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Abstract: Evidence from previous studies supports the concept that spinal cord injury (SCI)-induced neuropathic pain (NP) has its neural roots in the peripheral nervous system. There is uncertainty about how and to which degree mechanoreceptors contribute. Sensorimotor activation-based interventions (eg, treadmill training) have been shown to reduce NP after experimental SCI, suggesting transmission of pain-alleviating signals through mechanoreceptors. The aim of the present study was to understand the contribution of mechanoreceptors with respect to mechanical allodynia in a moderate mouse contusion SCI model. After genetic ablation of tropomyosin receptor kinase B expressing mechanoreceptors before SCI, mechanical allodynia was reduced. The identical genetic ablation after SCI did not yield any change in pain behavior. Peptidergic nociceptor sprouting into lamina III/IV below injury level as a consequence of SCI was not altered by either mechanoreceptor ablation. However, skin-nerve preparations of contusion SCI mice 7 days after injury yielded hyperexcitability in nociceptors, not in mechanoreceptors, which makes a substantial direct contribution of mechanoreceptors to NP maintenance unlikely. Complementing animal data, quantitative sensory testing in human SCI subjects indicated reduced mechanical pain thresholds, whereas the mechanical detection threshold was not altered. Taken together, early mechanoreceptor ablation modulates pain behavior, most likely through indirect mechanisms. Hyperexcitable nociceptors seem to be the main drivers of SCI-induced NP. Future studies need to focus on injury-derived factors triggering early-onset nociceptor hyperexcitability, which could serve as targets for more effective therapeutic interventions., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Objective: The aim of the study was to assess factors determining the utilization of physical and occupational therapy in people with spinal cord injury., Design: Data from the German Spinal Cord Injury study conducted in 2017 were analyzed. The 12-mo prevalence of physical therapy and occupational therapy utilization was determined. To identify underlying determinants, multivariable logistic regression was used., Results: Of 1479 participants (response = 26.4%), 72.9% were male, with a mean (SD) age of 55.3 (14.6) yrs and a mean (SD) time since injury of 14.0 (12.0) yrs; 51.2% were people with paraplegia and 66.3% had an incomplete spinal cord injury. In the past 12 mos, 78.1% received physical and 29.3% occupational therapy. Physical therapy and occupational therapy were significantly associated with time since spinal cord injury occurrence, participation in lifelong care programs, and electric wheelchair dependency. Spinal cord injury characteristics, level of impairment, and time since spinal cord injury had a greater impact on occupational therapy than on physical therapy utilization., Conclusions: The use of physical therapy and occupational therapy is much higher in Germans with spinal cord injury than in the general population and in people with similar neurological conditions. Further research should focus on the frequency of use and the types of interventions. Guidelines for lifelong care should include recommendations on physical therapy and occupational therapy.

Below-level central neuropathic pain (CNP) affects a large proportion of spinal cord injured individuals. To better define the dynamic changes of the spinal cord neural network contributing to the development of CNP after spinal cord injury (SCI), we characterized the morphological and behavioral correlates of CNP in female C57BL/6 mice after a moderate T11 contusion SCI (50 kdyn) and the influence of moderate physical activity. Compared with sham-operated animals, injured mice developed mechanical allodynia 2 weeks post injury when tested with small-diameter von Frey hair filaments (0.16 g and 0.4 g filament), but presented hyporesponsiveness to noxious mechanical stimuli (1.4 g filament). The mechano-sensory alterations lasted up to 35 days post injury, the longest time point examined. The response latency to heat stimuli already decreased significantly 10 days post injury reaching a plateau 2 weeks later. In contrast, injured mice developed remarkable hyposensitivity to cold stimuli. Animals that underwent moderate treadmill training (2 × 15 minutes; 5 d/wk) showed a significant reduction in the response rate to light mechanical stimuli as early as 6 days after training. Calcitonin gene-related peptide (CGRP) labeling in lamina III-IV of the dorsal horn revealed significant increases in CGRP-labeling density in injured animals compared with sham control animals. Importantly, treadmill training reduced CGRP-labeling density by about 50% (P < 0.01), partially reducing the injury-induced increases. Analysis of IB4-labeled nonpeptidergic sensory fibers revealed no differences between experimental groups. Abnormalities in temperature sensation were not influenced by physical activity. Thus, treadmill training partially resolves signs of below-level CNP after SCI and modulates the density of CGRP-labeled fibers.

