTO3 showed a favorable safety profile, with no dose-limiting toxicities or cases of AUTO3-related severe cytokine release syndrome or neurotoxicity reported. At 1 month after treatment the remission rate (that is, complete response or complete response with incomplete bone marrow recovery) was 86% (13 of 15 patients). The 1 year overall and event-free survival rates were 60% and 32%, respectively. Relapses were probably due to limited long-term AUTO3 persistence. Strategies to improve CAR T cell persistence are needed to fully realize the potential of dual targeting CAR T cell therapy in B-ALL.
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Antígenos CD19/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Receptores Quiméricos de Antígenos/administración & dosificación , Lectina 2 Similar a Ig de Unión al Ácido Siálico/genética , Adolescente , Adulto , Antígenos CD19/inmunología , Niño , Preescolar , Femenino , Humanos , Inmunoterapia/efectos adversos , Inmunoterapia/tendencias , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/tendencias , Lactante , Masculino , Pediatría , Supervivencia sin Progresión , Receptores Quiméricos de Antígenos/inmunología , Lectina 2 Similar a Ig de Unión al Ácido Siálico/inmunología , Adulto JovenRESUMEN
Raloxifene hydrochloride (R-HCl), a BCS class II drug, remains a mainstay in the prevention and pharmacologic therapy of osteoporosis. Its absolute bioavailability, however, is 2% due to poor solubility and extensive first pass metabolism. The present study describes two simultaneous approaches to improve its bioavailability, complexation of R-HCl with cyclodextrin(s), and formulation of mucoadhesive microspheres of the complex using different proportions of carbopol and HPMC. Microspheres were pale yellow in color, free-flowing, spherical, and porous in outline. The particle size ranged between 3 and 15 µm, and entrapment efficiency was found to be within 81.63% to 87.73%. A significant improvement in the solubility of R-HCl was observed, and it differed with the combination of excipients used. X-ray diffraction and differential scanning calorimetry studies revealed that enhancement in drug solubility was resulted due to a change in its crystallinity within the formulation. Microspheres possessed remarkable mucoadhesion and offered controlled drug release, lasting up to 24 h. They produced a sharp plasma concentration-time profile of R-HCl within 30 min post-administration to Wistar rats. [AUC](0-24 h) was found to be 1,722.34 ng h/ml, and it differed significantly to that of pure drug powder (318.28 ng h/ml). More than fivefold increase in AUC and more than twofold increase in MRT were observed. FT-IR studies evidenced no interaction among drug and excipients. The results of this study showed that mucoadhesive microspheres could be a viable approach to improve the pharmacokinetic profile of R-HCl.
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Química Farmacéutica/métodos , Microesferas , Clorhidrato de Raloxifeno/química , Clorhidrato de Raloxifeno/farmacocinética , Adhesivos Tisulares/química , Adhesivos Tisulares/farmacocinética , Animales , Disponibilidad Biológica , Química Farmacéutica/normas , Evaluación Preclínica de Medicamentos/métodos , Evaluación Preclínica de Medicamentos/normas , Femenino , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/metabolismo , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Masculino , Clorhidrato de Raloxifeno/normas , Ratas , Ratas Wistar , Solubilidad , Adhesivos Tisulares/normas , Difracción de Rayos X/métodos , Difracción de Rayos X/normasRESUMEN
Traumatic posterior dislocation of hip associated with ipsilateral displaced femoral neck fracture is a rare injury. Moreover, the management of such patients evokes strong views regarding primary replacement or preserving the femoral head. We presented a case of young adult with such an injury. He was operated upon with reduction of the dislocation and fixation of femoral neck fracture with the help of cancellous screws. Two years later, the fracture had united and the patient was asymptomatic. We further proposed the mechanism of injury for such a fracture and discussed the management in the changing trauma scenario of the developing world.
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Fracturas del Cuello Femoral/complicaciones , Luxación de la Cadera/complicaciones , Adulto , Fracturas del Cuello Femoral/cirugía , Fijación Interna de Fracturas , Luxación de la Cadera/cirugía , Humanos , MasculinoRESUMEN
BACKGROUND: Pilomatricoma, a benign skin adnexal tumor, frequently leads to false positive diagnosis cytologically. We report a rapidly growing nodular swelling misdiagnosed as round cell tumor cytologically and found to be pilomatricoma histopathologically. CASE: A 32-year-old man presented with a rapidly growing, mobile nodule on his left arm for 4 months with fixed, shiny overlying skin. Fine needle aspiration cytology (FNAC) sample was cellular, showing round to ovoid cells dispersed or in clusters with occasionally rosette-like appearance. Cells displayed round, granular nuclei, single to multiple small nucleoli, absent to scant cytoplasm, a moderate amount of granular cytoplasm and apoptotic and mitotic figures in places. Nuclear moldings were encountered occasionally. Cytologically the diagnosis of blue round cell tumor was made. Histopathologic examination showed islands of basaloid cells with scant cytoplasm and shadow cells and occasional giant cells. The diagnosis was pilomatricoma bistopathologically. Rapidly growing, early lesions of pilomatricoma are predominantly composed of basaloid cells and mostly devoid of other diagnostic clues, leading to a false impression of malignancy. To avoid misdiagnosis, all skin-based nodules should undergo extensive cytologic sampling from diferent sites. Pilomatricoma should be considered in diferential diagnosis when primitive-appearing cells are aspirated, especially in rapidly growing early lesions.