In 2011, an 80-year-old Brazilian man, presented to our hospital with anemia, thrombocytopenia, and monocytosis (>1000/mm3). He had dizziness and normal blood pressure levels. A myelogram showed dyserythropoiesis, dysgranulopoiesis, and dysmegakaryopoiesis; blasts were approximately 2.2% (Fig. ). Cytogenetic analysis showed a normal karyotype. A bone marrow biopsy showed hypercellularity with significant expansion of granulocytic and megakaryocytic series. Mild focal reticulin thickening was observed. He had not received any blood transfusions and had no infection reports. Routine examinations, including renal function and electrolytes, were within the normal ranges. An immunohistochemistry analysis showed normal expression of precursor cells; there was a moderate increase in vasculature and nuclear positive reaction to p53 (2%). The diagnosis was MDS with multiple lineage dysplasia. He was classified as low-risk MDS, according to IPSS-R (score-2.2 (Table )).
Currently, he is 85 and has difficulty walking, but with a good overall health status, despite his limitations. In both cases, patients with these mutations have had a good evolution despite a positive p53 expression.


The patient was a 45-year-old man who presented with a headache for 3 months which was progressive and had been intolerable for 2 weeks. However, the patient was a football player with good health. There was no such family history and family members were perfectly well. There were no other clinical symptoms reported by the patient.
The patient was advised to do CT-scan and MRI. Interestingly both CT-scan and MRI revealed brilliantly enhancing left lateral ventricular lesion with unilateral hydrocephalus (). T1 Image axial view postcontrast () and precontrast film () were also examined. T1 image of coronal view in postcontrast film was also evaluated (). T2 image in sagittal view () also found the SOL.
Flare image () was examined as well. All other investigations were within normal limit. Then the patient was advised for surgery for removal of the lesion. In this context, left parietal craniotomy was performed with total removal of the lesion through intraparietal approach. Reversal from GA and the postoperative period was uneventful and the patient had got rid of clinical symptom completely after surgery.
The tumor was well defined preoperatively and was removed under microscopic surgery meticulously. The patient was very poor to bear the cost of postoperative CT-scan and hence it was not done. The biopsy was sent for histopathological examination. The lesion was nearly spherical measuring 3.0 cm + 2.5 cm, whitish, and firm.
There was no evidence of necrosis. Microscopy revealed multicystic appearance with cyst lined by columnar epithelium with apical mucin. Few goblet cells were seen. Few areas had shown pseudostratified lining epithelium with nuclear hyperchromasia, nuclear enlargement, and increased mitosis.
There was no evidence of stromal invasion. The mucinous material was seen within the lumen. Hemosiderin laden macrophages were present in the stroma. It was confirmed as a lateral ventricular enterogenous cyst. Then the patient was well in around one year. After about one year of the surgical removal of the lesion, there was a recurrence of a headache whose intensity was more than the previous one.
Then the patient was advised to do a CT-scan which revealed lesion of the same pattern in the same location as before (). The patient was reexplored surgically and the tumor was removed completely through the same route and histopathology was again revealed it as a case of the enterogenous cyst. Again the total removal of the lesion from the brain was confirmed by postoperative CT-scan. Then the patient was advised for radiotherapy. After completion of radiotherapy, the patient was perfectly well at 13th postoperative month ().


A 62-year-old African American male was diagnosed with Rai stage I CLL (ZAP 70+, CD38+, deletion 11q+) in 2005 on a cervical lymph node biopsy. He remained on observation until 2009. At that time, his cervical lymphadenopathy worsened, and he presented with new constitutional symptoms of weight loss, fatigue, and night sweats. Therefore, he was treated with six cycles of FCR (fludarabine, cyclophosphamide, and rituximab). He achieved a complete response (CR) and remained under surveillance until 2014 when he presented with rapidly expanding right-sided cervical lymphadenopathy compressing on his esophagus and new lymphocytosis of 20,000/μL. Lymph node biopsy was consistent with Richter's transformation to diffuse large B-cell lymphoma (DLBCL). Targeted genomic analysis showed missense and frameshift mutations in the PRDM1 and SPEN genes.
After the diagnosis of Richter's transformation, he was treated with six cycles of R-CHOP chemotherapy (rituximab, cyclophosiphamide, doxorubicin, vincristine, prednisone) followed b a autologous stem cell transplant with BEAM conditioning (carmustine, etoposide, cytarabine, melphalan) which was completed in March 2015. Post transplant, he remained on close clinical follow-up. In August 2015, he presented with fatigue and abdominal pain and was found to have bulky intra-abdominal lymphadenopathy. He was treated with four cycles of R-ICE (rituximab, ifosfamide, carboplatin, and etoposide), but the disease remained refractory. As ibrutinib has shown activity in Richter's transformation, ibrutinib 420 mg was started 4 weeks after the last cycle of R-ICE. Throughout his entire course including the different chemotherapy regimens since diagnosis and in the 6 days before initiation of ibrutinib, the patient's liver function tests (LFTs) remained normal.
Two weeks after initiation of ibrutinib, routine blood work revealed new onset LFT abnormalities (Table ) and his only reported symptom was dark-colored urine for 3 days. At the time of ibrutinib initiation, the patient was not on any medications including herbal, dietary supplements, or over-the-counter medications. A complete infectious workup including serologic testing for cytomegalovirus, Epstein-Barr virus, hepatitis viruses (hepatitis C virus antibody, hepatitis B surface antigen, hepatitis B core antibody, and hepatitis E IgG and IgM), blood cultures, screening for autoimmune diseases including ANA (antinuclear antigen), antimitochondrial antibodies, antismooth muscle antibodies, and antiliver kidney microsomal antibodies (anti-LKM antibody) were all negative. Imaging studies including an ultrasound of the liver and CT scan of the abdomen did not show any changes in his disease status compared with prior imaging, nor any evidence of obstruction at the level of the biliary tree was seen. As drug-induced liver injury was suspected, ibrutinib was stopped and to delineate further he underwent two liver biopsies, as his LFTs never normalized. The liver biopsy showed centrilobular intrahepatic and canalicular cholestasis, ceroid-laden macrophages (highlighted on PAS-D stain), and rare apoptotic bodies, which was consistent with a drug-induced liver injury (Fig. ). His LFTs down trended 3 months after stopping ibrutinib but did not normalize (Table ) and he continued without further therapy. Unfortunately, he passed away due to the progression of CLL and a decline in his performance status in May 2016.


A 14-year-old girl presented with bilateral lower limb paresthesia and weakness that progressed over a few days. Nine months later, she developed upper extremity weakness with sensory dysfunction at the level of C7 that worsened in a step-wise manner over a period of 3 months to paraplegia, sensory loss and sphincter dysfunction. Spinal MRI () showed tumefactive, T2 high-intensity lesions from C3 to T4 (with contrast enhancement) and T9 to T12 (without contrast enhancement). Brain MRI revealed only a few nonspecific cerebral white matter lesions. She then underwent thoracic spinal cord biopsy for suspicion for a spinal astrocytoma. However, the initial pathological analysis excluded tumor, and no definite diagnosis was made. Later, her serum AQP4 antibody returned as positive, and she was diagnosed with NMOSD. Cerebrospinal fluid (CSF) analysis revealed mild pleocytosis with 17 cells/mm3 (12% neutrophils), and an increased protein level of 81.4 mg/dl. No clinical response was observed with high-dose methylprednisolone.
Re-assessment of the biopsied spinal cord specimen () revealed massive necrotic areas with prominent cellular infiltration, cystic inflammatory lesions with hyalinized or thickened vessel walls and astrocyte rarefaction. In perivascular areas, we observed inflammatory cells including eosinophils, neutrophils and lymphocytes. Immunohistochemistry revealed the AQP4 immunoreactivity loss to be more extensive than that of glial fibrillary acidic protein (GFAP), whereas myelin basic protein (MBP)-stained myelinated fibers were relatively preserved. The cellular infiltrates in the severely affected area included CD68-positive macrophages. The deposition of immunoglobulin G (IgG) and C9neo complement was present at the astrocytic foot processes and microvenules, but there was no typical rosette-pattern of C9neo deposition. Moreover, neurofilament-positive axons were relatively spared even in lesions demonstrating a complete loss of AQP4 and GFAP.