Study Design: Retrospective case series., Objective: To evaluate biopsy results obtained during vertebral augmentation (kyphoplasty) for presumed/confirmed osteoporotic vertebral compression fractures (VCFs)., Summary of Background Data: Kyphoplasty to augment vertebrae in osteoporotic VCFs is well established. When VCF etiology is in question, bone biopsy can be performed at that time. Biopsy results, however, can be misleading without careful clinical correlation., Methods: From July 2003 to July 2006, 94 vertebral biopsies were obtained from 66 patients during kyphoplasty for VCFs. Average patient age was 73 (range, 22-99), including 47 females and 19 males. There were 48 one-level, 17 two-level, and 4 three-level biopsies. Biopsy levels included: T6 (3), T7 (7), T8 (7), T9 (3), T10 (3), T11 (8), T12 (21), L1 (18), L2 (13), L3 (8), L4 (2), L5 (1). Histologic/immunohistochemical evaluations were performed., Results: All specimens showed features of fracture in various stages of bony healing. Initially, 13 of 66 (19.7%) cases were read by a surgical pathologist as chronic inflammation, with 6 having features suggestive of chronic osteomyelitis, including polyclonal plasma cells, necrosis, and lymphoplasmacytic infiltrate. For this study, these biopsies were evaluated by an independent surgical pathologist (N.W.). Re-review showed 7 of the 13 cases were consistent with osteoporotic VCF healing in various stages with adjacent trilineage hematopoiesis. Six of 13 (46%), were read as containing fragmented bony spicules, fibrotic and fatty marrow, lymphoplasmacytic inflammation, and aggregates of mature, polyclonal plasma cells, suggesting the possibility of chronic osteomyelitis. However, at average follow-up of 37 months (range, 21-57 months), no patient demonstrated clinical and/or laboratory evidence of infection. Additionally, biopsies from 4 patients confirmed suspected or unsuspected malignancy, or confirmed no recurrence of malignant disease., Conclusion: Patients undergoing first-time vertebral augmentation should be considered for vertebral biopsy. Tissue examination is useful and may reveal pathologic fracture or possible infection. However, if infection is reported, clinical and laboratory correlation are important to make a diagnosis of osteomyelitis.

Accurate diagnosis and grading of anal intraepithelial neoplasia (AIN) can be problematic, especially in separating AIN from anal transitional-zone epithelium. Immunohistochemistry (IHC) for p16 correlates with human papillomavirus (HPV) integration into the host genome, and HPV subtyping by in situ hybridization (ISH) is now readily available. To investigate if p16 would help in more accurately diagnosing and grading AIN, particularly when attempting to distinguish benign transitional-zone epithelium from high-grade AIN, we separately assessed these stains in a blinded manner on a large number of consecutive anal biopsies and anal tissues and correlated the findings with the diagnosis and grade of AIN. One hundred thirty-three consecutive anal tissue specimens, from 128 patients were studied. One hundred and eight were anal biopsies and 25 were hemorrhoidectomy specimens. All specimens were stained with hematoxylin and eosin, p16 (Lab Vision), and HPV-ISH (Ventana HPV-III Inform). No gold standard was chosen, rather, comparisons between the 3 tests were made and agreement between tests was tested for statistical significance using the kappa value (kappa). The comparisons included AIN grade (negative, 1, 2, 3) with nuclear intensity of p16 IHC (0 to 3+), AIN grade with IHC nuclear staining patterns (contiguous, patchy/rare), AIN grade with HPV-ISH [negative, low-risk (LR), high-risk (HR)] and, nuclear intensity of p16 IHC with HPV-ISH. One hundred percent of AIN2 and 3 cases were strongly positive for nuclear p16, whereas 80% of AIN1 were positive. Yet, 33% of AIN negative cases were positive for nuclear p16, although with less nuclear intensity than for AIN2 or 3. The kappa value for AIN/nuclear p16 intensity agreement was 0.61 (ie, substantial agreement). Seventy-nine percent of AIN3 cases were strongly positive for HR, and 9% for LR HPV; whereas 75% of AIN2 were positive for HR and 5% for LR HPV. Forty percent of AIN1 cases were positive for HR and 24% for LR HPV. Yet, 12.5% of AIN negative cases were positive for HPV for both LR and HR types. The kappa value for AIN/HPV agreement was 0.62 (ie, substantial agreement). One hundred percent of HR and 85% of LR HPV were positive for p16. Yet, 6% of negative p16 were positive for HPV (all were LR), whereas 43% of negative HPV showed some p16. Of the latter, 40% were 3+ by p16. The kappa value for HPV/nuclear p16 intensity agreement was 0.56 (ie, moderate agreement). Of interest, 30 cases were negative for AIN and p16 staining and of these, 2 (7%) were positive for HPV (both LR subtype). Three cases positive for HR HPV were negative for AIN with only patchy nuclear p16 positivity. We conclude that the correlation between AIN and p16 and HPV is strong enough to be quite useful in distinguishing true AIN from benign mimics, such as benign transitional-zone epithelium. In selected cases, p16 and HPV may be valuable in grading as well.

