A 60-year-old female patient with a medical history of hypertension came to our attention because of several neurological deficits that had developed over the last few years, significantly impairing her daily life. Four years earlier, she developed sudden weakness and hypoesthesia of the right hand. The symptoms resolved in a few days and no specific diagnostic tests were performed. Two months later, she developed hypoesthesia and weakness of the right lower limb. On neurological examination at the time, she had spastic gait, ataxia, slight pronation of the right upper limb and bilateral Babinski sign. Brain MRI showed extensive white matter hyperintensities (WMHs), so leukodystrophy was suspected. However, these WMHs were located bilaterally in the corona radiata, basal ganglia, the anterior part of the temporal lobes and the medium cerebellar peduncle (A–D), and were highly suggestive of CADASIL. Genetic testing was performed, showing heterozygous mutation of the NOTCH3 gene (c.994 C<T; exon 6). The diagnosis of CADASIL was confirmed and antiplatelet prevention therapy was started. Since then, her clinical conditions remained stable, and the lesion load was unchanged at follow-up brain MRIs for 4 years until November 2020, when the patient was diagnosed with COVID-19 after a PCR nasal swab. The patient developed only mild respiratory symptoms, not requiring hospitalization or any specific treatment. Fifteen days after the COVID-19 diagnosis, she suddenly developed aphasia, agraphia and worsened right upper limb motor deficit, but she did not seek medical attention. Some days later, she reported these symptoms to her family medical doctor, and a new brain MRI was performed, showing a subacute ischemic area in the left corona radiata (E,F). Therapy with acetylsalicylic acid was switched to clopidogrel as secondary prevention, while her symptoms improved in the next few weeks. The patient underwent a carotid doppler ultrasound and an echocardiogram, which did not reveal any pathological changes. The review of the blood pressure log, both in-hospital and the personal one the patient had kept, excluded uncontrolled hypertension.


The mother, 34-years old, primigravida (G0P0), underwent all recommended tests. The first-trimester morphology scan revealed normal crown-rump length, visible nasal bone, and normal nuchal translucency value. Moreover, the double marker for chromosomal aneuploidies (13, 18, and 21) indicated a low-level risk. The TORCH IgM and IgG screening showed no acute or recent infection (negative IgM), and the IgG titer was high. The woman had not been previously exposed to harmful factors that would have justified placing the pregnancy in the high-risk category. The second-trimester morphology scan performed at 22 weeks confirmed the normal development of a female fetus.
However, at 33 weeks of pregnancy, the first abnormal sign was noted. The amniotic fluid quantity started to increase, leading to the diagnosis of polyhydramnios. Another visible alteration was the shape and position of the lower fetal limbs, indicating minor clubfoot and altered fetal biophysical profile. By the time the pregnancy reached 36 weeks, the biophysical variables were severely modified. The fetal heart rate monitored using the non-stress test was worrying. There were significant decelerations, abnormal fetal movement, and poor muscular tonus. Additionally, the quantity of amniotic fluid continued to rise. Cumulatively, these observations led to the decision to deliver the baby prematurely via emergency C-section, 36 weeks into the pregnancy.
The C-section was uneventful, and the mother made a fast recovery, but the female newborn weighing 2200 g received an APGAR score of 3. Unfortunately, when thoroughly examined by our team, it was noticeable that the fetus’s movement, breathing, and swallowing capacity were impaired, and she was unable to sustain spontaneous breathing. The newborn was constantly and fully dependent on assisted mechanical ventilation. Her condition continued to deteriorate despite all the efforts. Unfortunately, at two months of age, the baby succumbed to respiratory failure and multiple associated complications.
Based on the clinical signs and paraclinical tests, we were able to establish the following diagnostics: generalized congenital muscular atony, right diaphragmatic hernia, cerebral atrophy, neonatal anemia, bilateral varus equinus, neonatal hypocalcemia, prematurity and low birth weight, ostium secundum atrial heart defect, and tricuspid valve dysplasia.
Thoracic X-rays show reduced ribcage expansion of the right hemithorax, suggestive of right diaphragmatic hernia. The transfontanelar ultrasound and head CT showed moderate cerebral atrophy, mostly in the frontal lobe. The generalized and severe muscular hypotonia was investigated using a muscular biopsy that showed no significant alterations. Both tests for aminoacidopathies and spinal muscular atrophy were negative. Serum levels of creatine kinase (CK) and lactate dehydrogenase (LDH) were high but with a tendency to normalize. The karyotype showed a normal profile 46XX.
Given the multitude of heterogenic clinical symptoms, we suspected a genetic syndrome yet to be diagnosed, so we proceeded to perform an Array Comparative Genome Hybridization (aCGH) with Single Nucleotide Polymorphism (SNP). aCGH+SNP was conducted on a blade with 4 ∗ 180,000 (180 K) samples (110.112 CGH samples, 59.647 SNP samples, 3000 replicated samples and 8121 control samples) covering the entire human genome with a spatial resolution of ~25.3 kb DNA (G4890A, design ID: 029830, UCSC hg19, Agilent). The scans were interpreted with the CytoGenomics Agilent software, using standard interpretation parameters with a SureScan Microarray Scanner. The resulting profile was abnormal: there were three areas associated with loss of heterozygosity on chromosomes 1 (q25.1–q25.3) of 6115 kb, 5 (p15.2–p15.1) of 2589 kb and 8 (q11.21–q11.23) of 4830 kb, a duplication of 1104 kb on chromosome 10 in the position q11.22, and duplication of 1193 kb on chromosome 16 in the position p11.2p11.1.
Considering this abnormal genetic profile, the parental couple received genetic counseling. Furthermore, we continued to test both partners through Next Generation Sequencing (NGS) by Illumina.
The results confirmed the following abnormal genetic profile; TTN (NM_001267550.1, sequencing): heterozygous variant on Chr2(GRCh37):g.179479653G>C—TTN variant c.48681C>G p.(Tyr16227*)—exon 260, heterozygous variant on Chr2(GRCh37):g.179396832_179396833del—TTN variant c.104509_104510del p.(Leu34837Glufs*12)—exon 358 (TTN: NM_001267550.1—reference sequence). The TTN variant c.48681C>G p.(Tyr16227*) creates a premature stop codon. Sanger sequencing also confirmed this variant and was classified as likely pathogenic (class 2). The TTN variant c.104509_104510del p.(Leu34837Glufs*12) creates a shift in the reading frame starting at codon 34837. The new reading frame ends in a stop codon 11 positions downstream. This variant has been confirmed by Sanger sequencing, and it is also classified as likely pathogenic (class 2) ().
In light of the clinical outcomes, based on the previous unfortunate experience, the couple agreed to receive genetic counseling. The couple was advised to pursue in vitro fertilization (IVF) with preimplantation genetic testing (PGT-M). Considering the mother’s age and weight, her Anti-Müllerian hormone (AMH) serum level and antral follicle count, we used a short-antagonist ovarian stimulation (OS) protocol with 200 UI of FSH (follitropin beta) concomitantly with 150 UI of combined FSH and LH (menotropin). Ten days later, seven oocytes were retrieved through transvaginal, sonographically controlled follicle puncture. Five of them were injected through intracytoplasmic intracytoplasmatic sperm injection (ICSI), resulting in two blastocysts. The embryonic biopsy was performed on day 6 of the blastocyst stage for these two embryos ().
The amplification of the entire genome was performed using the SurePlex DNA Amplification System by Illumina Inc. 2018, California US. Using the BlueFuse Multi Analysis Software (Illumina Inc. 2018, San Diego, CA, USA), all 24 chromosomes were detected euploid for embryos. The identification of the mutation TTN gene on exon 358 (father’s mutation) and exon 260 (mother’s mutation) was performed only for euploid embryos using Sanger sequencing with specific primers on ABI 3500. PCR products for both embryos were purified and sequenced in both senses with a BigDye Terminator v3.1 Cycle Sequencing Kit by Thermo Fisher Scientific. Specific primers were manually designed according to both mutations and tested afterwards using blood samples from the parents. Both embryos tested by PGT-A were euploid. One of them was a carrier of the mother’s mutation c.48681C>G p.(Tyr16227), exon 260, and the other was a wild type (WT) for both mutations ().
We performed a frozen-thawed embryo transfer in the following cycle, transferring the WT euploid embryo after endometrial preparation with exogenous estrogen. The result was positive, and we confirmed the ongoing viable pregnancy via ultrasound 14 days after.
Throughout the pregnancy, we performed the non-invasive double marker test (low-risk result) and fetal DNA analysis using maternal blood (low-risk result) and an invasive amniocentesis at 17 weeks of gestation, indicating a normal genetic profile. To test whether or not the second fetus presents a genetic abnormality, we extracted the DNA directly from the amniotic fluid. Targeted sequencing was performed on both DNA strands of the relevant TTN region. The reference sequence is TTN: NM_001267550.2. To exclude maternal cell contamination (MCC), we analyzed 15 STR autosomal markers plus amelogenin using the PowerPlex 16HS multiplex kit (Promega, Madison, Wisconsin, USA). Moreover, all the non-invasive ultrasound scans showed a normal growth rate and organ development. The evolution of the pregnancy was uneventful, and at 38 weeks, we carried out the C-section delivery of a healthy female baby of 2990 g, receiving an APGAR score of 9.