A 47-year-old woman presented with left shoulder pain, motor weakness and paroxysmal spasms in her left upper extremity over a month period. Spinal cord MRI demonstrated an edematous T2 hyper-intense lesion extending from the medulla to C7 with central contrast enhancement. Brain MRI was normal. She was treated with high-dose methylprednisolone for five days with a partial recovery. Four months later, acute transverse myelopathy developed over a few days with paraparesis, loss of sensation in both legs and sphincter dysfunction. A second spinal MRI revealed a caudal extension of the lesion to the T2 level with marked swelling and gadolinium enhancement (). The patient underwent a cervical cord biopsy based on a presumptive diagnosis of spinal astrocytoma, but the initial pathology showed no evidence of tumor. Further investigation revealed that her serum AQP4 antibody was positive.
Re-assessment of the spinal cord specimen () revealed some cystic changes in the tissues, vascular wall thickening and hyalinization, but no inflammatory cell infiltration. Immunohistochemistry demonstrated the demyelinated lesions to be mostly covered by fibrous astrogliosis that stained strongly for AQP4. MBP-positive myelinated fibers were partially observed. The lesion also contained some cystic necrotic spots with losses of AQP4 immunoreactivity.


A 55-year-old male with a notable history of diabetes, hypertension, obesity, and chronic kidney disease was found to have bilateral kidney masses while undergoing ultrasound for evaluation of recurrent kidney infections. He was eventually referred to our institution. Computed Tomography (CT) at that time showed a left upper pole 3.2 cm mass, left lower pole 1.4 cm mass, a right mid-kidney 6.6 cm mass, and an upper pole 2.1 cm mass () which were felt to be stable from a prior CT. A review of a prior biopsy showed small fragments of tissue with CK7 positive, focally CD10 positive clear cells, and mild nuclear atypia which was suspicious for clear cell papillary renal cell carcinoma (CCPRCC).
Resections from the left kidney were performed. The upper pole, lower pole, and the large mid-portion to lower pole masses were removed. All resections showed a histologically typical CCPRCC with a background of simple renal cysts and moderate global glomerular sclerosis, hyperplastic arteriolosclerosis, and lymphoplasmacytic interstitial nephritis.
Several months later, a radical nephrectomy of the right kidney was performed (, inset). Pathologic evaluation showed a 6.5 cm CCPRCC, ISUP (International Society of Urological Pathology) grade 2, of the mid-lower pole which was limited to the kidney (). These cells were positive for carbonic anhydrase IX (CAIX) in a cup-like staining pattern, cytokeratin 7 (CK7), and paired box 8 (PAX8) and were negative for neuroendocrine markers synaptophysin and chromogranin. Interestingly, GATA3 also showed diffuse strong positivity of CCPRCC. No abnormalities of Von Hippel-Lindau (VHL) gene, including mutations, methylation abnormalities, and LOH3p, were identified by genetic testing at an outside institution. Just adjacent to the CCPRCC, a microscopically separate 1.5 cm well-differentiated neuroendocrine tumor was identified focally invading the hilar fat (). This was diffusely positive for synaptophysin and chromogranin, variably positive for CK7, and negative for CAIX, PAX8, and GATA3. Of note, no symptoms of carcinoid syndrome were present. In addition to the above histologic findings, simple 0.5–1.5 cm cortical cysts were identified in a background of focal global glomerulosclerosis with tubular atrophy, interstitial fibrosis, and moderate to severe arteriosclerosis.
One year after his partial nephrectomy, the patient is doing well with no evidence of recurrence. The patient's chronic kidney disease is stable with creatinine of 1.81 mg/dL (0.8 mg/dL prior to surgery) and does not require dialysis.


A 68-year-old Caucasian woman recently diagnosed with CMML presented to our rheumatology office for evaluation of an abnormal chest computed tomography (CT) showing inflammation surrounding the entire thoracic and abdominal aorta. She was experiencing shortness of breath, fatigue, fevers, and night sweats for about four months previously. She additionally had an unintentional weight loss of 35 pounds over the past 2 years which was initially attributed to Nissen fundoplication procedure for gastroesophageal reflux. She denied any headaches, vision changes, scalp tenderness, jaw pain, dysphagia, joint pain, joint swelling, muscle pain, or photosensitivity.
For the past eight months, she had been undergoing hematological workup of abnormal blood counts. Her white blood cell (WBC) counts were elevated with monocytosis and varying degrees of neutrophilia over the past 3 years. She had thrombocytosis. Her initial evaluation was negative for BCR-ABL PCR testing, Janus kinase-2, calreticulin, and MPL mutations. There was no hepatosplenomegaly on imaging. After these tests returned negative, she was planned for a bone marrow biopsy for further evaluation of monocytosis but opted to wait as she was asymptomatic. However, she presented back with a nontender, erythematous lesion on her left breast. About two weeks later, similar scattered pink small dermal papulonodules were present on the posterior neck, left shoulder, abdomen, and left thigh. Left breast punch biopsy described a dense dermal infiltrate with small lymphocytes with cytologic atypia. There was no significant epidermal involvement. The lymphocytes were positive for CD4 and CD43, myeloperoxidase, and lysozyme. The overall morphologic and immunohistochemical findings were those of a malignant neoplasm. Although this was originally thought to be a possible T cell lymphoma, case was discussed at the hematopathology conference and the overall presentation correlated with more systemic process, such as CMML.
Subsequent bone marrow biopsy and aspiration showed pieces of hypercellular bone marrow with overall cellularity of 50%, trilineage hematopoiesis, hypogranular myeloid cells, and increase of monocytoid cells with somewhat immature appearing features. Increased monocytosis (20%) with oval-shaped, slightly irregular nuclei was present. There was no evidence of fibrosis on reticulin staining. Adequate megakaryopoiesis and erythropoiesis without dysplastic changes was noted. The myeloid-to-erythroid ratio was mildly increased. Cytogenetic evaluation exhibited a normal karyotype (46, XX). Flow cytometry revealed CD14+/CD16- monocytes that are characteristic of CMML []. CMML diagnosis was made based on the above findings, persistent peripheral blood monocytosis ≥ 1 × 109/L, with monocytes accounting for ≥10% of the WBC count, no evidence of PDGFRA/PDGFRB, <20% blasts in the blood and bone marrow, not meeting WHO criteria for BCR-ABL1 positive chronic myeloid leukemia, primary myelofibrosis, polycythemia vera, or essential thrombocytosis and all other causes of monocytosis excluded []. For staging, she underwent positron emission tomography (PET) and computed tomography (CT) scans and both imaging studies showed soft tissue density surrounding the entirety of the thoracic and abdominal aorta, consistent with large-vessel vasculitis (see Figures and ).
Laboratory studies were positive for antinuclear antibody (ANA) with a titer of 1 : 640 in a nucleolar and speckled pattern as well as elevated RNP antibody (ab) at 1.1. Her inflammatory markers were elevated: erythrocyte sedimentation rate (ESR) 36 mm/hr and C-reactive protein (CRP) 35.3 mg/L. The negative serologies included an anti-neutrophil cytoplasmic ab, anti-proteinase 3 ab, anti-myeloperoxidase ab, SS-A/SS-B ab, anti-Smith ab, anti-dsDNA ab, anti-smooth muscle ab, rheumatoid factor, anti-cyclic citrullinated peptide ab, and hepatitis panel.
For symptomatic aortitis, we started treatment with prednisone 1 mg/kg/day. Within a week, patient had significant improvement. Her shortness of breath subsided and she felt strong and energetic. Objectively, while on steroid therapy, her WBC count initially dropped. Since the aortitis related symptoms were improving, the hematology team planned to start her on treatment with a hypomethylating agent—azacitidine.
Steroid therapy was slowly tapered given her good response to initial high-dose steroids. However, two months later, she developed steroid-induced myopathy and prednisone was tapered more quickly. Within two weeks, she became more dyspneic and hypoxic. Her respiratory status deteriorated quickly, requiring intubation and mechanical ventilation. She was treated with broad-spectrum antibiotics for possible infectious etiology. CT chest demonstrated stable aortitis but increased diffuse ground-glass opacity throughout both lungs and bilateral pulmonary consolidation. These findings were attributed to paraneoplastic infiltrates from leukemia and less likely to be infectious. Cultures from bronchoalveolar lavage and Pneumocystis jirovecii testing were negative. Coincidentally, prior to this admission, she had a stable WBC count of 18,600/μL that now has progressed to WBC count of 77,000/μL, despite negative infectious workup, aortitis being asymptomatic and stable on CT imaging study.
Given her clinical deterioration from leukemia, in her final days she received her first treatment of CMML with hydroxyurea, then underwent leukapheresis, and received one dose of chemotherapy with decitabine one day prior to expiration. Unfortunately, she continued to deteriorate and was placed on hospice. Her family refused an autopsy.


