In-depth characterization of a new patient-derived xenograft model for metaplastic breast carcinoma to identify viable biologic targets and patterns of matrix evolution within rare tumor types.

Metaplastic breast carcinoma (MBC) is a rare breast cancer subtype with rapid growth, high rates of metastasis, recurrence and drug resistance, and diverse molecular and histological heterogeneity. Patient-derived xenografts (PDXs) provide a translational tool and physiologically relevant system to evaluate tumor biology of rare subtypes. Here, we provide an in-depth comprehensive characterization of a new PDX model for MBC, TU-BcX-4IC. TU-BcX-4IC is a clinically aggressive tumor exhibiting rapid growth in vivo, spontaneous metastases, and elevated levels of cell-free DNA and circulating tumor cell DNA. Relative chemosensitivity of primary cells derived from TU-BcX-4IC was performed using the National Cancer Institute (NCI) oncology drug set, crystal violet staining, and cytotoxic live/dead immunofluorescence stains in adherent and organoid culture conditions. We employed novel spheroid/organoid incubation methods (Pu·MA system) to demonstrate that TU-BcX-4IC is resistant to paclitaxel. An innovative physiologically relevant system using human adipose tissue was used to evaluate presence of cancer stem cell-like populations ex vivo. Tissue decellularization, cryogenic-scanning electron microscopy imaging and rheometry revealed consistent matrix architecture and stiffness were consistent despite serial transplantation. Matrix-associated gene pathways were essentially unchanged with serial passages, as determined by qPCR and RNA sequencing, suggesting utility of decellularized PDXs for in vitro screens. We determined type V collagen to be present throughout all serial passage of TU-BcX-4IC tumor, suggesting it is required for tumor maintenance and is a potential viable target for MBC. In this study we introduce an innovative and translational model system to study cell-matrix interactions in rare cancer types using higher passage PDX tissue.

Glossopharyngeal nerve regeneration is essential for the complete recovery of quinine-stimulated oromotor rejection behaviors and central patterns of neuronal activity in the nucleus of the solitary tract in the rat.

The peripheral, central, and behavioral consequences of glossopharyngeal nerve transection (GLX), regeneration, and the prevention of regeneration on the quinine-elicited responses of adult rats were concurrently examined. Oromotor taste reactivity (TR) was videotaped during intraoral infusion of 7 ml of either quinine (3 mm) or distilled water at 17, 52, or 94 d after surgery. We confirmed previous findings by showing that 17 d after neurotomy, (1) the number of circumvallate (CV) and foliate taste buds, (2) gapes (a characteristic aversive TR response), and (3) the number of Fos-like immunoreactive (FLI) neurons in the gustatory NST (gNST), particularly in the medial portion (subfield 5) of the rostral central subdivision (RC), were all severely attenuated in GLX rats. We extended these findings by showing that these lesion-induced effects were enduring when the GL did not regenerate (up to 94 d). In contrast, when the GL regenerated, as few as 52 d were sufficient to re-establish quinine-elicited TR, especially gaping, and FLI expression in RC, particularly within subfield 5, to values comparable with quinine-stimulated sham-operated rats. Evidently, the gNST maintains its potential to restore accurately the organization of neural activity that is disrupted by nerve injury, as assessed by FLI, ultimately leading to the return of normal protective oromotor responses, provided the nerve regenerates. This recovery was complete despite the reappearance of a reduced population of CV taste buds ( approximately 75% control values) and may relate to peripheral and/or central changes that occur in tandem with regeneration of the GL.

Glossopharyngeal nerve transection eliminates quinine-stimulated fos-like immunoreactivity in the nucleus of the solitary tract: implications for a functional topography of gustatory nerve input in rats.