We report the case of a 31-year-old Caucasian woman, gravida 3, para 1, who was referred after a second trimester fetal anatomy screening at 20 weeks gestational for a suspicion of a complex fetal cardiac malformation, for which several specialized opinions tried to reach consensus.
The obstetrical history of the patient includes a previous Caesarian section with a normal course of parturition and a spontaneous miscarriage. The current pregnancy presented a low risk for aneuploidy according to the performed cell-free fetal DNA test. The classical karyotype performed after the abortion did not reveal any chromosomal abnormalities.
Previous ultrasound evaluations were incongruent and reported the following findings:an isolated aortic arch anomaly (supposedly aneurysmal dilation from which the left common carotid artery emerges) and coarctation of the aorta with the anterograde flow; ventricular septal defect, coarctation of the aorta, and a vascular formation located superior from the aortic arch with the appearance of an arteriovenous fistula; aneurysmal dilation located above the pulmonary trunk bifurcation and a dilated left common carotid artery with a retrograde flow; minor ventricular septal defect with a normal ductus venosus triphasic flow.
We performed fetal echocardiography, which demonstrated a mild cardiomegaly with a left deviated 72-degree heart axis, normal aspect of the four-chamber view, a small membranous ventricular septal defect, and ductal aortic coarctation; the ductus venosus flow was normal (, and ). In addition, we identified an aneurysmal structure measuring 1.63/1.25/1.16 cm with turbulent Doppler flow, situated above the emergence of the pulmonary trunk and continued by a dilated vascular structure that bifurcates in the cervical region; the aneurysm seemed connected to the left pulmonary artery as well. A dilated left subclavian artery was also suspected (, and ).
In the context of complex cardio-vascular malformations, the patient requested the termination of the pregnancy by drug-induced abortion.
The hands-on dissection of the fetus revealed a set of abnormalities that could stand as an anatomical basis for what has been found during the ultrasound examination.
The first and the most pronounced aspect was the distention of the whole venous system of the neck and mediastinum. The specimen presented a linguo-facial vein that described a rather sinuous pathway alongside the inferior margin of the mandible (). Both the linguo-facial vein and the external jugular vein appeared with a markedly increased caliber, around 4–5 times larger than expected for this gestational age. Both left and right jugular veins and the right subclavian vein were assessed as three times larger than usual, respecting the normal relations to the neighboring structures ( and ).
The confluence between the left jugular and subclavian vein into the left brachiocephalic vein was observed to be very dilated to superior and inferior, extending above the superior margin of the omohyoid muscle as well as below the inferior concavity of the aortic arch. Moreover, on the inferior side of the enlarged brachiocephalic vein, a vessel could be observed descending lateral to the left vagus nerve and communicating with the left pulmonary artery. The left pulmonary artery was observed to be dilated as well, around twice as normal ().
Regarding the great vessels of the heart, there are some anomalies to be discussed. A narrowing of the aortic arch was identified distally to the emergence of the left subclavian artery ( and ). A large, patent ductus arteriosus was found, ending right at the narrowing level observed in the aortic arch (ending right at the coarctation level) (). The left subclavian artery was dilated as well, sizing as much as the ascending aorta and the aortic arch, creating the illusion of a terminal branch rather than a lateral one ( and ).
Heart analysis concluded no distinct changes in heart architectural formation for this gestational age. Atrioventricular and ventriculoarterial concordance was noted. Atria and ventricles were increased in relation to the mediastinum. Surprisingly for an aortic coarctation, the right atrium was not found to be enlarged.


Female, 83 years old (y/o), with hypertension, hypercholesterolemia, carotid vasculopathy (type III, AHA) and history of (h/o) smoking affected by degenerative aortic stenosis, underwent valvular replacement with a St. Jude 21 mm mechanical prosthesis in 2000. Twenty years later, she was hospitalized for respiratory distress. TTE showed left ventricle (LV) dysfunction with severe prosthetic valve stenosis (aortic acceleration time (AAT): 140 ms, transaortic maximum speed: 4.8 m/s, maximum/median gradient: 90/52 mm Hg, indexed effective orifice area (EOA): 0.3 cm2/mq, EF: 35%). TEE showed hypomobility of the anterior leaflet. Due to the shielding from the prosthesis, it was unclear if there was a thrombus or a pannus (). As it is possible to differentiate between a pannus and a thrombus due to their different radiological density (HU > 145 and > 90, respectively) [], MDCT was performed, and it showed that the anterior aortic leaflet was stuck and surrounded by hypodense tissue (Hounsfield units (HU): 203.8) interposed between native and prosthetic annuli (effective orifice area (EOA): 45 mm2, EOA/0.15) indicating a pannus (a–c). This information was of utmost importance as instead of staring anticoagulant treatment, the patient directly underwent repeat surgical repair with a bioprosthesis. The diagnosis of pannus was confirmed by pathology.


Female, 44 y/o, affected by mitral valve (MV) dysplasia (parachute valve with double medioposterior papillary muscle) and subaortic stenosis caused by a fibromuscular ring, underwent subaortic membrane resection and septal myectomy in 1989. Due to worsening exertional dyspnea and persistence of subaortic stenosis, a St. Jude Regent 17 mm was implanted in 2006 (40 y/o) with improvement of her physical condition. In the last 2 years, TTE detected a progressive increase of the intraventricular gradient with LV hypertrophy (maximum speed, 4.1 m/s, maximum/median gradient: 64/39 mm Hg). TEE performed in May 2020 showed normal excursion of the prosthesis’ leaflets and confirmed severe subaortic stenosis (speed: 5.5 m/s, maximum/median gradient: 120/63 mm Hg) (). New subaortic membrane formation (SAM) was suspected but not clearly detected by TEE. MDCT provided accurate 3D reconstructions of the LV outlet tract (LVOT) with a better topographic assessment of the new SAM and its surrounding structures. The SAM was located 7 mm below the aortic prosthetic annulus, with the maximum thickness of 5 mm and hemicircumferential extension along the interventricular septal surface. This information was crucial to guide surgical excision of the SAM (a,b).


Male, 80 y/o, with a metabolic syndrome. He underwent thromboendarterectomy because of right internal carotid artery serrate stenosis. Due to bivasal critical coronary stenosis (anterior descending (DA) and left circumflex (LCx)) and severe degenerative aortic stenosis, he underwent coronary artery bypass graft (CABG: left internal mammary artery (LIMA-IVA)) and aortic bioprosthesis implantation (Intuity 25 mm) in 2019. Ten months after surgery, he started developing intermittent fever with serial hemocultures growing Enterococcus faecalis. TTE detected paravalvular regurgitation (PVR) with focal hyperechogenic thickening of the leaflets. Diagnosis of endocarditis was made, and antibiotic treatment was started (meropenem shifted to ampicillin and ceftriaxone according to the antibiogram). TEE showed a pulsatile perivalvular pseudoaneurysm in the mitroaortic intervalvular fibrosa (). MDCT was performed a few hours later, confirming the presence of a pseudoaneurysm with the maximum axial size of 15 × 10 × 30 mm communicating with LVOT through a 5 mm window, and also detected a periaortic abscess in the anterolateral side of the vessel with longitudinal extension of 4 cm, which was only poorly detected by TEE (a–c).


Male, 69 y/o, with hypertension, hypercholesterolemia and previous myocardial infarction. He was affected by severe degenerative aortic stenosis and underwent trans-catheter aortic valve replacement (TAVR) with LOTUS Edge 27 mm in April 2020. TTE performed a few days after the TAV implantation detected an increased transprosthesis gradient (maximum/median gradient, 78/52 mm Hg) in the absence of fever or positive hemoculture. TEE showed hypomobility of the noncoronary cusp of the bioprosthesis (). Valve’s thrombosis was suspected and heparin administration was started. MDCT detected a paravalvular leak caused by misfolding of the prosthesis’ frame; the suspicion of valve thrombosis was also confirmed by the finding of two hypodense appositions at the lower edge of the valve. The patient underwent balloon valvuloplasty with complete resolution of the valvular dysfunction (a–c).


A 12-year-old girl developed abdominal pain and reported frequent bloody stools for over a month. She had been diagnosed with moderate left-sided UC at nine years of age. Remission was initially induced with prednisolone, and she remained in remission with azathioprine due to mesalazine intolerance. She experienced moon face and increased appetite as side effects while taking prednisolone. She was later diagnosed with a UC relapse based on colonoscopic findings of marked erythema and the absence of vascular pattern. Because of the side effects of previous prednisolone therapy, the patient and her guardian declined further steroid therapy. We decided to induce remission with GMA. However, securing two blood vessels for GMA was expected to be difficult because of the patient's small anthropometric measurement (height: 134.9 cm, weight: 31.7 kg). Therefore, we elected to perform GMA with the single-needle method. She underwent GMA once per week for 10 weeks. A 17-gauge dialysis puncture needle (outer diameter: 1.4 mm, length: 25 mm) was inserted into the right elbow (). The dialysis console processed a blood flow rate of 40 mL/min (total blood volume: 1,800 mL). In this case, the treatment time was 90 minutes. No decrease in blood pressure was observed during this procedure. Heparin was used as an anticoagulant. All 10 GMA treatments were completed without puncture failure or poor blood removal. Additionally, no side effects were observed. However, the patient did not attain remission with GMA. After an unsuccessful attempt of oral tacrolimus therapy, remission could be achieved and has maintained with infliximab (5 mg/kg, every 8 weeks) for 10 months.


A 70-year-old Caucasian woman with medical history significant for stage III chronic kidney disease, transitional cell ureteral cancer status post-left-sided nephroureterectomy, and three-year history of Waldenstrom's macroglobulinemia (WM) presented with complaints of right-sided weakness associated with paresthesias, dysarthria, and blurry vision of three weeks duration. Magnetic resonance (MRI) imaging of the brain demonstrated an enhancing, hypercellular mass centered in the left thalamus with additional foci of signal abnormality and enhancement in the cortex of the left frontal lobe and subcortical white matter (Figure ). These findings were concerning for an intracranial neoplastic process, especially given her history of WM.
Regarding her oncological history, she was initially diagnosed with WM at the age of 67 after workup for complaints of chronic fatigue revealed elevated IgM levels (3370 mg/dl) as well as serum hyperviscosity. Bone marrow biopsy showed a low-grade B-cell lymphoma with plasmacytic differentiation and 60%–70% bone marrow involvement. Neoplastic cells were found to be lambda restricted and negative for CD5, CD10, and CD23 by flow cytometry. An increased number of lambda predominant cells were confirmed by flow cytometry and CD138 immunostaining. The patient was started on first-line therapy with the Bruton tyrosine kinase inhibitor ibrutinib; however, due to worsening adverse effects after 6 months of therapy she transitioned to rituximab, an anti-CD20 monoclonal antibody. Unfortunately, the patient was found to have worsening IgM levels and serum viscosity while on rituximab monotherapy over the next 6 months. Thus, she was restarted on ibrutinib while continuing rituximab every 3 months and had significant improvement on this combination of therapy.
She completed two years of maintenance rituximab and reduced-dose ibrutinib (140 mg) at time of presentation with the most recent IgM levels of 299 mg/dl prior to the onset of her previously mentioned neurological symptoms. Given her MRI findings, computed tomography (CT) imaging of the head, chest, abdomen, and pelvis was completed, which revealed multiple intracranial lesions but no evidence of lymphadenopathy or neoplastic process elsewhere. She further underwent lumbar puncture for cerebral spinal fluid (CSF) analysis with flow cytometry showing mostly T cells without evidence of B-cell non-Hodgkin lymphoma. As there remained high suspicion for central nervous system (CNS) lymphoma, the patient ultimately had a left parietal stereotactic brain biopsy with pathology findings of diffuse aggressive B-cell non-Hodgkin lymphoma (Figure ). Immunohistochemical studies were positive for CD20, CD23, BCL-6, MUM1, and LE1 (Figure ) with approximately 80% of cells expressing Ki-67 proliferation antigen (Figure ). Fluorescent in situ hybridization (FISH) analysis was negative for c-MYC, BCL-6, or BCL2 gene rearrangements. Lastly, mutation testing using next-generation sequencing returned positive for MYD88 L265P mutation.
The patient was placed on oral dexamethasone 4 mg four times daily with noticeable improvement in her speech and mobility. Due to the patient's poor renal function, she was not a candidate for induction therapy with methotrexate. Thus, she began treatment with whole brain radiation therapy (WBRT) to 30.6 Gy while continuing systemic treatment with ibrutinib. A repeat MRI of the brain two months later demonstrated near resolution of the patient's lymphoma with findings of only a few small foci of nonspecific enhancement adjacent to the biopsy cavity within the left thalamus (Figure ). There was no evidence of intracranial mass effect, midline shift, or abnormal extra-axial collection.