A 68-year-old Japanese man was hospitalized with giant gastric tumor identified by endoscopy. He had not had a significant symptom, except for discomfort in abdomen one year ago. He had smoked 40 tobaccos a day for 10 years and drunk 5 glasses of whisky a day for 5 days/week. Moreover, he had prostate hyperplasia and hypertension in his medical history. No remarkable information was recorded in family medical history.
Since fecal occult blood detected by routine health check-up, he underwent biopsy of stomach by endoscopy and specimen was sent to Department of Pathology. Microscopically, submitted specimen was composed of malignant epithelial and neuroendocrine components. The epithelial component was mainly composed of tall columnar cells with a distinct tubular structure. The nuclei are enlarged, hyperchromatic, and pleomorphic with loss of nuclear polarity. The malignant epithelial cells have eosinophilic cytoplasm with abundant mucus production. They were classified into well-differentiated and moderately differentiated tubular adenocarcinoma (tub1 and tub2) based on JGCA 2010 Classification of Gastric Carcinoma (6) (). The neuroendocrine component has nesting and trabeculae patterns. Tumor cells have round, ovoid, or spindled nuclei and scant cytoplasm. Cell borders are rarely seen. Nuclear chromatin is finely granular and nucleoli are absent or inconspicuous. Based on nuclear structure and cell size of neuroendocrine component, the diagnosis was small cell carcinoma corresponding WHO 2010 Classification of Tumors of the Digestive System (). Therefore, the pathological diagnosis was considered as gastric mixed adenoneuroendocrine carcinomas (MANEC) as stated in WHO 2010 Classification. It was then confirmed by immunostaining with neuroendocrine component positive for synaptophysin (3+), chromogranin A (3+), and CD56 (2+) (; ). We also verified expression of HER2 for targeted therapy and the proliferative index by Ki67. The result was HER2 (3+) only in adenocarcinoma component and Ki67 labelling index is strongly positive (; ). By scrutinised cT4a (SE) N3b M1, gastric cancer was diagnosed at stage IV. At the same time, hepatic metastases were also found.
Laboratory test revealed tumor markers ().
After the first pathological report as poorly differentiated adenocarcinoma, clinicians decided to start chemotherapy (S-1, CDDP) as soon as possible due to advanced condition of our patient. The additional report of immunohistochemistry confirmed the presence of neuroendocrine component and the adenocarcinoma component was strongly positive for HER2. Therefore, clinicians added Trastuzumab in chemotherapy regime to control tumor progression.
Our patient was given total 5 cycles of chemotherapy (S-1, CDDP, Trastuzumab) but liver lesions tended to increase markedly by interval CT-scan checking and hence main treatment shifted to neuroendocrine carcinoma (NEC) with Sandostatin-LAR. Before starting therapy with somatostatin analogue, we carefully checked expression of somatostatin receptors and mTOR peptide by immunostaining. His result was SSTR2 (2+), SSTR5 (2+), and mTOR (−). Totally, this patient was given 2 injections. Eventually, he was given palliative treatment without surgery due to his general weakness. He died as a result of liver failure after 7 months treatment in total.
The hospital autopsy was performed to help answer specific questions about the cause of death. His body was carefully examined and we found many lesions at different organs. On macroscopic examination, the primary tumor was on middle part and the lesser curvature of stomach (M less). The macroscopic type was type 3 which means infiltrative and ulcerative type []. The tumor was measured 9 × 6 cm in size. Metastatic lesions could be found in liver, diaphragm, pancreas, and periaortic lymph nodes as multinodular appearance and all of them are comprised of only neuroendocrine carcinoma component.
By careful autopsy examination, the final conclusion was gastric MANECs with neuroendocrine carcinoma component metastasis to liver, pancreas, diaphragm, and periaortic lymph nodes. Adenocarcinoma was not detected in the metastatic lesions and liver failure, due to metastasis of NEC, was the cause of death (Figures , , and ).
To confirm our diagnosis of MANEC as definition in WHO 2010 Classification, we ordered for immunostaining on autopsy slides and summarized immunoprofile as in . In general, adenocarcinoma component took place 10–20% areas of the gastric tumor, which was confirmed by autopsy examination.


The patient is a 44-year-old female, with a medical history of migraines, mild arterial hypertension, and a left vertebral artery dissection in 2014, without brain infarction (Figures and ). She was using losartan and aspirin daily. The patient suffers from recurrent headaches related to the first 3 days of her menstruation cycle. Her 75-year-old mother was diagnosed with a thoracic aortic aneurysm 10 years previously.
In September 2016, she presented with oppressive headache with left predominance, photophobia and nausea, lasting for 6 days. The intensity of the pain was 8 out of 10 on a visual analog scale (VAS). She also complained of cervical discomfort. A computed tomography angiography (CTA) showed left internal carotid artery dissection extended between the upper cervical and supraclinoid segments (Figures and ). No ischemic brain damage was observed. Therefore, she was admitted to the emergency department, and aspirin orally was administered in doses of 250 mg at bed time. There were no focal neurological signs on physical examination. The patient had good spatial–temporal orientation and was afebrile.
We attributed the headache to both the left internal carotid artery dissection and the migraine. There was an insufficient response to a combination of ketoprofen and metamizole i.v. Thus, intravenous betamethasone was added to the treatment regimen to provide a rescue medication for the refractory pain. However, the patient showed only a partial response after a 3-day course. She was then prescribed oral topiramate 50 mg two times a day as preventive therapy and naproxen sodium 550 mg as acute treatment option.
One week later, a new CTA was performed and showed no changes compared to the previous imaging.
Apart from hypertension and migraine, we did not identify other putative risk factors for dissections of extracranial arteries such as recent respiratory tract infection and hyperhomocysteinemia. There was no history of major or minor cervical trauma, chiropractic maneuver, or hyperextension injury. Infectious-inflammatory pathology of the paranasal sinuses was excluded with a computed tomography. The patient did not have signs of either hypermobility or dermic lesions. A dermatologist ruled out connective tissue disorders. Renal fibromuscular dysplasia was ruled out using non-invasive imaging duplex ultrasound. Transthoracic echocardiography revealed no abnormalities such as congenital heart defects and left ventricular outflow tract malformations. A computed tomographic scanning and aortography ruled out aortic aneurysm.
To determine the possible nature of this recurrent dissection, an aortopathy comprehensive panel was ordered with sequence analysis and exonic deletion/duplication testing of 25 genes (ACTA2, CBS, COL3A1, COL5A1, COL5A2, EFEMP2, FBN1, FBN2, FLNA; MAT2A, MED12, MYH12, MYH11, MYLK, NOTCH1, PLOD1, PRKG1, SKI, SLCA10, SMAD3, SMAD4, SMAD6, TGFB2, TGFB3, TGBR1, TGFBR2). This test is a comprehensive analysis of genes associated with inherited aortopathy and connective tissue disorders. We ordered it because of the antecedent of maternal thoracic aortic aneurysm (INVITAE, San Francisco, CA, USA; ).
A heterozygous variant was identified in the NOTCH 1 gene (exon 34, c.6365C>T). This sequence replaces proline with leucine at codon 2122 of the NOTCH 1 protein (p.Pro2122Leu). Her mother was also tested, and she was positive for this variant in heterozygous state.
The patient was discharged without focal neurologic deficit with a National Institutes of Health Stroke Scale (NIHSS) of 0 (0–42). After 6 months, she was on aspirin 100 mg and topiramate 100 mg per day, remained with NIHSS 0 and was able to return to normal activities. There was a reduction in the headache days to about 1 day/month and in the headache severity (VAS = 2).
The study was conducted according to International Standards of Good Clinical Practice (ICH guidelines and the Declaration of Helsinki). The project was approved by the local Research Ethics Committees of Universidad de Chile Hospital, Santiago, Chile. The subject gave written informed consent for the publication of this case report in accordance with the Declaration of Helsinki.
For the genetic definitions, see Table .