Approximately 10% to 20% of nonsmall cell lung cancer patients respond to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, such as gefitinib. Responders are mostly nonsmokers and women with tumors displaying bronchioloalveolar features. Mutations of the tyrosine kinase domain of the EGFR gene have been associated with a clinical response to gefitinib. A recent study reported that the terminal respiratory unit (TRU)-type adenocarcinoma shares the clinical profile and EGFR mutations of gefitinib responders. EGFR immunoreactivity in this context has not been reported in the literature. We performed a detailed immunohistochemical analysis of EGFR expression on 124 consecutive lung resection specimens for malignancy, to survey the EGFR immunoreactivity in lung cancers in general and to correlate EGFR immunoreactivity with EGFR mutations and TRU-type histology. EGFR positivity was seen most frequently in squamous cell carcinomas (77%), followed by TRU-type adenocarcinomas (63%), large cell carcinomas (23%), and non-TRU-type adenocarcinomas (12%). A distinctive basally oriented cytoplasmic positivity was observed exclusively in TRU-type adenocarcinomas. EGFR mutation was identified in 6 of 54 cases studied and all 6 cases were TRU-type adenocarcinomas. Five of six cases with EGFR mutation were positive for EGFR immunostain with the basal cytoplasmic localization. In conclusion, EGFR immunoreactivity with basal cytoplasmic pattern was exclusively seen in TRU-type adenocarcinoma and a subset of these cases was seen with EGFR mutations in the responders to EGFR inhibitor therapy.

Mutation of the platelet-derived growth factor receptor-alpha (PDGFRA) gene has been well documented as an alternative oncogenic mechanism in a subset of gastrointestinal stromal tumors (GISTs) lacking c-kit mutations. However, the role of PDGFRA immunohistochemistry in the diagnosis of GISTs has not been well studied. We investigated PDGFRA immunoreactivity in GISTs and in other intra-abdominal mesenchymal tumors, and correlated PDGFRA expression with CD117 positivity and with the mutational status of PDGFRA and c-kit genes. In addition, expression of phosphorylated AKT, an activated downstream molecule in the PDGFRA and c-kit signaling pathways, was correlated with PDGFRA and CD117 status. A total of 39 GISTs and 20 other mesenchymal tumors in the abdomen were included in this study. Thirty-five of 39 GIST cases (89.7%) were positive for PDGFRA and 19 of these 35 positive cases were strongly positive. Five of 20 non-GIST lesions (25%) were positive for PDGFRA, but none of these cases were strongly positive. With one exception, PDGFRA-positive cases were also positive for CD117. Phosphorylated AKT positivity was not associated with the immunoreactivity or mutation of PDGFRA and c-kit, suggesting that the activation of AKT is probably independent of the activation of PDGFRA and c-kit in GISTs. Of 14 GISTs assayed, 4 had mutations in c-kit at exons 11 or 17, and 4 had mutations in PDGFRA at exons 12 or 18. Three of 4 GIST cases with PDGFRA mutations show epithelioid morphology and strong PDGFRA immunoreactivity with prominent perinuclear dotlike accentuation (so-called Golgi pattern). In conclusion, strong PDGFRA positivity with Golgi pattern is a useful adjunct in the diagnosis of GISTs with PDGFRA mutation.

The authors report a unique case of an intra-abdominal, epithelioid mesenchymal tumor that had an activating mutation of PDGFRA and a strong PDGFRA immunoreactivity but lacked both c-kit mutation and c-kit protein (CD117) expression. IHC study showed that the tumor cells were diffusely and strongly positive for PDGFRA, vimentin, CD34, and Bcl-2 but completely negative for CD117 as well as for muscle, epithelial, endothelial, endocrine, mesothelial, neural, and melanocytic cell markers. Molecular study revealed a mutation at the juxtamembrane domain of exon 12 in PDGFRA gene with GTC to GAC transition at codon 561 (V561D), as shown in the previous mutational studies on gastrointestinal stromal tumor (GIST). This case likely represents an example of GIST with PDGFRA activating mutation and PDGFRA immunoreactivity without CD117 positivity, which has not been documented in the literature. STI 571 (imatinib mesylate [Gleevec]) might be an effective therapy in this case, since Gleevec targets both PDGFRA and c-kit oncoproteins.