A female patient aged 27 years presented with a slow-growing abdominal lump of nine months duration. There were no other symptoms except for fullness of the abdomen after taking food and weight loss. Clinical examination revealed large, non-tender, soft cystic swelling occupying the entire upper abdomen.
On radiological investigations, ultrasonogram (USG)-complex cystic mass with internal septation was present. Contrast-enhanced computed tomography (CECT) abdomen showed a large multiseptated cystic lesion occupying almost the entire abdomen and adhered to the pancreas with mass effect. The lesion was well defined, lobulated, hypodense in nature, and associated with main pancreatic duct dilatation. There was also portal vein thrombosis with portal cavernoma on the CECT abdomen (Figure ).
USG-guided FNAC revealed straw-colored aspirate with mature lymphocytes; no atypical cells were noted. Cyst amylase and carcinoembryonic antigen (CEA) were within the normal range (Figure ).
After complete preoperative workup, the patient underwent surgical exploration. On exploration, there was a large multiloculated cystic lesion extending through gastrocolic omentum, pushing the stomach up and transverse colon downwards with hundreds of cystic spaces containing lymphatic fluid (Figure ).
Cysts were decompressed, and the entire lesion was excised. The anterior surface of the pancreas was forming the base of the lesion. Postoperatively patient had continued lymphatic discharge from the abdominal drain, and the patient was discharged with it (Figure ).
Final histopathological examination showed unremarkable pancreatic tissue with attached lesion consisting of dilated lymphatic spaces with lymphatic follicles in the wall, with congested blood vessels and fibrocollagenous tissue with chronic inflammatory infiltrate. Cytocentrifuged smears from fluid show lymphocytes, and no malignant or atypical cell was seen. The patient was followed regularly in outpatient department, and drain output gradually decreased over two weeks and was removed (Figure ).


A two-year-old female, previously healthy and normally developing, presented with a six-week history of macrocephaly and truncal and peripheral ataxia. An eye examination showed a lack of papilledema but was suspicious for mild peripheral loss of vision. Her past medical history was unremarkable. She did not have diencephalic syndrome at presentation. An urgent brain MRI demonstrated the presence of a large lobulated multicompartmental supra-sellar mass centered within the hypothalamus/optic chiasm (5.4cm x 3.4cm x 5cm) (Figure ), with extension into the surrounding structures and mass effect on the midbrain and third ventricle causing obstructive hydrocephalus. She initially underwent an endoscopic biopsy and septostomy, along with a right-sided ventriculoperitoneal (VP) shunt to manage her hydrocephalus. The pathology of the lesion confirmed the diagnosis of a low-grade glioma (LGG) that was BRAF-V600E negative on immunohistochemistry but positive on next-generation sequencing (Figure ). She was started on chemotherapy with vincristine and carboplatin, but unfortunately she had rapid tumor progression with worsening hydrocephalus six weeks into chemotherapy. This progression caused the patient to develop further complications, including progressive right-sided hemiparesis, bitemporal hemianopia, central hypothyroidism, and feeding difficulties requiring a gastrostomy tube and placement of a second VP shunt. After extensive discussions and mutual expert consensus, her chemotherapy was stopped, and she was started on the novel targeted agent dabrafenib (5.25mg/kg/day). By three months of starting dabrafenib, the size of her tumor decreased by more than 70% (2.5cm x 3.5cm x 2.7cm), with continued decline until plateauing after two years of therapy (Figure ). Prior to dabrafenib, the patient had marked motor and speech impairments but is now able to perform all age-appropriate developmental skills independently. She no longer requires tube feeding and has been growing well. Her bitemporal hemianopia has improved markedly. Her visual acuity is the only symptom that has not shown significant recovery, as she continues to have low but stable visual acuity bilaterally. Our patient is currently five years old, has been on dabrafenib for 30 months, and, to date, she has not experienced any side effects while on targeted therapy. Our plan is to continue on dabrafenib as long as the patient is tolerating the therapy well with no recurrence or progression of the tumor.
Consent was obtained from the parents for sharing of the clinical information and participation in the ORCYD (Oncology Repository for Children and Young Adults) biomarker study. Samples (both blood and CSF) were collected every three months after starting targeted therapy with dabrafenib. Cell-free DNA (cfDNA) from CSF and plasma isolated from blood collected in DNA BCT tubes (Streck, La Vista, NE) were extracted using the QIAamp® Circulating Nucleic Acid kit (Qiagen, Hilden, Germany). Samples were quantified with Qubit™ and the 1X dsDNA high sensitivity (HS) kit (ThermoFisher, Waltham, MA); 1-ul aliquots were loaded on HS DNA chips and run on a Bioanalyzer (Agilent, Santa Clara, CA) to check for cfDNA profile. Samples were pre-amplified with the SsoAdvance™ PreAmp Supermix (Bio-Rad, Hercules, CA) for 10 cycles (annealing temperature = 58°C) following manufacturer's instructions. Diluted pre-amplified samples were mixed with 2X droplet digital polymerase chain reaction (ddPCR) probe mix then used to generate droplets on a QX200 DG (Bio-Rad). Droplets were then submitted to PCR amplification: 95°C for 10 minutes, 94°C for 30 seconds, 56°C for 1 minute (45 cycles), and 98°C for 10 minutes. Droplets were then read on a QX200 Droplet Reader, and data were analyzed using QuantaSoft™ version 1.7 software (Bio-Rad). The primers/probes sequences used for pre-amplification and ddPCR steps are given below:
5’-TCTTCATGAAGACCTCACAGTAA-3’ (BRAF_Fw76pb)
5’-ATGGGACCCACTCCATC-3’ (BRAF_R-long/short)
Wild-type probe: /5HEX/AGATTT+C+A+CTG+T+AGC/3IABkFQ/
Mutant probe: /56-FAM/AGATTT+C+A+CTG+T+AGC/3IABkFQ/
Three months after starting dabrafenib, the patient was enrolled in the ORCYD biomarker study to test her plasma and CSF for the presence of the BRAF-V600E mutation and to correlate the assay results with the MRI changes observed while on dabrafenib therapy. Samples were collected from the patient (peripheral blood and CSF obtained by lumbar puncture) while sedated for follow-up MRIs over the course of a year. However, the BRAF-V600E mutation was not detected in any of the samples from either plasma or CSF (Figure ).


A 33-year-old woman, with severe postburn mentosternal contracture and cicatricial carcinoma, presented for skin grafting surgery in our hospital. The burn occurred when she was 4-year-old. She underwent two reconstructive procedures at 7 and 14 years in local medical centers. Due to the pain caused by the occurrence of cicatricial carcinoma, affecting eating and speaking, she had tried several medical centers for treatment in the past year, but failed for unsuccessful ATI. In preoperative physical examination, severe scar contractures and large tumor of approximately 15 × 12 cm were observed on the lower lip, neck, and anterior chest (Figure ); the chin, chest, and bilateral armpits fused together; the cervicomental and mentosternal angles completely obliterated; the anterior neck structures, including the larynx, the trachea, and the carotid arteries, were unidentifiable or impalpable. Mouth opening was limited (15 mm) and Mallampati test could not be performed. The left nostril was obstructive for stenosis, but the right nostril breathing was smooth. Preoperative X-rays and a computed tomography scan (data not shown) revealed distortion of the upper airway and no stenosis of the trachea. It was difficult to perform face mask ventilation because of the nearly fixed neck and regressed mandible.
According to the guidelines on the management of difficult airway, awake flexible bronchoscopic intubation with topicalization is preferred in such patients, but the patient rejected ATI for discomfort and nociceptive recall before. Meanwhile, other awake strategies, including lightwand, GlideScopeⓇ Video laryngoscope, laryngeal mask airway, oral or nasal blind intubation, retrograde intubation, surgical tracheostomy, seem impossible. Therefore, a flexible bronchoscopic intubation protocol under precise sedation, topicalization, and spontaneous respiration preservation seems a promising strategy, but the airway should be secured for there was no definite backup plan.
A written informed consent was taken with explanation focused on the risks of difficult airway. Atropine 0.5 mg was intramuscular injected to reduce secretion 30 min before transferring to the operating room. The patient was monitored by respiration rate, ventilation volume, pulse oximetry, electrocardiogram, blood pressure and bispectral index (BIS), and preoxygenated once she arrived in the operation room. Vital signs were stable. A pillow and some folded sheets were stuffed between the patient back and the operating bed to make her feel comfortable. Intravenous midazolam 2 mg and sufentanil 5 μg were given. Nasal passage was anesthetized by pledgets with 2% lidocaine and 0.25% phenylephrine. Sevoflurane 2% with a flow rate of 4 L/min with 100% O2 was administered via an endoscopic mask connected to the ventilator circuit. The concentration of sevoflurane was gradually increased to 4% and stopped when the BIS reached 55–60 within 3 min, then airway reassessment and precise topicalization were achieved by a modified SAYGO technique., , An epidural catheter (Figure ), with an outer diameter of 3.8 mm, was fixed and 1.5 cm longer was applied at the end of the fiberscope (MDH A10; Zhuhai Mindhao Medical Technology Co., Ltd., ShenZhen, China). Topicalization was achieved by spraying 2% lidocaine (7 ml) via the catheter onto the posterior nasal canal, pharyngeal cavity, epiglottis, glottis, and tracheal (Figure ). Meanwhile, supplemental oxygen 10 L/min was delivered by a hose (Figure ) through the mouth to avoid hypoxemia. When lidocaine worked, about 5 minutes later, sevoflurane was inhaled again until the BIS reached 55–60. Then, a Parker Flex-Tip® tube with an inner diameter of 6.0 mm (Lead Medical Instrument Co., Ltd., Guangzhou, China), which was heated by 40 ℃ and lubricated in advance, was successfully and smoothly inserted into the trachea from the direction of flexible bronchoscopy (Figure ). No stress reactions, including cough, hypertension, tachycardia, arrhythmia, hypoxia, and bronchospasm, and no intubation related complications, such as airway trauma, airway obstruction, and bleeding, were occurred during intubation. Finally, the patient was very satisfied with this experience after emergence.