The proband (II-2 in Fig. ) is a 45-year old woman, who first presented to our university hospital at the age of 35 and was referred to us because of her pregnancy. She has congenital deafness, first experienced syncope at the age of 3, and was diagnosed with epilepsy. She was treated with anti-epilepsy medications; however, she subsequently experienced several instances of syncope. At the age of 13, she had a syncope event, and was suspected of having JLNS because of her congenital deafness and prolonged QT interval. Her syncope was diagnosed as an arrhythmic episode when she was aware of tachycardia and as epilepsy when she was not. She also had a subarachnoid hemorrhage at the age of 29.
When she first presented at our hospital, she was not taking beta-blockers, because of a history of asthma, but was taking mexiletine in addition to phenytoin. Her QTc was found to be prolonged (584 ms) at presentation and administration of atenolol was initiated. She delivered her baby (III-1 in Fig. ) through Caesarean operation at our hospital at the age of 35. At 37, she delivered her second baby (III-2 in Fig. ) through Caesarean operation at our hospital. Despite administration of beta-blockers, her QTc remained prolonged (600 msec at the age of 37, 780 msec at 44) (Figs. and ), which is not unexpected because treatment with beta-blockers in LQTS1 is not expected to overtly reduce QTc []. However, she continued to experience occasional syncope and finally underwent an implantable cardioverter defibrillator (ICD) operation at 38 years of age. Subsequently, she is in a stable clinical condition. Because the proband was suspected of JLNS and both infants had a measured QTc of 500 ms or greater within 1 month after birth, beta blockers were initiated and both children remain in stable condition at ages 10 and 8 (Figs. and ). QTc of the son (III-1 in Fig. ) was measured as 500 ms one month after birth, while the QTc of his sister (III-2) was 530 ms at birth.
The father (I-1) and mother (I-2) of the proband were first cousins. There is no history of sudden unexplained syncope or death of children or adults in the immediate family members, despite the prolonged QTc of the children.
Clinical evaluation and consultation of the proband and her family members were performed at Chiba University Hospital. Clinical phenotypes were deduced from the clinical history, physical examinations, and ECG. Blood samples were collected from the proband and her family members following genetic counseling, and written informed consent was obtained prior to sample collection.
Genomic DNA was isolated from peripheral blood lymphocytes according to established protocols at our laboratory []. Entire coding exons, including the intronic boundaries of the genes, of KCNQ1 (NCBI ref: NM_000218) and other LQT causative genes (KCNH2, SCN5A, KCNE1, KCNE2, KCNJ2, SCN4B, KCNJ5) were amplified by polymerase chain reaction (PCR), according to established protocols in our laboratory. Briefly, 30–100 ng of genomic DNA was subjected to PCR amplification with DNA polymerase (PrimeSTAR GXL DNA Polymerase; Takara Bio Inc., Kusatsu, Japan) and primer sets.
The amplicons were subjected to conventional sequencing with Sanger sequencers (Applied Biosystems 3730/3130 DNA analyzers; Thermo Fisher Scientific, Waltham, MA, USA). The sequence data were processed with Gene Codes Sequencher Software (Takara Bio Inc.) and mapped to the human genome sequence (build GRCh37/hg19).
Genetic analysis was performed to screen all coding exons and the exon–intron boundaries of the KCNQ1 gene (NCBI ref: NM_000218.2, NP_000209.2) with concurrent screening of other LQT causative genes (KCNH2, SCN5A, KCNE1, KCNE2, KCNJ2, SCN4B, KCNJ5). We detected a novel homozygous nonsense variant, NM_000218.2:c.115G > T (p.Glu39X, in exon 1a), in the KCNQ1 gene of the proband, as well as a homozygous common variant (NM_000218.2:c.1343C > G, p.Pro448Arg) (Additional file : Table S1). Genetic screening of her mother (I-2) and children (III-1 and III-2) revealed that they were heterozygous for the nonsense variant (Fig. ). Her husband (II-3) was also screened and found to be heterozygous for the common variant (NM_000218.2:c.1343C > G, p.Pro448Arg). The proband is a child from a first-cousin marriage, and we have concluded the homozygous nonsense variant in the proband is the cause of her JLNS1. The proband was negative for pathogenic variants in other LQT causative genes, including the KCNE1 gene (Additional file : Table S1).


A previously healthy 22-year-old Japanese man without a medical or surgical history presented to Anjo Kosei Hospital with complaints of fever and dyspnea. Physical examination revealed a temperature of 37.8°C and tachycardia. CT scans revealed a 14.4 × 9.8 × 10.0 cm mass in the anterior mediastinum with compression of the heart. Pertinent laboratory values included an AFP level of 31,536 ng/mL and an LDH level of 604 IU/L. His hCG level was within the normal range. Physical examination of the testes showed no neoplastic parenchymal involvement. A needle core biopsy revealed a malignant germ cell tumor, and immunohistochemical staining was positive for AFP. From these data, the patient was finally diagnosed with a yolk sac tumor.
The patient received combination chemotherapy consisting of BEP every 3 weeks for a total of 3 cycles. After that, an additional 2 cycles of EP chemotherapy were administered in order to normalize his serum tumor marker levels. His AFP level decreased to 46 ng/mL after 3 cycles of BEP and further normalized after 2 cycles of EP. After 5 courses of preoperative chemotherapy, resection of the tumor was performed, resulting in a complete pathologic response (). The patient is alive and in CR without any evidence of recurrence.


A previously healthy 25-year-old Japanese man was admitted to our hospital with complaints of chest pain. His history was unremarkable. Physical examination did not reveal any significant findings. A CT scan revealed a 7.6 × 6.5 × 3.5 cm mass in the anterior mediastinum and no metastases at the initial diagnosis. His laboratory values included an AFP level of 3,034 ng/mL and an hCG level of 20.6 ng/mL. Ultrasonography of the testes revealed a uniform pattern without any findings suggestive of malignancy. Needle core biopsy was not performed. Based on suspicion for PMGCT, the patient was referred for thoracic surgery. The tumor was histopathologically diagnosed as a yolk sac tumor. After the operation, the patient received 4 total courses of BEP and EP chemotherapy. Upon completion of the chemotherapy, his serum tumor marker levels normalized (). The patient is alive and in CR without any evidence of recurrence after 3 years.