The relationship between specific gustatory nerve activity and central patterns of taste-evoked neuronal activation is poorly understood. To address this issue within the first central synaptic relay in the gustatory system, we examined the distribution of neurons in the nucleus of the solitary tract (NST) activated by the intraoral infusion of quinine using Fos immunohistochemistry in rats with bilateral transection of the chorda tympani (CTX), bilateral transection of the glossopharyngeal nerve (GLX), or combined neurotomy (DBLX). Compared with nonstimulated and water-stimulated controls, quinine evoked significantly more Fos-like-immunoreactive (FLI) neurons across the rostrocaudal extent of the gustatory NST (gNST), especially within its dorsomedial portion (subfield 5). Although the somatosensory aspects of fluid stimulation contributed to the observed increase in FLI neurons, the elevated number and spatial distribution of FLI neurons in response to quinine were remarkably distinguishable from those in response to water. GLX and DBLX produced a dramatic attenuation of quinine-evoked FLI neurons and a shift in their spatial distribution such that their number and pattern were indiscernable from those observed in water-stimulated controls. Although CTX had no effect on the number of quinine-evoked FLI neurons within subfield 5 at intermediate levels of the gNST, it produced intermediate effects elsewhere; yet, the spatial distribution of the quinine-evoked FLI neurons was not altered by CTX. These findings suggest that the GL provides input to all FLI neurons responsive to quinine, however, some degree of convergence with CT input apparently occurs in this subpopulation of neurons. Although the role of these FLI neurons in taste-guided behavioral responses to quinine remains speculative, their possible function in oromotor reflex control is considered.

Recurrent nocardiosis in a renal transplant recipient.

As the case presented here illustrates, nocardiosis, like other infections in which cell-mediated immunity plays a large defensive role, can relapse after apparent cure and occasionally at times remote from the original infection. Although relapse in patients with transplants has been cited as a reason for continued prophylaxis, only a few of these cases are adequately documented. This case supports the advice of those authors who give suppressive antibiotic therapy for the duration of immunosuppression in transplant recipients recovering from infections due to Nocardia sp. Alternatively, many transplant centers are routinely using TMP/SMX chemoprophylaxis in all solid organ transplantations to prevent opportunistic infections with Pneumocystis and Listeria sp. Primary prophylaxis has also been associated with a decreased incidence of nocardial infections.

Preoperative lymph node evaluation in prostatic cancer patients who are surgical candidates: the role of lymphangiography and computerized tomography scanning with directed fine needle aspiration.

A total of 53 consecutive patients who were candidates for surgical treatment of prostatic cancer underwent preoperative evaluation of the lymph node status by computerized tomography scanning and/or lymphangiography combined with skinny needle aspiration biopsy of any abnormal lymph nodes. In 7 of 14 patients (50 per cent) ultimately found to have stage D1 disease lymphatic metastases were confirmed histologically with needle biopsy alone, thus, obviating the need for pelvic lymph node dissection. Over-all sensitivity, specificity and accuracy rates were 50, 100 and 91.4 per cent, respectively, for computerized tomography scanning with biopsy and 53.8, 100 and 84.1 per cent, respectively, for lymphangiography with biopsy. Computerized tomography scanning and lymphangiography with aspiration biopsy are cost-effective means to identify approximately 50 per cent of the patients who ultimately have lymphatic metastases.

A comparison of clinical course with blood group antigen testing by specific red cell adherence and immunoperoxidase in ureteral and renal pelvic tumors.

Specimens of transitional cell carcinoma of the ureter and renal pelvis from 20 patients were tested for blood group antigenicity using immunoperoxidase and specific red cell adherence methods. The results of antigen testing were correlated with tumor stage and grade as well as the subsequent clinical course of the patients. The specific red cell adherence test was negative in 80 per cent and the immunoperoxidase test was negative in 40 per cent of all tumors. Of the 4 patients with positive specific red cell adherence tests 3 had high grade (II to III), invasive tumors as did 7 of 12 with tumors that were positive by immunoperoxidase testing. Blood group antigen testing did not prove helpful in predicting the clinical course of our patients. In addition, a careful review of previously published data does not support the conclusion that blood group antigen testing is a valuable predictor of upper tract tumor aggressiveness.

Immunohistochemical demonstration of blood group antigens in neoplastic and normal human urothelium: a comparison with standard red cell adherence.

The specific red cell adherence test as a method to detect blood group antigen deletion in urothelial malignancy has been reported to yield approximately 40 per cent false negative results in 0 blood group patients. Our study of multiple sections of 8 normal ureters from blood group 0 patients and more than 220 specimens of transitional cell cancer taken from 48 patients reveals that the immunoperoxidase technique is more specific than the specific red cell adherence method in predicting subsequent invasion in blood group O(H) patients presenting with superficial transitional cell carcinomas (71 compared to 29 per cent) but is no more specific for tumors containing A or B antigens. However, immunoperoxidase staining does improve discernment of underlying histologic detail and, thereby, facilitates recognition of false positive antigen testing associated with squamous and adenomatous metaplasia. Areas of squamous and adenomatous metaplasia in specimens we tested were frequently antigen positive in invasive tumors. Therefore, we believe that these areas must be disregarded in determining antigen deletion in transitional cell carcinomas.