A 4-year-old girl was referred to our tertiary hospital for the specialist evaluation of a non-specific cough, which was present for 6 weeks, associated with a right pulmonary mass. The physical examination was normal; on auscultation, diminished breath sounds were present on the right side of the lung. The medical history and growth were unremarkable. Chest radiograph revealed a mass located in the right upper lobe and the middle lobe of the right lung, with a central area of calcification (Figure ). Chest computed tomography (CT) scan confirmed the chest radiograph findings; a solid, well-contoured, heterogeneous, mass was noted in the right upper lobe and middle lobe of the lung with an area of central calcification (Figure ).
No lymphadenopathy was detected. Microscopy, culture and cytology of the sputum were unremarkable.
The erythrocyte sedimentation rate was 10, haemoglobin was 11.6 g/dl and the leucocyte count was 8.8 × 109/L. The other serum haematological and biochemical results were normal. The serology of Echinococcus and Mantoux test were negative.
The patient did not respond to antibiotics; therefore, surgical removal of the mass was performed. Thoracotomy performed on the right side showed a lesion in the lung parenchyma, extended to the upper and middle lobes. The differential diagnosis of congenital lesions of the lung was made. As there was no success with fine-needle aspiration in several cases, we decided to perform surgical resection.
The lesion was resected and lobectomy of both upper lobe and middle lobe was also performed. No associated lymphadenopathy was noted.
Macroscopically, a well-circumscribed mass measuring 5.5 × 5.5 × 4 cm was present. The excised tumour had an osseous centre measuring 2 × 1 × 1 cm. From the histological point of view, the mass consisted of disorganization of the normal bronchoalveolar parenchyma, myofibroblastic cells and inflammatory cell infiltrates, such as lymphocytes, neutrophils, eosinophils and histiocytes. In the centre of the lesion, a large ossification was found.
Immunohistochemistry revealed calponin antigens, SMA, desmin, P53, bcL2, CK, HMW, and, in several myofibroblastic cells, expression of ALK-1. It was negative for beta-catenin, cyclin D1, Myo-D1, S100p, CD34, CD99 and CD117.
The histological and immunohistochemistry characteristics were compatible with an inflammatory myofibroblastic pseudotumor.
The post-operative course was uneventful, and the patient was discharged home after 2 weeks of surgery. The patient re-presented to the hospital 1 year after surgery. The child had normal daily activities, normal chest x-ray and no recurrences.


A 59-year-old female patient presented to a plastic surgery clinic with a lump on her right medial thigh. She noticed the lump eight months ago and it was gradually increasing in size. It was painless initially; however, the lump gradually became tender. The patient was otherwise fit and well with no co-existing morbidities. Closer examination of the right thigh revealed a high consistency mass, with reduced mobility. There was no right inguinal lymphadenopathy or lymph nodes enlargement.
Laboratory blood tests were unremarkable. An MRI scan was requested to further assess the mass, which was irregular but well-defined in the medial compartment of the thigh, measuring 8.2 x 6.6 x 4.3 cm in size. The mass showed an intermediate signal on both T1 and T2-weighted imaging, appearing hyperintense compared to the adjacent muscular tissue, which also persisted on fat-suppressed imaging. The mass invaded the intramuscular fat planes and caused compression and displacement of the adductor muscles. There was no evidence of intra-muscular invasion. Normal cortical outline and medullary signal intensity of the femur were seen in the right thigh. There was no evidence of bone contusion, marrow oedema, fracture line, or cortical discontinuity. Other muscles of the thigh had a normal outline and signal intensity with no evidence of focal or diffuse oedema. Neurovascular structures were unremarkable. Overall, MRI findings were suggestive of soft tissue neoplasm, with a possibility of a neurogenic tumour. A wide excisional biopsy was then performed to further assess the tissue histologically by the pathologist and confirm the diagnosis. The removed mass measuring 8.5 x 6.5 x 5.4 cm and is shown in Figure . The mass had a smooth outer surface and a soft consistency. The cut surface showed a homogenous tan-white appearance with some slit-like spaces and occasional haemorrhagic spots. Multiple sections were processed for histopathological examination from different planes.
Histopathology of the mass revealed a tumour arranged in sheets and fascicles composed of round to oval cells along with variably sized adipocytes (Figure ). Numerous interspersed lipoblasts with indented nuclei were also seen. Moreover, severe nuclear atypia was noted including bizarre cells (Figure and Figure ). An area of necrosis was seen with a few areas, which showed malignant and fibrous histiocytoma-like features. Furthermore, a few thin-walled dilated and congested blood vessels were also noted. Also, brisk mitosis was noted (35-38 per 10 HPF) (Figure ). Immunohistochemical staining (IHC) was also performed and the tumour cells were diffusely positive for vimentin and focally positive for S-100; while negative for creatine kinase (CK), smooth muscle antigen (SMA), desmin, CD34 and MyoD1. Overall, the pathological findings are all suggestive features of a high-grade sarcoma, favouring the epithelioid variant of PLS.
The patient was also referred to the Department of Nuclear Medicine & Molecular Imaging for post-surgical restaging and assessment for possible metastases using 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET-CT) scan. The abdominopelvic section showed the liver measuring within normal limits; however, the scan revealed an ill-defined hypermetabolic hypodense lesion seen involving segment VI measuring approximately 2.8 x 1.8 cm suggestive of hepatic metastases with concurrent fatty liver. The scan was also remarkable for the musculoskeletal system, revealing multiple hypermetabolic osseous lesions involving the skull base, right iliac bone, and few vertebrae (predominantly T7-L1); which was suggestive of skeletal metastases. A non-hypermetabolic pulmonary nodule in the right lung field was also detected; it was considered to be likely benign, but interval scanning is suggested to monitor further progress. Finally, there was also evidence of diffuse subtle hypermetabolism at the site of surgery which is suggestive of postsurgical inflammatory sequelae; however, microscopic residual disease cannot be completely ruled out. These multi-organ lesions were due to be biopsied to examine their immunohistochemical findings to confirm metastatic lesions of primary pleiomorphic liposarcoma. However, the patient did not attend the follow-up appointments.


An eighty year-old female presented with bleeding from the prolapsed uterus. The patient was admitted to the department of Gynaecology/Obstetrics and Gynaecological Oncology of Hospital in Dębica, Poland. In an obstetric history, she reported 3 vaginal births, the last one at the age of 30. Last menstruation was at the age of 52. She did not complain of any past diseases or current chronic diseases, she did not report any addictions and remained in 1 relationship. On admission, a large part of the vagina containing the cervix and a part of the uterine body was found below the vaginal introits (International Continence Society grade 3). Examination revealed an exophytic infiltrating lesions covering entire surface of hypertrophic cervix spreading to the vaginal fornices (Fig. ).
Bimanual vaginal examination revealed a small myoma of 2 cm in diameter in the uterine body, adnexa impalpable. Per rectal examination showed a tumour in the anal canal. Moreover, the parametria were uninvolved in this examination.
In the diagnostic procedure, the lesion in the cervix was sampled parallelly with curettage of the cervical canal and the uterine cavity. Then, rectoscopy was performed with sampling of the anal canal lesion for histopathology. The rectoscopic image is shown in Figure and the microscopic images of the cervical and anal canal samples in Figure .
A polypoid lesion in the rectoscopy measuring 2.5 cm in diameter just behind the external sphincter and an infiltrating lesion occupying the posterior wall of the rectum, 4 cm away from the anal rim were found (Fig. ).
Histological images of the cervical and anal canal lesions are shown in Figure . Microscopic examination revealed, in the cervical specimen, moderately differentiated invasive squamous cell carcinoma (SCC) (Fig. A), featuring a strong and diffuse immunohistochemical p16 reaction in the neoplastic cells (Fig. B). In the search of HPV high risk, the polymerase chain reaction (PCR) reaction was performed, which confirmed the presence of high risk HPV (HPV 16 and additional one from the group of High Risk HPV 31,33,35,39,51,52,56,58,59,66,68) in the cervical SCC. The microscopic examination of the biopsy specimen from the anal canal lesion revealed moderately differentiated adenocarcinoma (Fig. C) with patchy p16 immunohistochemical stain in the cancer cells (Fig. D), while the polypectomy specimen showed the conventional serrated adenoma with low grade dysplasia. The low grade dysplasia was also found at the diathermied margin. The PCR reaction excluded the presence of high risk HPV in the anal canal adenocarcinoma, followed by the negative result for low risk HPV PCR test. In addition real-time PCR was carried out for anal canal adenocarcinoma confirming NRAS mutation and excluding KRAS and BRAF mutation. Physical, endoscopic and histological examinations were supplemented with magnetic resonance imaging (MRI). Examination revealed prolapsed cervix of irregular morphology with the disrupted cervical stroma ring (long arrow). Multiple low T2 signal round myometrial lesions was suggestive of uterine fibroids (short arrows; hollow arrows). MRI also revealed irregular mass-like thickening of the distal part of the rectum and anal canal, superiorly to the anal sphincters. Both internal and external sphincters seemed uninvolved. The lesion was confined to the intestine wall and did not infiltrate ischioanal fat nor adjacent pelvic structures (Fig. ).
The next lesion measuring 40 × 20 × 25 mm was identified in the cervix. It demonstrated a low signal on the T2-weighted sequence and a high signal in LAVA after contrast administration. No evidence of vaginal mucosa, bladder and rectal invasion was found. Superficial parametral invasion on the left was suspected (Fig. ).
Diffusion-weighted magnetic resonance sequences suggested the malignant character of the thickening (A) of the rectal and anal canal wall. High signal on B-value diffusion-weighted MRI (B) with corresponding low signal on apparent diffusion coefficient (ADC) map (C) confirmed water diffusion restriction – a sign of malignancy (hollow arrows; Fig. ). T stage corresponded to the size of the primary tumour assessed by measuring in its longest diameter on T2-weighted MR images. In our case, the maximum tumour diameter was 23 mm.
Based on the above data, cervical G2 squamous cell carcinoma FIGO II A 2 was diagnosed in the prolapsed cervix with the coexisting G2 anal canal adenocarcinoma pT1N0M0.
Due to the predominance of symptoms related to CC and prolapse, the patient was offered a treatment consisting of, at the first stage, radical vaginal hysterectomy with extensive colpectomy preceded by laparoscopic pelvic and paraaortic lymphadenectomy, followed by the removal of the anus in the second stage. The patient agreed to some of the proposed treatment, however, she did not consent to the anal extirpation. Therefore, only laparoscopic pelvic and paraaortic lymphadenectomy with radical vaginal hysterectomy were performed. The key step of vaginal radical hysterectomy with the isolation of the right ureter is shown in Figure . The dissected ureteric angulation, known as knee of the ureter, allowed excision of the parametria.
The postoperative course was uneventful. The patient was discharged on day 5. Microscopic examination of postoperative specimens revealed the cervix containing partially exophytic tumor measuring 2.5 × 3.5 × 7.5 cm, which appeared to be G2 HPV-associated squamous cell carcinoma, focally invading beyond the cervix into surrounding adipose tissue, sparing the parametria (pT2a2), with clear peripheral margins. The perineural and vascular space involvement was identified. Out of 13 regional lymph nodes examined, 2 showed metastasis (2/13).
Due to the refusal of both anal extirpation and adjuvant chemotherapy, after a multidisciplinary consultation, the patient was qualified for radiotherapy (RT). She was transferred to the Radiotherapy Department at the Regional Hospital in Tarnow. The RT was dedicated as definitive treatment for ACC and adjuvant therapy for CC. RT was delivered via a two-step 3D conformal technique. The lymph nodes affected by SCACC and regional lymph nodes of anal cancer were included in step 1 and the dose of 50.4 Gy in 28 fractions was delivered. In step 2, boost of 3.6 Gy in 2 fractions to the primary anal canal was added. As the patient did not want to undergo resection of the anus, we planned brachytherapy in the third stage, as a way of dose escalation. The prescribed dose was defined as 98% of the planning target volume that should receive 98% of the dose. organ and risks were contoured, including the peritoneal space (bowel bag), bladder and bilateral femoral head. All constrains of tolerance doses for organ and risks were maintained. The treatment was tolerated well, however, Common Terminology Criteria for Adverse Events (v4.0), including grade 2 diarrhoea and anal canal colitis, were demonstrated. RT was completed without discontinuation through treatment.
MRI performed on 45 postoperative days after radical vaginal hysterectomy and RT demonstrated a complete response. No sign of previous-seen mass-like thickening of the rectal wall on T2-weighted images (Fig. ). Diffusion-weighted imaging (Fig. ) confirmed no evidence of suspected regions of water diffusion restriction.
The duration of follow-up was 6 months.
Informed written consent was obtained from the patient for publication of this case report and accompanying images.