A 32-year-old male patient presented in October 2014 with complaints of pain, blurred vision, and photophobia in the right eye for approximately 1 week. In his medical history, he reported being followed at another center for keratoconus and undergoing keratoplasty 7 years earlier in his left eye and 6 months earlier in his right eye. He had been using moxifloxacin (Vigamox®, Alcon) every 3 hours for about 1 week. At presentation, his visual acuity was hand motions in the right eye, and his best corrected visual acuity in the left eye was 8/20. Slit-lamp examination of the right eye revealed conjunctival hyperemia, purulent secretions and a keratitis focus about 5x4 mm in size located centrally over the corneal graft, epithelial defect, and keratoplasty sutures (). The patient was recommended for admission with a prediagnosis of infectious keratitis; swabs from over the infiltration and its margins were sent to microbiology for Gram staining and culture. There were no filamentous extensions, satellite lesions, or ring ulcers suggestive of fungal keratitis. We also detected no hyphae-like structures suggesting fungal infection on confocal microscopy. Moxifloxacin was discontinued and treatment was initiated with topical fortified vancomycin 50 mg/mL (Vancotek®, Koçak Pharmaceuticals) and ceftazidime 100 mg/0.5 mL (Zıdım®, Tum Ekip), alternating between them hourly and replacing the drops every 2 days. Gram staining revealed no bacteria in the swab specimens, but Streptococcus pneumoniae grew in culture toward the end of the second week. Antibiogram showed the isolate was sensitive to vancomycin and ceftazidime, so the same treatment regimen was continued. Considering the lack of substantial improvement in the patient’s symptoms and the possibility of Candida superinfection due to long-term topical steroid use after keratoplasty, treatment was supplemented with topical amphotericin B 0.5 mg/mL (Fungizone®, Bristol-Meyers Squibb) every 2 hours and topical vancomycin/ceftazidime was reduced to every 3 hours. After 1 month of medical therapy, we observed that the corneal infiltration had deepened and the epithelial defect had not closed (). Therefore, we decided to perform CXL with UV-A and riboflavin. The patient was fully informed about the procedure and provided informed consent before the procedure.
In operating room conditions under topical anesthesia, the eye and surrounding area were cleaned with 5% povidone iodine and a sterile covering was placed. The damaged epithelial tissue over the infiltration was debrided using a blunt spatula and sent to microbiology. A riboflavin solution (1% isotonic M) was applied to the cornea at 3-minute intervals for a total of 30 minutes. An area of the cornea about 7 mm in diameter was exposed to 365-370 nm UV-A from a distance of 4-5 cm for 30 minutes at 3 mW/cm2. During this time, riboflavin solution and a lubricating agent (Tears Naturale Free®, Alcon) were applied every 4 minutes.
There was a substantial reduction in the patient’s photophobia and pain the day after CXL treatment. In subsequent examinations, the corneal infiltration became smaller and split into two foci, the surrounding corneal tissue regained transparency, and the epithelial defect also became smaller (). The dosage of topical antibiotics was reduced. On examination 1 month after the CXL procedure, we observed slackening of the keratoplasty sutures and corneal vascularization (). The keratoplasty sutures were removed and subconjunctival anti-vascular endothelial growth factor (anti-VEGF) (bevacizumab, Avastin®, Genentech) was administered. Preservative-free artificial tears (Tears Naturale Free®, Alcon) 5 times daily and fluorometholone (Flarex®, Alcon) 3 times daily were initiated. At 6 weeks after the CXL procedure, the peripheral corneal neovascularization had regressed, corneal opacity was reduced, and visual acuity was 20/400 ().


In July 2010, a 9-year-old Caucasian male presented to our attention for persistent left ankle pain that began 40 days before following an ankle sprain playing soccer. The pain was not present during night but occurred with sport activities and walking for long time. The clinical examination showed pain in the anteromedial and posteromedial region of the ankle without remarkable soft tissue swelling and a slight reduction (5°–10°) of the dorsiflexion in comparison to the contralateral ankle; there was no limping and the stability tests of the ankle were negative. Plain radiographs showed bony-like irregular protuberances localized at the anteromedial and posteromedial aspect of the talus (). Computed Tomography (CT, ) and Magnetic Resonance Imaging (MRI, ) were performed and they were useful to confirm findings consistent with Trevor's disease lesions. Because the young age, the first treatment approach was a rehabilitation program consisting in proprioceptive exercises, strengthening of calf muscle, physical therapy, and Ibuprofen 200 mg when needed. The outpatient examination after 1 month and 6 months did not show any improvement of the symptoms; then, in September 2011, an arthroscopic removal of the posteromedial protuberance was performed by a posterior two-portal approach (); the anteromedial exostoses were removed by an open surgical approach during the same session. After surgery the left ankle was protected with an elastic-compressive bandage for 2 weeks and active ROM recovery was encouraged. Progressive weight bearing on the left limb was allowed starting from the third week and the full weight bearing without crutches was achieved in 2 weeks. The outpatient clinic examinations were performed at 2 weeks, 4 weeks, and 3 months after surgery, when the patient was allowed to return to his daily and sport activities. At the 6-month follow-up, there was no recurrence of pain or any other issues. No perioperative and postoperative complications were recorded.
The patient was recalled in October 2016 (5 years after surgery) for a clinical and radiographic examination. The X-rays showed that the left ankle was free of recurrence and there were not ankle arthritis signs (). The clinical examination showed that the left ankle was stable, no limping, ROM similar to the contralateral ankle, absence of pain, and numbness (). The patient recovered his full daily and sport activities. He and his parents were satisfied with the result of the procedure.


In January 2011, a 10-year-old Caucasian male referred to our hospital for a 3-month ongoing story of pain and swelling of the medial aspect of the left ankle. There was no history of trauma, fever, other joints pain, and abnormalities. He experienced pain walking and playing sports, with limping at the end of the day. Clinically, the ankle joint was painful at the medial edge from the anterior to the posterior aspect. Both dorsiflexion and plantar flexion were reduced of 10°, with local swelling and mild warmth.
X-rays examination showed a protuberance of bony-like nature starting from the medial articular portion of the talus and with lobulated appearance and a large intra-articular cauliflower fashioned loose body (). The 3D reconstruction CT scan demonstrated an expansion of the bone arising from the anteromedial aspect of the talus associated with an irregularity of the distal third of the tibia (); MRI described a pedicled oval bone tumor arising from the talus ().
Because of the symptoms described and the imaging evidences, the first choice of treatment was the surgical arthroscopic removal by a posterior two-portal approach. The arthroscopy showed a flush reactive synovitis that was removed using the motorized tool. The intra-articular loose body was completely removed. The large pedicled prominence was arthroscopically detected but because of the need to perform the histological examination, the removal was performed by an open anteromedial approach. The rehabilitation program was the same as the previous case described. The histological examination showed a cartilaginous and bony-like mass without any evidence of neoplastic cells; then the clinical and pathological diagnosis was DEH of the ankle. The outpatient examinations were performed 2 weeks, 4 weeks, and 3 months after surgery, when the return to his days and sport activity was allowed. At the 6-month follow-up, there was no recurrence of pain and swelling or any other issues and there were no evidences of any perioperative and postoperative complication.
The patient was recalled in October 2016 (5 years after surgery) for a clinical and radiological examination. The X-rays () did not show signs of recurrence and there were no signs of ankle arthritis. The clinical examination showed that the ankle was stable; the ROM limitation was less than 5° in comparison with the contralateral without clinical significance; there was absence of pain and swelling (). The patient returned to his previous level of sport activity without restrictions. He was very satisfied and there were no other concerns.