Purpose of Review: Acute cerebral infarction causes irreversible locally restricted loss of the neuronal circuitry and supporting glial cells with consecutive functional deficits and disabilities. The currently available and effective therapy targets fast vessel recanalization accompanied by symptomatic measures. Research activities focusing on stem cells, which represent a promising source for organotypic cell replacement and functional recovery after stroke, have gained momentum in recent years, making regenerative cell-based therapies a much more feasible realistic approach. This review provides an update about preclinical and clinical cell-based studies in stroke focusing on stem cells derived from the adult central nervous and hematopoetic systems., Recent Findings: Endogenous neural stem cells, which have been shown to reside throughout life in the central nervous system, have the capacity to replace lost neurons in models for numerous disorders, including cerebral ischemia. Considering adult neural stem cell transplantation as a regenerative strategy after stroke, progress has been made in isolating human adult neural stem cells and demonstrating the feasibility of autologous neural stem cell transplantation. An increasing number of studies provide evidence that hematopoietic stem cells, either after stimulation of endogenous stem cell pools or after exogenous hematopoietic stem cell application (transplantation), improve functional outcome after ischemic brain lesions. Various underlying mechanisms such as transdifferentiation into neural lineages, neuroprotection through trophic support, and cell fusion have been deciphered., Summary: Many preclinical studies employing adult stem cell-based strategies hold great promise. For endogenous approaches the correlate of cell replacement underlying functional improvement needs to be demonstrated. Transplantation approaches on the experimental level need further development before clinical application can be considered.

Detecting Her2 gene amplification has become routine in predicting therapeutic responsiveness in patients with breast carcinoma. Fluorescence in situ hybridization (FISH) is a common technique for detecting Her2 amplification, yet dark field fluorescence microscopy remains problematic for many pathologists. Thus, a technique such as chromogenic in situ hybridization (CISH), in which the more familiar light microscopy can be used, is appealing. Paraffin-embedded sections from 61 breast carcinomas were tested for Her2 amplification by immunohistochemistry (IHC) and CISH. FISH was used to confirm CISH results. Excellent correlation was found between IHC and CISH except in cases considered negative (1+ on the DAKO scale) by IHC. CISH detected low-level Her2 amplification in 4 of 9 of these cases. Amplification was subsequently confirmed by FISH in all but 1 case. When compared with FISH, CISH was more sensitive than IHC for detecting low levels of Her2 gene amplification. Moreover, excellent concordance was found between FISH and CISH, supporting the conclusion that the CISH assay for Her2 gene amplification provides an accurate, effective, and practical alternative to FISH.

The morphologic distinction between papillary and follicular neoplasms of the thyroid gland can be difficult, especially on small biopsy specimens or in fine-needle aspirations. To determine whether immunohistochemistry could help in achieving the correct diagnosis, we characterized the staining pattern for a series of papillary and follicular neoplasms of the thyroid gland. A pilot study was performed using a panel of antibodies, including high-molecular-weight keratin (HMWK, 34 beta E12), cytokeratin (CK) 5/6, CK7, CK13, CK14, CK20, AE1/AE3, CAM5.2, involucrin, and villin. Of these antibodies, involucrin and HMWK showed strong differential staining between follicular and papillary neoplasms. HMWK stained 91% of papillary carcinomas, including follicular variants, with a median of 53% positive cells, and involucrin stained 72.5% of papillary neoplasms with a median of 45% positive cells. HMWK stained only 20% of follicular neoplasms, whereas involucrin stained 29% of cases. Papillary neoplasms showed strong, although patchy, staining with HMWK and involucrin, whereas those follicular neoplasms that did have staining showed a weak, diffuse pattern of staining. We believe that HMWK, and involucrin to a lesser degree, could be useful in differentiating papillary from follicular neoplasms, especially for cytologic cell block material or for cases in which the architectural pattern is follicular.

With greater public awareness and use of mammography, more breast carcinomas are detected early, before the axillary lymph nodes contain metastases. About 60% of patients will be node-negative; yet 20-30% of node-negative breast carcinoma patients will develop recurrent tumors, and they are at risk of dying of disease. These patients should be considered for adjuvant therapies, whereas the remaining 70-80% appear to be cured by surgery. Thus, accurate assessment of risk factors for recurrence provides valuable therapeutic information. This review focuses on recent reports that help identify subsets of patients at variable risk for recurrent disease.

We report a unique carcinosarcoma of the ovary having an organoid growth pattern that resembled immature teratoma. The tumor contained both adenocarcinoma and squamous carcinoma (focally sebaceous) admixed with chondrosarcoma, rhabdomyosarcoma, and malignant neuroectodermal components. The neuroectodermal components were prominent, resembling ependymoblastoma, medulloepithelioma, ganglioneuroblastoma, glioblastoma multiforme, and pigmented neuroectodermal tumor. Immunohistochemical studies dramatically revealed carcinoma and rhabdomyosarcoma admixed with malignant neuroectodermal tumor. Implants of papillary serous carcinoma (with psammoma bodies) were present in the opposite ovary, uterine serosa, omentum, and appendiceal serosa. Although a variant not previously described in the ovary, this ovarian carcinosarcoma closely resembled nasopharyngeal tumors described as teratoid carcinosarcoma or terato-carcinosarcoma.