History and physical examination
A 75-year-old female with a past medical history of fibromyalgia and Sjogren’s syndrome presented to the emergency department with severe hypertension. The patient was not taking any medication at home.
On physical examination, the patient was in slight distress. The vitals were as follows: blood pressure of 182/91 mmHg, heart rate of 72 beats per minute, respiratory rate of 15 breaths per minute, and oxygen saturation of 93% on room air. The patient had 2+ pitting edema of lower extremities. The rest of the physical examination was unremarkable.
Hospital course
The blood pressure of the patient improved after giving hydralazine and clonidine. Nephrology was consulted for evaluation of increased creatinine (3.8 mg/dl) with blood urea nitrogen of 29 mg/dl. Review of the past medical record in the hospital showed her creatinine level of 2.5 mg/dl, a year ago. Further workup revealed 24-hour proteinuria of 3.89 grams. Urine dipstick showed 3+ protein, 5-10 red blood cells and 10-15 white blood cells per high power field.
Considering the past medical history of Sjogren’s syndrome, the patient was suspected to have acute interstitial nephritis or possible immune-complex-mediated disease. Her C3 and C4 complement levels were low. Serum immunofixation did not reveal any monoclonal immunoglobulin. Serologies for antinuclear antibody was positive (titer, 1:640), negative for anti-double-stranded DNA, hepatitis B and C, and antineutrophilic cytoplasmic antibodies.
On light microscopy (LM), three glomeruli were present for evaluation, two of which were globally sclerotic and one showed segmental scarring. The segmental lesion had an accompanying fibrous reaction, suggestive of a possible healed/fibrous crescent. The glomeruli also featured noticeable mesangial expansion, which was negative for Silver methenamine and positive for Periodic acid-Schiff (PAS) staining. Congo-red stain was also negative. No capillary wall deposits were seen on special stains and no active necrotizing or crescent lesions were present. Moderate interstitial fibrosis was present in the interstitium. Furthermore, moderate intimal fibrosis was seen in vessels, with no thrombosis or vasculitis.
Immunofluorescent (IF) showed diffuse global 3+ smudgy mesangial; the capillary wall was positivity noted with immunoglobulin G (IgG) (Figure ). Glomerular staining showed 1+ IgM, C1q, 2+ C3, 1+ staining with both kappa and lambda light chains (Figure ). IgG and albumin stained protein reabsorption granules in the tubular cytoplasm were noted. No significant staining was seen with fibrinogen.
EM confirmed the presence of extensive electron dense deposits in the expanded mesangial regions and throughout the thickened glomerular basement membranes (Figures -). These deposits had a distinct fibrillary substructure and they did not show any transmembranous spicule formation. No extra-glomerular deposits were seen.


A 56-year-old Chinese Han female presented to Shanghai Dermatology Hospital in 2016 with symptoms of erythematous plaques and pain over her left upper limb for 2 days and foreign object sensation in the throat when swallowing for 3 days. The patient had a 6-year history of leprosy. She was diagnosed with BB in 2011 and received multidrug therapy (MDT) (600 mg of rifampin and 300 mg of clofazimine monthly; 100 mg of dapsone and 50 mg of clofazimine daily) for 1 year, resulting in a clinical cure in 2012.
T1LR were initially considered, followed by treatment with 20 mg/day of methylprednisolone given orally. Two days later, the patient’s symptoms were aggravated, with neck muscle tension and difficulty in opening her mouth, and the erythematous plaques had spread over most of her left upper limb.
On physical examination, the patient had a normal blood pressure and pulse with a temperature of 37.8 °C, but she displayed shortness of breath. Her facial expressions included a wry smile and trismus, with the corners of her mouth pulling outward and upward, and she had difficulty speaking. The patient’s abdominal muscles were too stiff for palpation of the patient’s liver and spleen. Persistent stiffness was found in the neck and four limbs, together with opisthotonus and occasional paroxysmal spasms. Anesthetic erythematous plaques were observed over her left upper limb (Fig. ). The bilateral ulnar nerves and right common peroneal nerve were thickened and exhibited tenderness. The patient exhibited right foot drop, atrophy of the extensor of the right lower leg, and an ulcer on the right foot. Laboratory examinations showed a white cell count of 12 000/mm3 (reference value: 3690–9160/mm3) and neutrophils 81% (reference value: 50–70%). Her liver and renal function tests were normal. Slit skin smears showed the presence of acid-fast bacilli ranging from negative to a score of 1+ at 6 different sites. According to her medical history and clinical symptoms, she was diagnosed with tetanus and BT accompanying T1LR.
This patient was given the following: 100 000 IU tetanus antitoxin in a 500-ml 5% glucose-saline intravenous infusion daily; 200 000 U penicillin in an intramuscular injection four times a day; and 200 mg of hydrocortisone in a 250-ml 5% glucose intravenous infusion daily. Additionally, 10 mg/day of diazepam and 50 mg/day of phenergan were given by intramuscular injection. The patient was hospitalized in a dark, quiet room to reduce light stimulation and prevent spasms. In addition, a dental pad was placed in the oral cavity to prevent the patient from biting her tongue. The ulcer on her right foot was debrided every day, followed by rinsing with 3% hydrogen peroxide and injection of 20 000 IU tetanus antitoxin around the wound. The paroxysmal spasticity and intensity of the spasms started to decrease after 5 days. Twelve days later, she was discharged from the hospital in stable condition. She was followed up in our outpatient department and treated with MDT and 40 mg/day of prednisone orally with taper to prevent T1LR for 4 months; the erythematous plaques and neuropathic pain eventually subsided.


A 5-year-old female Cownose (Rhinoptera bonasus) was managed in Oceanarium, the large scale exhibition area of Aquaria in Kuala Lumpur (KLCC) with over 40 species of elasmobranchs and teleost fish. She is fed with marine chopped fish twice a day and Mazuri supplement (vitamins and minerals).
Cownose's caretaker noticed her left eye ball is protruding out from the orbit. He suspected she had crushed into the artificial coral when the male rays chased her for mating, and the period correlates with the mating season. The case was presented to University Veterinary Hospital (UVH), Universiti Putra Malaysia, on the same day that he complained of the eye trauma during field visit to Aquaria KLCC.
Physical examination was carried out. The Cownose was alert and responsive as she was actively swimming in the holding area. She was weighing 8 kg and had a Body Condition Score of 3 out of 5 and less than 5% dehydration. Temperature and pulse rate were not obtained, while the respiratory rate was 65 breaths per minutes. The left eye globe with hyphema was protruded from the orbital space and attached to the optic nerve (). The pupillary reflex could not be assessed due to hyphema. The left orbital space was exposed and periocular tissue tear was present around the left orbit (). Besides, multiple abrasions were observed at the cranial margin of the both pectoral fins, which was more severe on left fin.
Immersion anaesthesia was opted. Seventeen ppm of isoeugenol (brand name: Aqui-s) was used as anaesthetic agent for both induction and maintenance of surgical plane. The anaesthetic bath was prepared by filling a tank with 475 L of artificial sea water from the holding area and added with 14.8 mL of Aqui-s. Ventilation rate was the only parameter that was used to monitor the anaesthesia depth of the Cownose. The normal ventilation rate was taken at rest before induction, which will be used as the baseline to monitor ventilation throughout the anaesthesia []. Ventilation rate of Cownose was taken by observing movement of spiracular flap and recorded every 5 minutes.
The Cownose was left in the anaesthetic bath for 10 minutes until its ventilation rate ceased to 40 breaths per minute and dropped in pectoral fin stroke activity (). Later she was transferred by using canvas hammock to surgical tank with wet towel at the bottom and covered with another wet towel on her dorsum to maintain skin moisture [] (). The maintenance of surgical plane and establishment of rebreathing system was done by flushing water with anaesthetics agent through the gills via right spiracle (respiratory opening caudal to eye) with a 20 mL syringe.
The Cownose was presented in ventral recumbency and assistants aided in restraining by gently exerting force at the dorsum as a part of tonic immobilization. Routine skin preparation around the left eye was done by using diluted chlorhexidine gluconate (dilution ratio 1 : 30) and diluted povidone iodine (dilution ratio 1 : 30) [].
A ring block was done around the left eye by using 5 mL 20 mg/mL Lidocaine as local anaesthesia to reversibly desensitize the skin as well as analgesia (). Diluted gentamycin (5 mL, 100 mg/mL gentamycin + 5 mL sterile water) was prepared to flush the left orbital space and globe to minimize secondary infection since sterile surgical field is impossible to be established in the field setting (). The optic nerve was clamped by using 2 Rochester Pean forceps (). A surgeon knot was placed proximal to the first forceps with 2.0 PDS to ligate the blood vessel for haemostasis. Then the optic nerve was transected between the 2 forceps by using scalpel blade #20 (). The globe, the remaining conjunctivae fat, and extraocular muscle tissue were removed. The pedicle was checked for presence of bleeding before releasing it into the orbital space. The inner and outer muscular attachments were sutured with 2.0 PDS using interrupted suture pattern to close the orbital space (). Periorbital skin closure was done with 2.0 PDS in interrupted suture pattern ().
The enucleation procedure took 15 minutes to be completed. Fresh sea water without an anaesthetic agent was used to flush through the spiracle to perfuse the gills and accelerate recovery from anaesthesia. The recovery from anaesthesia was indicated by increasing ventilation rate to preinduction rate, which was 66 bpm in Cownose and when she started struggling actively by flapping pectoral fins at 25th minutes.
Postoperatively, 5 mg/kg enrofloxacin was administered intramuscularly at the dorsolateral musculature close to the spine and terramycin ointment (active component: oxytetracycline hydrochloride) was applied twice a day topically on the suture site to prevent secondary infection of the suture site, orbital space, and optic sulcus []. Besides, the caretaker was instructed to apply povidone iodine (brand name: Betadine) on the abrasions of the pectoral fins twice a day until wound healed to prevent the proliferation of Fusarium sp., an environment saprophytic fungi [–].
Client education consisted of isolating the Cownose from the school in holding area until surgical wound healed before releasing it to the large exhibition area, for ease of monitoring and for the prevention of possible infection at suture site as well as for administering daily treatment []. Besides, daily monitoring of suture site for break and possible signs of secondary infection such as discolouration of skin, fungal growth on the wound, inappetence, and loss of body condition is recommended by Mylniczenko and Penfold []. Next, putting of the mating pairs into separate tanks during mating season is necessary and a good practice. The mating process of rays is always aggressive as female rays always are being bitten and injured by the male rays, in which death can occur in severe case []. Others include reducing risk of crushing into decorations; isolation also reduces the stress of mating animals by avoiding being attacked by other fish during and after mating.
At day 7 after operation, we had a revisit trip to Aquaria KLCC for the follow-up. She was responding well to the treatment with good appetite and no clinical abnormalities were observed, and suture materials were still intact (). The last follow-up was on day 24 after operation and was done by phone; Cownose was having good appetite and the scars were returning to normal skin colour.