A 45-year-old female presented to a university-based oral and maxillofacial surgery clinic complaining from pain in her jaws associated with failing fixed partial dentures and requested dental implants. Her medical history was positive for anemia and Crohn's disease. Upon examination, multiple asymptomatic papules were noted on her cheeks. The papules had hard consistency and the overlying skin appeared pitted (). The patient was then referred to the oral and maxillofacial radiology clinic at the same university for CBCT imaging of the jaws for implant treatment planning. A Classic i-CAT® Scanner (Classic i-CAT®, Imaging Sciences International, Hatfield, PA, USA) was used to image the patient using the following parameters: 11 cm diameter × 16 cm height field-of-view (FOV), 120 peak kilovoltage (kVp), 5 milliamperes (mA), and 0.4 mm voxel size.
Incidentally, multiple small round nodules of homogenous high density were noted. They appeared to be evenly dispersed within the thin layer of skin of the face (). These imaging features are most consistent with miliary type OC, which presents as numerous lesions especially on the face of female patients. The patient was referred to the dermatology clinic for management and follow-up especially considering the patient's history of severe acne as a teenager. All laboratory blood test levels were within normal limits.


A 12-year-old female patient presented from a referring institution in November 2015 for evaluation of 1-month history of an enlarging abdominal mass. The patient reported a 4.5 kg weight loss with increased lethargy. The physical examination was normal except for a large abdominal solid mass. Pelvic CT () revealed a large pelvic mass. Tumor markers were significant for alpha fetoprotein (AFP) 656 ng/mL (nml ≤ 7 ng/mL), CA-125 401 U/mL (nml < 35 U/mL), and CEA 6.7 ng/mL (nml ≤ 3.5 ng/mL). Inhibin A/B and β-HCG levels were normal. She underwent an exploratory laparotomy, right salpingoophorectomy, omentectomy, peritoneal washings, diaphragmatic/peritoneal/pelvic biopsies, and periaortic lymph node biopsy. Intraoperative findings were significant for a distinct right ovarian mass with evidence of prior rupture. Ascites was noted and aspirated. There was peritoneal seeding along the pelvis and right pericolic gutter and along the right hemidiaphragm. Gross residual disease remained consisting mostly of the peritoneal seeding despite removal of all gross abdominal disease. The cytology examination of the peritoneal fluid demonstrated no malignant cells. Histologically, all the pathology specimens returned with high grade immature teratoma (). She was diagnosed as grade 3, FIGO stage IIIC. Chromosome analysis returned trisomy 3 in four of her autosomal cells, consistent with the diagnosis of immature teratoma. Since there is currently no “standard of care” for pediatric grade immature teratoma FIGO stage IIIC, we elected to follow tumor markers closely. Following tumor markers, her AFP fell by approximately 50% every week almost normalizing over the course of three months from diagnosis (from 656 ng/mL to 9.78 ng/mL). In January 2016, repeat tumor marker labs demonstrated that AFP levels increased to 28.3 ng/mL and CA-125/β-HCG were within normal limits (18 units/mL CA-125, <3 units/mL). Repeat CT of chest, abdomen, and pelvis revealed that, in the abdomen and pelvis, she now had enlarged peritoneal implants, as large as 3.5 × 1.5 cm, but no other masses, and, in the chest, she had a 1.3 × 2 × 0.3 cm left anterior pleural nodule, as well as bilateral diaphragmatic lesions, 2.5 × 2.1 × 1.8 cm on right and 2.1 × 3 × 1.5 cm on left. She subsequently underwent chemotherapy with bleomycin, etoposide, and cisplatin (BEP) between February and May 2016 for high risk malignant ovarian germ cell tumor. After 4 cycles, her AFP was 0.84 ng/mL.
After 4 cycles, she underwent interval radiologic evaluation in preparation for second look surgery. The CT scan of the chest, abdomen, and pelvis in May 2016 revealed a significant increase in the size of the thoracic masses, as well as the size and a number of abdominal and pelvic masses (). The largest mass was 7.9 × 7.7 × 8.7 cm in the rectouterine pouch with evidence of fat and calcification. There was also a 4.4 × 7.2 × 6.6 cm peritoneal implant superior to the liver that also had similar visual findings. There were also findings of bilateral cardiophrenic masses, with the largest measuring 2.1 × 1.3 × 1.1 cm. In June 2016, she underwent a second debulking procedure consisting of complete infracolic omentectomy, para-aortic lymph node dissection, hepatic mass resection, and pelvic tumor removal on the right side. Gross residual disease remained in her abdomen and pelvis, since she had innumerous peritoneal studding, and thus her thoracic tumors were not removed. A total of 5 pelvic masses and 3 liver masses were excised, and pathologic analysis indicated mature teratoma (). At the time of surgery her liver masses were found to compress the parenchyma of the liver and were not invasive.
Due to the massive growth of tumor in 4 months, as well as recently undergoing 2 major surgical debulkings, and still being unable to completely resect her tumors, medical treatment was discussed with the patient and her parents. In an attempt to prevent regrowth of her tumors, in August 2016, the patient was started on experimental protocol #009 of the Neuroblastoma and Medulloblastoma Translational Research Consortium (NMTRC). This treatment regimen consists of temozolomide 40 mg/m2 PO daily (days 1–28), tretinoin 25 mg/m2/day PO BID (days 1–14), and sorafenib 150 mg/m2 PO BID (days 1–28). Thalidomide was started during cycle 2. This protocol was chosen as this study tests the feasibility of experimental technologies to determine a tumor's molecular makeup. This technology includes a genomic report based on DNA exomes and RNA sequencing that will be used to discover new ways to understand cancers and potentially predict the best treatments for patients with cancer in the future. Prior to the experimental therapeutics, a CT scan was obtained to evaluate disease progression. She is currently without new tumor growths.


A 66-year-old Caucasian male with no known past medical history presented with bilateral lower extremity weakness for 4 weeks. He initially went to a chiropractor and on no improvement sought medical attention. He denied any recent travels, camping in woods, sick contacts, recent flu-like illness. or diarrhea, rash, statin use, and tick bites. He also denied any vision loss, diplopia, active malignancy, or family history of any neurological disorder. The patient showed some improvement in muscle strength with corticosteroid therapy, refused muscle biopsy, and was discharged home on tapering dose of steroids. One week later he again presented to the hospital with dysphagia and shortness of breath. He was subsequently intubated and put on mechanical ventilator as he could not protect his airway and was started on high-dose corticosteroid therapy with IVIG.
The patient was alert, awake, and oriented to time, place, and person. Complete neurological examination was performed, which showed 1/5 power in both lower extremities, intact sensations, and absent ankle and knee reflex bilaterally. There was no rash, neck stiffness was not noticed, and there was negative Brudzinski’s sign.
Myositis
Dermatomyositis
Polymyositis
Necrotizing myopathy
Guillain-Barre syndrome
Lyme disease
Tick paralysis
Initial laboratory workup revealed creatine kinase (CK) of 23 000, myoglobin of 7000, positive ANA, and negative testing for Lyme. All other relevant autoimmune workup was unremarkable (), and the patient was started on high-dose corticosteroid therapy. Electromyography (EMG) showed moderate peripheral polyneuropathy in the lower extremities. Magnetic resonance imaging of cervical, thoracic, and lumbosacral spine did not show any evidence of cord compression or radiculopathy, but diffuse myositis was noticed in all paraspinal muscles. This time he agreed to both lumbar puncture and muscle biopsy. Lumbar puncture was unremarkable, but muscle biopsy revealed very frequent necrotic and regenerative muscle fibers without any inflammatory process (-), findings classically consistent with necrotizing myopathy. Anti-signal recognition particle (anti-SRP) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) could not be performed as he refused to pursue further medical testing.
The patient did not show much improvement in his respiratory status with corticosteroids and IVIG therapy. Eventually he got tracheostomy and a PEG tube and was transferred to a long-term rehabilitation facility on a short course of corticosteroids and IVIG. This is a very rare entity of myopathy that sometimes present with respiratory and bulbar muscle weakness requiring ventilator support and can prove fatal.