A 20-year-old female patient presented to our hospital with a history of severe and dull substernal chest pain and breathlessness after being hit by a baseball to her chest 2 h ago. Immediately after being hit, she had an episode of syncope briefly without convulsion. The symptoms lasted for half-an-hour and resolved spontaneously. Her vital signs showed blood pressure of 95/64 mmHg and pulse of 70 beats/minute. There was no sign of chest wall penetrating injury. Electrocardiogram (ECG) revealed sinus rhythm with QS complexes in leads V2 to V3, ST segment elevation and T-wave inversion in leads V2 to V5 (Fig. ). Laboratory tests showed cardiac Troponin I level of 19.03 ng/ml (normal range < 0.01 ng/ml). Chest computer tomography (CT) revealed no traumatic injury but demonstrated coronary artery calcifications (Fig. ). Her parents recalled a history of high fever lasting for several days at the age of 5-year-old. The patient was admitted to our hospital diagnosed of acute traumatic MI. Serum Troponin I was peaked to 20.3 ng/ml, creatine phosphokinase(CK) to 1237 U/L and CK-MB to 101 U/L 12 h after admission. Serum BNP level was normal at 85.9 pg/ml on admission. During hospitalization, serial ECG changes were consistent with an evolving MI. She had frequent ventricular premature beats on the Holter monitor. Trans-thoracic echocardiography revealed normal left ventricular size and mild anterior hypokinesis. Notably, multiple giant left anterior descending (LAD) aneurysms with diameters from 7.5 to 8.5 mm (Fig. ) and slow flow velocity were detected. To further assess CAA, we performed contrast enhanced coronary artery computer tomography angiography (CTA)with three-dimensional (3-D)reconstruction of coronary arteries. A ringed calcification in the proximal portion of LAD artery with multiple aneurysms, thrombi and occlusions were visualized (Fig. ). CTA also demonstrated multiple aneurysms with beads-on-string appearance in the LAD artery (Fig. ). Antinuclear antibody (ANA) was minimally positive (1:10) with unknown significance. Serum levels of C3 (0.864 g/L), C4 (0.912 g/L), CRP (< 1.0 mg/L), ASO (< 25 IU/ml), ESR (15 mm/h), Rheumatoid Factor (< 25 IU/ml) and ANCA were within normal ranges. Those results did not seem to support active vasculitis, rheumatic or immunologic diseases. Based on the typical images and her childhood fever history, we recognized that the patient’s underlying coronary structural abnormality was most likely originated from KD. Considering stable hemodynamic parameters and multiple giant aneurismal dilatations of LAD artery, we managed this young patient with a conservative strategy including dual anti-platelet treatment with aspirin and clopidogrel for at least 1 year, and titrations of captopril and metoprolol to prevent ventricular remodeling. At the 2-month follow-up, the patient remained asymptomatic. ECG showed QS complex only in V2 and V3 leads and other abnormalities were resolved (Fig. ). Echocardiography revealed left ventricular diastolic dimension of 48 mm, normal LAD artery velocity, and no ventricular dilatation or akinesis. She remained asymptomatic two year later.


An 11-year, 7-month-old girl visited the Kyungpook National Children’s Hospital because of a short stature. The patient had been born via vaginal delivery at a gestational age of 38 weeks; she weighed 2.6 kg at birth, and there were no perinatal problems. However, she had an incomplete cleft palate and craniosynostosis at birth. Hearing loss in both ears was detected at the age of 1 month by brainstem-evoked response audiometry during an initial screening test. An ‘inborn errors of metabolism’ workup performed after birth revealed congenital hypothyroidism, for which the patient received levothyroxine at the local hospital until she was 3 years old; normal thyroid function was confirmed after discontinuing the medication.
When she was 1 year old, she was transferred to our hospital because of a developmental delay and for a repair of her incomplete cleft palate and craniosynostosis. Brain computed tomography revealed an auditory defect, and she began wearing hearing aids, as prescribed by an otolaryngologist. The patient underwent skull reconstruction and incomplete cleft palate repair at the Departments of Plastic Surgery and Neurosurgery, respectively. She was scheduled for follow-up at the Department of Pediatric Neurology due to her developmental language delay, but she was lost to follow-up.
When the patient re-visited our hospital at the age of 11 years and 7 months, she had a height of 124.8 cm (standard deviation score [SDS]: − 3.6), weight of 46 kg (SDS: 0.65 kg), and body mass index (BMI) of 29.53 kg/m2 (Z score: 1.89). She had distinctive facial features, including abnormally long openings between the eyelids, arch-shaped eyebrows, a thin upper lip, and large ears (Fig. ). Moreover, she showed postnatal growth retardation and skeletal anomalies, including an incomplete cleft palate, craniosynostosis, and brachydactyly (Fig. ). These dysmorphic features and her developmental delay were considered suggestive of Kabuki syndrome. Her karyotype was 46,XX. Her bone age was 8 years and 10 months, which was considered delayed according to the Greulich and Pyle atlas []. Based on these characteristic clinical features, mutational analyses for the KMT2D and KDM6A genes were performed.
The CARE guidelines were followed in reporting this case, and the molecular analyses were approved by the Institutional Review Board of the Kyungpook National University Chilgok Hospital after obtaining informed consent from the patient’s parents. Genomic DNA was extracted from peripheral blood, and library preparations were performed with the TruSight One Sequencing Panel (Illumina, Inc., San Diego, CA, USA), which enriches a 12 Mb region spanning 4813 genes of clinical relevance. Large-scale parallel sequencing was performed with the Illumina NextSeq platform. Sequence reads were aligned with the hg19 reference sequence using the Burrow-Wheeler Aligner (version 0.7.12, MEM algorithm). Duplicate reads were removed using Picard Tools (version 1.96). Local realignment and base quality recalibration were performed with the Genome Analysis Toolkit (GATK, version 3.5), and variant calling was performed using the GATK HaplotypeCaller. Variants were annotated with the Variant Effect Predictor and AnnoVar. Common variants with minor allele frequencies (≥1%) were filtered out using public databases (1000 Genomes Project, Exome Variant Server, and Exome Aggregation Consortium). Population-specific common variants were further filtered using the Korean Reference Genome Database []. The patient had the nonsense mutation of c.8200C > T, p(Arg2734*) in exon 32 in the KMT2D gene. As neither parent had this mutation, as determined by Sanger sequencing, the patient had a de novo heterozygous mutation in the KMT2D gene (Additional file : Figure S1).
We then performed additional examinations to detect other anomalies associated with Kabuki syndrome. Two-dimensional echocardiography, abdominal ultrasonography, and brain magnetic resonance imaging that had been performed at 1 year of age, showed no abnormalities. Ophthalmological findings were also normal.
The patient exhibited several endocrine problems (transiently congenital hypothyroidism, CDP, obesity and GH deficiency); additional endocrine tests were performed upon admission to our hospital (at the age of 11 years and 7 months).
The patient had transiently congenital hypothyroidism. When she was 7 days old, her free thyroxine (T4) was 1.09 ng/dL (reference range [RR], 0.8–2.0 ng/dL), triiodothyronine (T3) was 1.3 ng/mL (RR, 0.2–2.0 ng/mL), and thyroid-stimulating hormone (TSH) was 22.8 mIU/L (RR, 0.7–13.1 mIU/L). She received levothyroxine until she was 3 years old, and normal thyroid function was confirmed after discontinuing the medication. Upon admission to our hospital, she was 11 years and 7 month old her free T4 was 1.6 ng/dL (RR, 0.8–1.8 ng/dL), T3 was 0.8 ng/mL (RR, 0.6–1.9 ng/mL), and TSH was 3.5 mIU/L (RR, 0.3–4.0 mIU/L), indicating normal thyroid function.
Regarding puberty, the patient showed Tanner stage I–II of breast development; her basal luteinizing hormone level was < 0.07 mIU/mL (RR, 5–20 mIU/mL), basal follicle-stimulating hormone level was 6.19 mIU/mL (RR, 0.3–10 mIU/mL), and estradiol level was < 11.8 pg/mL (RR, 0–16 pg/mL), suggesting a CDP.
She was obese and had a buffalo hump. Her cortisol levels while awake at 8 AM, 5 PM, and midnight were 6.93 μg/dL (RR, 3–22 μg/dL), 12.46 μg/dL (RR, 3–22 μg/dL), and 14.87 μg/dL (RR, < 7.5 μg/dL), respectively. Her corresponding adrenocorticotropic hormone levels were 34.2 pg/mL, 40 pg/mL, and 42.8 pg/mL, respectively (RR for all, 0–60 pg/mL). Her urine-free cortisol was 28.9 μg/dL (RR, 4.3–176 μg/dL). Even though the midnight cortisol level was elevated, a low-dose dexamethasone suppression test showed a cortisol level of 0.68 μg/dL (RR, < 1.8 μg/dL). A lipid profile showed a total cholesterol level of 150 mg/dL (RR, 125–200 mg/dL), triglyceride level of 66 mg/dL (RR, < 200 mg/dL), and LDL-cholesterol level of 53 mg/dL (RR, < 130 mg/dL). Her aspartate aminotransferase and alanine aminotransferase levels were 24 U/L (RR, < 97 U/L) and 17 U/L (RR, < 41 U/L), respectively.
A GH stimulation test (spanning 2 days) was performed because of her short stature and delayed bone age. On the first day, the patient was administered levodopa (500 mg); the samples for the GH assessment were acquired at 0, 30, 60, 90, and 120 min. On the next day, the patient fasted for 8 h in the morning and was intravenously administered 0.1 U/kg of rapid-acting insulin diluted in 5 mL of normal saline for over 1 min, after which the samples for GH assessment were acquired at 0, 15, 30, 60, 90, and 120 min. The maximum GH concentrations in both tests were below 5 μg/L (RR, > 7 μg/L); therefore, the patient was diagnosed with GH deficiency. Her insulin-like growth factor 1 (IGF-1) and insulin-like growth factor-binding protein 3 (IGFBP-3) levels were 130.5 ng/mL (RR, 99–537 ng/mL, SDS: − 1.67) and 3760 ng/mL (RR, 2400–8400 ng/mL, SDS: 0.91), respectively. The patient started GH replacement therapy (Eutropin 0.03 mg/kg/day) when she was 11 years and 7 months old and is currently scheduled for regular follow-ups for growth and puberty changes.


A 26-year-old Yemeni male patient from Taiz Province was referred to the restorative dental clinics at King Saud University, Saudi Arabia. His chief complaint was an unpleasant smile caused by generalized tooth discoloration. His medical history was irrelevant. The fluoride level in the water around Taiz Province is >3.6 mg/l [].
Clinical examination revealed generalized fluorosis with loss of the outermost enamel in irregular areas involving less than half of the entire surface, as well as changes in the morphology caused by merging pits and marked attrition (). In this case, based on the Thylstrup and Fejerskov index (TFI) for dental fluorosis classification, the dental fluorosis was classified as TFI = 7 [].
After the clinical examination, radiographs, preoperative photographs, and upper and lower alginate impressions for diagnostic models were taken. The patient was presented with treatment options, which included ceramic or composite veneers, along with the advantages and disadvantages of each option. The patient agreed to smile enhancement using ceramic veneers for his upper teeth given that he desired an optimum aesthetic and a long-term result. The veneers would be placed on the patient's upper teeth, from his upper right 2nd premolar to upper left 2nd premolar. The patient decided to postpone veneering his lower teeth, given his limited financial capacity. Diagnostic models were analyzed to evaluate the occlusion, and a diagnostic wax-up was made of white-colored wax. The use of the wax-up allows the patient to preview the desired appearance of his teeth, and this wax-up is also essential for the fabrication of a clear matrix for temporary restorations.
The desired shade was selected using the VITAPAN classical shade guide (VITA Zahnfabrik, Germany). The enamel of the eight maxillary teeth was prepared using a flat-end tapered diamond bur to a depth of 0.5–0.75 mm facial reduction with 1.5 mm incisal reduction (). A chamfer finish line was maintained at the level of the gingival margin. The proximal margin was extended into the facial and gingival embrasures.
Following tooth preparation, gingival retraction was achieved using retraction cords (Ultrapak Cord #00, Ultradent Products Inc., South Jordan, UT, USA) soaked in a hemostatic agent. Impressions were taken with a polyvinylsiloxane material (Virtual, Ivoclar Vivadent, Amherst, NY). The impression material was manipulated according to the manufacturer's instructions. Temporization was performed by spot etching on the facial surface of each prepared tooth with 37% phosphoric acid (Total Etch, Ivoclar Vivadent, Schaan, Liechtenstein). Bonding agent (OptiBond Solo Plus, Kerr, Orange, CA, USA) was applied on the enamel-etched spots and light cured for 20 seconds using a high-intensity light-emitting diode (LED) curing light (Elipar S10, 3M ESPE, MN, USA). The clear matrix that was previously fabricated was loaded with a temporization material (Protemp Plus, 3M ESPE, MN, USA) and placed over the prepared teeth. Light curing was done for 10 seconds per tooth. Then, the matrix was gently teased away from the prepared teeth. A number 12 scalpel blade was used to remove the partially cured temporization material. Facial and lingual embrasures were refined with a thin diamond disk, the occlusion was adjusted, and the temporary restorations were polished using polishing discs and points ().
Ceramic veneers were fabricated with a lithium disilicate-reinforced glass ceramic material (IPS e.max Press, Ivoclar Vivadent, Schaan, Liechtenstein). Temporary veneers were removed, and the teeth were cleaned using pumice. Ceramic veneers were tried-in using a transparent shade try-in paste (Variolink Veneer try-in paste, Ivoclar Vivadent, Schaan, Liechtenstein) to assess marginal adaptation and shade.
Afterwards, veneers were prepared for bonding. Fitting surfaces of the veneers were etched with hydrofluoric acid (Porcelain Etchant 9.5%, Bisco Inc., Schaumburg, IL, USA) for 60 seconds, washed under running water for another 60 seconds, and dried with an air syringe. A layer of silane coupling agent (Monobond Plus, Ivoclar Vivadent, Schaan, Liechtenstein) was applied on the veneers' fitting surfaces and gently air-dried after one minute. Then, the prepared teeth were etched using 37% phosphoric acid for 30 seconds, rinsed, and dried. A clear mylar strip was placed interproximally to prevent inadvertent bonding to the adjacent tooth and to facilitate the subsequent removal of excess resin cement in the embrasures. A layer of bonding agent (Adhese Universal, Ivoclar Vivadent, Schaan, Liechtenstein) was applied on the prepared tooth surfaces and air-thinned. Then, Heliobond (Ivoclar Vivadent, Schaan, Liechtenstein) was placed on the prepared tooth surfaces. The inner surface of the veneers was covered with light-cured resin cement (Variolink Veneer, transparent shade, Ivoclar Vivadent, Schaan, Liechtenstein). Veneers were positioned appropriately on the teeth by applying gentle pressure, following which excess resin cement was carefully removed with an explorer before light curing. Light curing was first performed for 2 seconds, and the excess resin cement was removed with a microbrush. After that, each veneer was light-cured from the facial aspect for 40 seconds and from the lingual aspect for 40 seconds. The two veneers of the central incisors were first simultaneously cemented. This was followed by cementation of the veneers of the two lateral incisors. Then, the veneers of the two canines were cemented. Finally, veneers for the first and second premolars were cemented simultaneously on each side.
Minimal gingival flash of the resin luting cement was removed with a number 12 scalpel blade. A flame-shaped fine diamond bur was used to finish the ceramic margins and to contour the embrasure surfaces. Occlusion was assessed and adjusted. Flossing was performed to ensure interproximal contact patency. Ceramic polishing was performed using a series of polishing cups and points (OptraFine polishing system, Ivoclar Vivadent, Schaan, Liechtenstein). Interproximal contacts were finished with finishing and polishing strips. Final surface lustre was achieved by using a diamond polishing paste with a rubber prophylaxis cup. The postoperative clinical photographs are shown in . The patient was satisfied with the final result ().


A 38-year-old North African man, with no past medical history, consulted our out-patient clinic for a painless left scrotal mass. There was no history of previous orchitis or scrotal contusion. He noted the mass a month ago. A physical examination found a 2 cm palpable mass in the upper pole of his left testis. There were no signs of scrotal inflammation. The mass had a firm consistency and regular margins. Palpation of his right testis and the lower pole of his left testis were normal. Routine blood tests were normal. As a testicular tumor was strongly suspected, a bioassay of testicular tumor markers was ordered. Alpha-fetoprotein, human chorionic gonadotropin (hCG), and lactate dehydrogenase (LDH) were in the normal ranges. There was no bacterial growth in urine analysis, including Mycobacterium tuberculosis screening. A scrotal ultrasound showed a homogeneous testicular parenchyma, with a conserved vascularization on Doppler. An extratesticular mass was observed, attached to the upper pole of his testis. The mass was isoechoic to the testis parenchyma, and poorly vascularized Doppler (Fig. ).
He underwent a radical inguinal orchiectomy. We first performed a high ligation of the spermatic cord. The operative specimen included the testis and the tunica vaginalis in one piece (Fig. ). The macroscopic aspect of the supratesticular mass looks similar to splenic tissue (Fig. ). There were no macroscopic lesions of the testis and the spermatic cord. His postoperative course was uneventful. He was discharged on the second postoperative day.
Histological examination of the operative specimen confirmed the presence of regular splenic tissue in the suspect mass, without any signs of malignancy. The splenic proliferation had its proper and regular capsule, demarcating it from the testis. Testicular pulp, the albuginea and the tunica vaginalis had a preserved microscopic architecture (Fig. ). He was examined 3 weeks after orchiectomy and he was examined again 2 months after the orchiectomy in our out-patient unit. An abdominal ultrasound showed an habitual location with standard measurements and a regular aspect of his spleen.


A 35 year-old male was referred to our unit with a right distal tibial non-union, which had progressively deviated into varus deformity. He had initially sustained a high-energy, multifragmentary compound (Gustilo–Anderson Type 3A) fracture in a road traffic accident 4 months earlier. After successful treatment of the soft tissue injuries he had been managed in a below-knee, weight-bearing Sarmiento cast. His non-union (, ) was stabilised with a retrograde 10 mm × 340 mm expandable nail. Regular clinical and radiological follow-up revealed that the non-union had solidly united within 6 months of the operation (). The patient was able to walk comfortably and return to work as a carpet fitter.
Nine months after insertion of the nail there were radiological appearances suggestive of calcaneal resorption around the neck of the nail, therefore we recommended removal of the nail. This was attempted under general anaesthesia using the kit and technique described by the manufacturer. After deflation of the nail, attempts were made to “back-slap” the nail out of the tibia. This failed as the nail fractured at the junction between the valve and the metal fins (). Further attempts to remove the nail using grabbers and a mole wrench were unsuccessful and the procedure was abandoned.
The patient returned to theatre for a second attempt. Initial attempts at removal through the entry point using grabbers and large diameter crown drills were unsuccessful as the broken end of the nail had split, with the fins separating, like an inverted cone. A further attempt at pushing the nail down using an antegrade nail was also unsuccessful. Eventually, the nail was removed piecemeal through a 6 cm × 2 cm antero-medial tibial window using a Midas Rex® burr (Medtronic Ltd., Watford) (). The tibia was protected in a below-knee walking cast for 6 weeks and the patient made an uneventful recovery with no further complications.


A 67 year-old female was referred with a right distal tibial non-union with progressive valgus deformity following a fragility fracture five months previously. It was initially treated with locked antegrade intra-medullary nailing.
The initial nail was removed and an expandable retrograde nail was inserted. Two months later an Ilizarov frame was applied over the nail to provide further compression. The non-union united and the frame were removed three months later. The nail was left for six more months in order to allow further consolidation of the non-union.
The first attempt to remove the expandable nail was made ten months after insertion. The standard technique to remove the nail was attempted, but again the procedure failed because the nail fractured at the junction between the valve and the fins. Further attempts to remove the nail with grabbers at that time were unsuccessful and the procedure was abandoned. Two months later, a second attempt was undertaken as the patient was complaining of ankle pain. The track from her primary nail was re-opened from the proximal end and the expandable nail was successfully pushed out using an antegrade nail. This procedure passed without incident and she made a good post-operative recovery.