A 19-year-old Japanese woman with active TAK refractory to combination therapy with conventional immunosuppressants and infliximab was given tocilizumab therapy. She was diagnosed as having TAK at age 15 when she developed abdominal pain, right carotidynia, low-grade fever, and claudication in both legs and the left arm. Contrast-enhanced computed tomography (CT) revealed wall thickening and stenosis of the descending aorta near of the aortic hiatus and main branches of the aorta. The thickened wall of the affected portion of the aorta was enhanced by contrast material. CRP and ESR were elevated at 6.03 mg/dl and 122 mm/hour, respectively. She was initially treated with 40 mg per day of prednisolone. She developed reversible cerebral vasoconstriction syndrome in the initial treatment course of TAK, which was described in our previous report on this patient []. She relapsed on prednisolone 15 mg per day, was given azathioprine with no remarkable response, and required dose increments of prednisolone up to 40 mg per day. Following that, therapy with intravenous cyclophosphamide and methotrexate was instituted but failed to control her disease activity. One year before starting tocilizumab, she started infliximab, whose dose was increased to 6 mg per kilogram of body weight, every four weeks after week 10, in addition to prednisolone 6 mg per day and methotrexate 17.5 mg per week. Six months later, CT showed exacerbation of the preexisting lesion of the descending aorta and newly emerged lesions in both femoral arteries. Then prednisolone dose was increased to 20 mg per day, and tacrolimus 3 mg per day was added. Three months before starting tocilizumab, she again developed claudication in both legs and the left arm (). CRP and ESR levels had been 0.08 to 1.3 mg/dl and 10 to 20 mm/hour, respectively. Plasma pentraxin-3 levels measured using the Human Pentraxin3/TSG-14 ELISA System, by Perseus Proteomics Inc. Tokyo, Japan, had remained high ranging from 5.00 to 7.35 ng/ml during the last three months of infliximab therapy. The geometric mean [confidence intervals] of plasma pentraxin-3 levels in healthy Japanese woman was reported to be 2.12 [2.05, 2.19] ng/ml []. We switched from infliximab to tocilizumab, 8 mg per kilogram of body weight, every four weeks. Improvement of claudication of symptoms was observed in four weeks and continued over six months. Contrary to CRP and ESR, which were decreased to <0.03 mg/dl and 3 mm/hour at four weeks, pentraxin-3 levels had decreased with fluctuation over five months after starting tocilizumab. By her wish, we switched from intravenous tocilizumab to subcutaneous form, 162 mg per body, every other week, at 35 weeks, and when pentraxin-3 levels were 1.59 ng/ml. Four weeks later, claudication in the left arm was worsened when we switched the form of tocilizumab back to intravenous form. CRP and ESR had remained unchanged, but pentraxin-3 levels were slightly increased to 2.77 ng/ml. Four weeks after resuming intravenous tocilizumab, pentraxin-3 levels were decreased to 1.22 ng/ml. Just after switching to subcutaneous tocilizumab, the transient decrease of serum IL-6 and subsequent increase of IL-6 were observed. CT obtained one year after starting tocilizumab revealed normalization of the appearance of both femoral arteries and improvement of the arterial wall thickening in the lesion of the descending aorta (). Tocilizumab treatment could allow tapering off prednisolone over 27 months. No serious adverse events were observed during tocilizumab treatment.


A 33-year-old female patient with no significant past medical history presented originally for an elective nasal septoplasty at an outpatient surgical center for a deviated nasal septum. On pre-procedure assessment, her blood pressure was 112/70 mmHg, heart rate 82 beats per minute (bpm), respiratory rate 18 per minute and temperature 98°F. The patient denied having any allergies, alcohol, tobacco or illicit drug use. On cardiovascular examination, she had regular rate and rhythm with no murmurs. Her respiratory, abdominal and neurological exam was also unremarkable.
After preliminary assessment, she was intubated with propofol and succinylcholine. The patient was then given 60 milliliters (ml) of 2% lidocaine with 1% epinephrine subcutaneously in the nasal mucosa. Shortly after receiving the lidocaine, the patient experienced bradycardia followed by a pulseless electrical activity (PEA). Cardiopulmonary resuscitation (CPR) was initiated with the administration of one milligram (mg) of epinephrine a total of three times as per advanced cardiac life support (ACLS) algorithm. Twenty minutes into chest compressions, local anesthetic systemic toxicity was suspected by anesthesia, and the patient was given a 100 ml bolus of 20% intravenous lipid emulsion (intralipids) with restoration of normal sinus rhythm within three minutes of injection. The patient was then placed on the intralipid and norepinephrine infusion and was subsequently transferred to our cardiac intensive care unit (CICU).
The patient was hypotensive upon arrival with a blood pressure of 60/40 mmHg and a heart rate of 115 bpm. The initial laboratory evaluation showed a normal complete blood count, comprehensive metabolic panel and troponin T level. The electrocardiogram revealed sinus tachycardia. A chest x-ray was obtained that showed evidence of bilateral pulmonary edema. A transthoracic echocardiogram (TTE) showed a severely reduced left ventricular systolic function with estimated ejection fraction between 10-15% (Figure ).
No valvular abnormalities were noted.
The patient was started on furosemide drip. She was titrated off norepinephrine and started on dobutamine for inotropic support. The case was also discussed with the poison control center and we were recommended to continue with supportive management and intralipid therapy. Next day, a repeat TTE showed improved an ejection fraction of 55% (Figure ).
The patient was subsequently weaned off the dobutamine drip and the lipid infusion. She was successfully extubated at the same time as well. A cardiac magnetic resonance imaging looking for infiltrative or inflammatory cardiomyopathy was obtained and was negative. Two days later the patient was discharged and was faring well on follow-up.


A 22-year-old Caucasian woman with juvenile glaucoma underwent a conventional trabeculectomy with mitomycin C 0.4 mg/mL OD. The mitomycin was applied beneath conjunctiva/Tenon’s capsule and scleral flap for 3 minutes after performing a 4x4 mm limbal-based scleral flap, and prior to sclerotomy. The surgery took place without any complications.
In the immediate postoperative period, we observed a hyperfiltrating bleb without Seidel phenomenon. This led to hypotony refractory to conservative measures such as pressure patching, decreased of corticosteroids dosage and use of aqueous suppressants and three weeks after, she developed hypotony maculopathy with low visual acuity (VA = 20/60 OD) (Figure 1 ).
A surgical revision with 2 additional sutures in the scleral flap was performed. Three weeks later, the hypotony remained as well as the thin conjunctiva, so we decided for a conjunctival autograft from the inferior bulbar conjunctiva. The result was satisfactory and the hypotony resolved (Figure 2 ), although, in the early postoperative period, there was a history of minor blunt ocular trauma without further complications.
After two years, the patient attended our appointment due to low visual acuity. On examination, VA OD was 20/200, IOP was 5mm Hg with a thin, avascular and transudative bleb, visualizing the underlying uveal tissue with chorioretinal folds (Figure 3 ). Connective tissue diseases were excluded.
A new trabeculectomy revision was performed. During the procedure, it was not possible to identify the scleral flap (Figure 4 ), so we used 2 layers of Tutopatch® (a collagenous membrane derived from solvent preserved irradiated bovine pericardium) to close the fistula (Figure 5 ).
The 2 layers of Tutopatch® were attached to each other with fibrin sealant and the graft sutured to the adjacent sclera with 10-0 nylon and covered by the conjunctiva (Figure 6 ).
A good clinical evolution occurred and after 2 months, IOP was 15 mmHg without Seidel phenomenon or changes in the fundus and VA was 20/20 OD (Figure 7 ). After 8 months of follow-up, the clinical situation remains stable.