A 73 year-old male presented to our unit with a multifragmentary Pilon fracture and was treated with primary retrograde expandable Fixion® nail. Regular follow-up revealed good union at 22 weeks and the patient was able to walk without significant pain. Although we recommended the removal of the nail, the patient didn't consent on it.
Two and a half years later the patient requested removal of the nail because of chronic heel pain presumably due to slight prominence at the bottom end of the nail. Using the standard extraction technique an attempt to remove the nail was performed but resulted in fracture of the nail at the junction of the valve and fins (). The end cup and valve were removed but attempts to remove the remaining part of the nail with grabbers failed and the procedure was abandoned.
The patient was advised to keep the nail remnant unless it becomes symptomatic. He is still under follow-up and currently asymptomatic.


A 45-year-old male from the Netherlands presented with a painless right parotid swelling that was progressively increasing in size for the past 8 months. Though occasionally he suffered from jaw lock, other symptoms associated with neurologic deficit such as drooling, facial weakness, paresthesia, or auditory defects were absent. Apart from being a social alcohol consumer, there was no history of smoking, prior radiation, or significant family medical history, especially in regard to his present illness.
Physical examination revealed a tender right parotid swelling below the ear lobule, which extended inferiorly to the angle of the mandible (). The skin overlying the swelling was slightly erythematous, thickened, and nodular. The swelling was firm, diffused, and fixed to the underlying muscles, and there was no associated lymphadenopathy. Otoscopic examination of both ears was within normal limits.
The patient initially had a neck ultrasound and then a magnetic resonance imaging (MRI) to characterize the nature of the lesion. The neck CT scan revealed a well-defined altered signal enhancing mass measuring 3.5 × 2.2 × 2.0 cm at the posterior aspect of the superficial part of the right parotid gland (). The radiologist's impression was an altered signal enhancing mass lesion, likely to be a benign pleomorphic adenoma. The patient then underwent MRI of the parotid glands, which showed a well-defined focal lesion of altered signal intensity at the posterior aspect of the superficial part of the right parotid gland, measuring 3.5 × 2.2 × 2.0 cm along its maximum transverse, craniocaudal, and anteroposterior diameters, respectively. The impression was again benign pleomorphic adenoma of the right parotid gland. However, the radiologist could not exclude other diagnostic possibilities and recommend fine-needle aspiration cytology.
Fine-needle aspiration cytology of the mass was nonconclusive as the smears only showed polymorphous population of lymphoid cells in keeping with intraparotid lymph node. In view of these clinical findings, a superficial parotidectomy with facial nerve monitoring and preservation was planned.
A modified Blair incision was done, with elevation of a skin flap and control of hemostasis during the surgery. The dissection was rather difficult! The superficial parotidectomy was done in piecemeal as the mass was unexpectedly adherent to the skin and underlying fascia (). The facial nerve was intact and was examined branch by branch. No frozen section was done during the operation.
Histopathologic examination showed a widely infiltrative tumor involving the parotid parenchyma and extending into the surrounding adipose tissue and skeletal muscles (). The tumor was predominantly composed of bland spindle cells with wavy nuclear contours, embedded within a fibrillary, pale pink matrix, which resembled a neurofibroma (). Of concern, there were evidently distinct scattered more cellular foci of epithelioid tumor cells with nuclear atypia and increased mitotic activity (). The tumor was diffusely and intensely positive for the S100 protein and neuron-specific enolase (NSE) immunohistochemical stains, with a low Ki-67 proliferation index. In addition, the CD34 immunohistochemical stain was focally positive in tumor cells. On the other hand, the tumor lacked immunoreactivity for AE1/AE3, p63, EMA, Melan-A, and HMB-45 immunohistochemical stains, thus excluding carcinomas, clear-cell sarcoma, melanoma, and other salivary gland tumors. Based on morphologic and immunophenotypic features of the tumor, the diagnosis rendered was low-grade malignant peripheral nerve sheath tumor (MPNST) arising in a diffuse neurofibroma.
Given the rare presentation and the association of such tumors with NF1, the patient was evaluated clinically for features of the syndrome. Multiple café au lait macules were subsequently discovered on his trunk (). The patient was referred to a cancer center for further management and follow-up.
Further clinical examination of the patient and MRI revealed no distant metastasis. The patient underwent several courses of radiotherapy and is currently eighteen months' disease free.


We present the case of a white, Hispanic, 58-year-old, non-smoker female. She has a past medical history of obstructive sleep apnea and chronic obstructive pulmonary disease (chronic bronchitis). Her travel history includes the Dominican Republic and Caribbean Islands. She worked for several years in an automobile repair shop and was exposed to lead and paint. Her current occupation is as a telephone operator in a call center, which requires her to speak continually.
Fifteen years ago, she developed a progressive cough. During the following four years, she was evaluated by more than eight pulmonologists who were unable to make a diagnosis. She developed a productive cough with white sputum and blood titer. Her alpha-1-antitrypsin serum, perinuclear anti-neutrophil cytoplasmic antibody (P-ANCA), cytoplasmic antineutrophil cytoplasmic antibody (C-ANCA), and rheumatoid factor were all within normal limits. Her purified protein derivative (PPD) and fungal infection tests were negative. Lung function tests revealed an obstructive pattern. Her forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) was 70% and total lung capacity (TLC) was 72%. A computed tomography (CT) scan showed mild ground glass infiltrates in the lung bases (Figure ).
Finally, in December 2011, a lung biopsy via assisted thoracoscopic surgery (VATS) was performed, and she was diagnosed with constrictive bronchiolitis and diffuse idiopathic neuroendocrine cell hyperplasia with carcinoid tumorlets. She was treated with octreotide; however, the treatment was interrupted several times due to issues with insurance and difficulties visiting the medical center. Her treatment was restarted in our hospital after three years in May 2014. Since then, CT scans taken every six months show a stable disease. She currently has a stable radiographic disease with no new complaints during the over two years of follow-up.


A 53-year-old white man presented to our Department with a 2-month history of a painful and moderately swollen left wrist. His past medical history was unremarkable. Standard anteroposterior and lateral X-rays of his left wrist revealed two osteolytic lesions involving the distal ulna and the lunate fossa of the distal radius without any joint involvement (Fig. , ). Subsequent biopsy of his left ulna under regional anesthesia produced brown spongy material, histologically characterized by the presence of large numbers of multinucleated giant cells and spindle cells in a dense collagenous background. These findings were histologically consistent with a diagnosis of GCT and correlation with the clinical and radiological findings was recommended by the pathologist. As he had no other skeletal manifestations, a complete resection of the distal ulna (9.5 cm length) followed, along with curettage and cementoplasty of the distal radial metaphysis, to support the articular surface (Fig. , ). The resected distal ulna specimen and the curettings from the distal radius were submitted for histopathological evaluation; our patient was discharged 2 days later, with a forearm cast and instructions to attend the clinic in 2 weeks’ time for re-evaluation and removal of sutures.
Two weeks postoperatively, he was re-admitted to our orthopedic department with diffuse musculoskeletal soreness, anorexia, constipation, nausea, and localized abdominal pain. He also reported weight loss of approximately 5 kg. On palpation he had tenderness in the thoracic wall, the second and fifth metacarpals of his right hand, the left tibia, the pelvic ring, and the left shoulder girdle and humerus. Plain radiographs revealed multiple osteolytic lesions in his ribs, right hand, left tibia, and scapula (Fig. –).
A histopathological examination of both the resected ulna (Fig. –) and the curettings of the radius (Fig. ) revealed similar findings: numerous, multinucleated, osteoclast-type giant cells were noted amid a mononuclear, spindle cell, histiocytoid component (Fig. ). Many of the giant cells were clustered in large nodular aggregates separated by fibrous septa containing fibroblast-like spindle cells. The spindle cell component showed no evidence of atypia or sarcomatoid features (Fig. ). There were prominent foci of hemorrhage with relatively restricted hemosiderin deposition (Fig. ). Mitoses were observed (up to five mitotic figures/ten high power fields) but no atypical mitoses or necrosis were seen. On the resection specimen of the ulna, the lesion focally disrupted the cortex producing periosteal reaction with woven bone trabeculae, extending in the surrounding adipose tissue and skeletal muscle (Fig. ). Based on the similar findings of both lesions and the rarity of multifocal GCT of bone the histopathology report included in the differential diagnosis a BT of hyperparathyroidism, either primary or in the setting of a paraneoplastic PTH-like protein production and suggested further patient evaluation.
Our patient’s laboratory examination showed high total serum calcium (14.5 mg/dl, normal range 8.8–10.4), low serum phosphorus (2.3 mg/dl, normal range 2.5–4.5), and low 25-hydroxyvitamin D (9.74 ng/ml, normal range > 30). PHPT was suspected and confirmed by the elevated PTH levels of 1453 pg/mL (normal range 15–65). Serum potassium and sodium concentrations and thyroid hormone levels were in reference range as well as the main cancer indicators: cancer antigen (CA) 15-3, carcinoembryonic antigen (CEA), CA 125, and prostate-specific antigen (PSA). Serum protein electrophoresis was also normal. His human chorionic gonadotropin (hCG) was elevated (25.3 mUl/ml, reference level < 5). An isotope bone scan showed multiple sites of uptake over his ribs bilaterally, the lower pole of both scapulae, multiple foci in his pelvis, the metacarpal bones of his right hand, and his right tibia. At subsequent radiological work-up, both computed tomography (CT) and ultrasonography of his neck revealed a 4.5 × 2.5 × 3.2 cm mass emanating from the right lobe of his thyroid gland. Parathyroid subtraction technetium-99m (99mTc) sestamibi (MIBI) scintigraphy showed extensive uptake in his right lower parathyroid gland (Fig. ). Multiple endocrine neoplasia was excluded because of the normal MRI imaging of his pituitary gland.
Appropriate medical care was given to our patient including hyperhydration and high doses of diuretics and diphosphonates. After his health status improved and his serum calcium nearly normalized, a specialist surgeon was consulted for further surgical treatment. Surgery consisted of extensive resection: total thyroidectomy with removal of the parathyroid glands. A mass measuring 4.8 cm in greatest diameter, abutting the thyroid gland was documented at surgery. The mass was surrounded by a thick capsule, had a tan-brown, solid, and microcystic cut surface, and rubbery consistency. On histologic examination, the tumor comprised small cells with minimal to scanty cytoplasm and round nuclei, arranged in an organoid pattern, with frequent perivascular pseudorosettes. Thick fibrous septa emanating from the capsule were noted within the tumor. There was capsular invasion, with extension of neoplastic groups in the surrounding loose connective tissue adjacent to striated muscle, and foci of vascular invasion in the tumor capsule. The histologic findings were consistent with a parathyroid carcinoma. The neoplasm did not appear to invade the adjacent thyroid lobe and did not involve the margins of resection.
Our patient experienced postoperatively persistent hypocalcemia requiring calcium and vitamin D replacement. His condition was characterized as “hungry bone syndrome.” He is now recovering 12 months after surgery, with a serum PTH level of 7.1 pg/mL and serum calcium level of 10.7 mg/dl and he is under calcium and vitamin D replacement therapy. The lytic bone lesions have almost disappeared (Fig. –) and no other additional orthopedic intervention is necessary. He is closely followed by general surgeons, oncologists, and endocrinologists.