A 32-year-old female was admitted to a specialized inpatient rehabilitation program utilizing a comprehensive rehab team focused on assessing patients with severe traumatic brain injury with the goal of providing accurate diagnosis, family training, and intensive therapy to promote best outcomes. The team included a physician, neuropsychologist, physical therapist, cognitive therapist, speech therapist, occupational therapist, and nurse. This multidisciplinary team collaborated towards the final diagnosis described here and together established a personalized plan of care and discharge recommendations.
Acute care records showed patient had undergone CT of the brain revealing right frontal parenchymal contusion and a diffuse area of subarachnoid blood. No midline shift, herniation, or mass effect was identified. Other acute comorbidities included right subcondylar mandible fracture requiring her jaw to be wired shut, further complicating assessment during her inpatient stay. No reports regarding MRI or angiography were received from the acute care setting which may have expedited diagnostics prior to admission to inpatient rehabilitation.
Initial team evaluation in the specialized program focuses on identifying and differentiating purposeful and generalized responses to stimuli using a combination of testing components derived from the Western, CRS-R, and Glasgow []. Observations of purposeful activity during initial evaluation were not observed due to lack of any spontaneous movement of the patient; however, the patient appeared generally awake based on observation of open eyes and spontaneous visual tracking. Ocular bobbing, which is characterized by a fast down beat of the eyes and slow return to baseline, was observed in addition to a distinct sustained and direction-changing nystagmus []. The functional independence measure (FIM) was used to capture the patient's disability and how much assistance the patient required to perform activities of daily living. Refer to for further examination findings and for FIM scoring.
Based on the patient's wakefulness and consistent meaningful and purposeful interactions with the environment through eye gaze communication, a disorder of consciousness was ruled out. Further, understanding of the anatomy of the described reflexes and presentation guided the team towards isolation of a ventral pons lesion location and the suspected diagnosis of LIS, with need for further work-up to confirm.


A 39-year-old woman (gravida 3, para 2) was referred to our department during the 24th week of pregnancy due to gross hematuria. Τhe pregnancy was uncomplicated till then; however the diagnosis of complete placenta previa was made during the anatomic scan three weeks prior to her admission. She had two previous cesarean sections and no other medical history. An abdominal sonographic evaluation revealed a viable fetus with appropriate biometrical parameters and normal amniotic fluid, while transvaginal scan suggested the presence of complete placenta previa with bladder wall invasion (). She was admitted to our department for expectant management. A course of steroids was administered to promote fetal lung maturation. On hospital day #1, bladder irrigation was performed by the urologists and a Foley catheter was placed in order to control hematuria. The patient had intermittent macroscopic hematuria and cystoscopy was performed on day #4 in order to confirm the diagnosis; however the examination was inconclusive. On hospital day #10, evaluation of the placenta with magnetic resonance imaging (MRI) was also nondiagnostic. The patient was asymptomatic by day #20 and she was discharged from the hospital. Two days later, however, the woman became symptomatic and was then readmitted with hematuria and vaginal bleeding. She had a hematocrit of Ht 22.1% and hemoglobin Hb 6.8 mg/dL and was transfused with two units of blood. The patient went into labor and she was immediately transferred to the operating room. A multidisciplinary team by obstetricians, midwifes, urologists, neonatologists, and anesthetists was on site. A viable male baby, weighing 1000 gr, was delivered by cesarean section and concomitant abdominal hysterectomy. The baby was transferred to the NICU where he was intubated. Dissection of the placenta from the anterior uterine wall created a large defect on the dome of the bladder. The bladder was repaired with two layers of continuous Vicryl 0 suture. A Foley catheter and an intraperitoneal drain were placed. The patient required transfusion of 20 units of various blood products intraoperatively. The postoperative course was uneventful and the patient was discharged on the 10th postoperative day. She made a good recovery; however urologic evaluation one month postoperatively revealed a vesicovaginal fistula, which was surgically treated at a later date. The baby was discharged three months after delivery.


A 26-year-old woman (gravida 4, para 3) presented in our emergency department with vaginal bleeding during the 35th week of pregnancy. She had three previous cesarean sections and no antenatal screening during the present pregnancy. She was transferred to the labor ward where appropriate for gestational age embryo and anterior placenta previa detected during abdominal ultrasound scan. An emergency cesarean section was scheduled and just prior to the operation a Foley catheter was inserted to the bladder which drained blood. The cesarean section was carried out with a vertical incision high in the anterior uterine wall. A male baby weighing 2250 gr was delivered with Apgar scores of 8 and 9 and was transferred to the NICU for further evaluation. Interrupted Vicryl 1 sutures were used for closure of the uterine wall. Intraoperative bleeding was moderate and no transfusion was necessary at that point. A urologist evaluated and repaired the bladder defect which was away from both ureteral orifices. The patient made an unremarkable recovery and both she and the baby were discharged on the 5th postoperative day. The Foley catheter was removed on the 10th postoperative day.


A 27-year-old female presented with intermittent dull-aching right flank pain for one month. It was associated with frontal headache, sweating, and palpitation. She had history of normal vaginal delivery 45 days back. She had no significant past medical and familial history. Blood pressure at presentation was 180/110 mmHg with pulse of 90 beats/min. There was mild tenderness in the right flank with no other significant findings. USG abdomen revealed right adrenal mass. CECT abdomen and gadolinium-contrast MRI abdomen revealed 6 × 4 cm heterogeneously enhancing mass with delayed washout suggestive of right adrenal malignancy with invasion to right IVC wall leading to narrowing and presence of nonenhancing IVC thrombus extending from the level of renal veins to the level of confluence with hepatic veins (). Venous Doppler of both lower limbs and echocardiography were unremarkable. Her routine laboratory investigations including serum creatinine, electrolytes, liver function tests, adrenocorticotropic hormone, and cortisol level were normal. Similarly, 24-hour urine fractionated metanephrines, vanillylmandelic acid, cortisol, serum metanephrines, and catecholamines were also within normal limits. With a provisional diagnosis of right adrenocortical carcinoma with IVC thrombosis, right adrenalectomy with IVC thrombectomy was planned. Two weeks prior to surgery, prazosin was started and titrated to 5 mg orally per day to control her blood pressure. Subsequently, 50 mg atenolol was added orally once a day for tachycardia. Lower molecular weight heparin was also started. With right anterior subcoastal approach, right adrenal mass was mobilized. Control of right renal artery and vein, left renal vein, and infrarenal IVC was taken. Right lobe of the liver was mobilized medially and infradiaphragmatic control of the IVC was attempted but failed. Therefore, with right thoracotomy, supradiaphragmatic control of IVC was taken. Serial clamping of infrarenal IVC, right renal artery and vein, left renal vein, and supradiaphragmatic IVC was undertaken. Pringle maneuver was applied to control bleeding from the hepatic veins. Longitudinal venotomy extending from the right adrenal vein to IVC was given and thrombus was removed along with the adrenal mass. The intraoperative finding revealed 6 × 5 cm encapsulated firm adrenal mass not invading surrounding organs and organized firm greyish thrombus mixed with clots extending to IVC up to the level just caudal to confluence of hepatic vein. On cut section, the mass was flesh coloured with central pale area containing some hemorrhagic areas (). Intraoperative and postoperative period were uneventful with total of three units of packed red blood cell transfusion. Postoperatively, her blood pressure was normal without antihypertensive drugs and she was discharged on seventh postoperative day on aspirin. Histopathology of the mass turned out to be pheochromocytoma with thrombus revealing fibroadipose tissue with fibrin (). There was absence of mitotic figures, necrosis, and capsular and vascular invasion. Immunohistochemically, the tumor cells were positive for chromogranin A. MIBG scan done after 6 weeks and CECT abdomen done after 6 months were unremarkable.


A 25-year-old male presented to the Emergency Department with progressively worsening left-sided chest pain and dyspnea on exertion over the past four days. His medical history was notable for coronary artery disease and has had seven stents placed since the age of 18. He also had a history of systemic lupus erythematous (SLE), hypertension, hyperlipidemia, obesity, and end-stage renal disease (ESRD) on hemodialysis. Subsequent history revealed 11 pack years of smoking and noncompliance with medication regimens, hemodialysis schedule, and nutrition therapy. There was no family history of premature cardiovascular disease.
Cardiac enzyme values were as follows: troponin 0.05 ng/mL, creatine kinase 36 U/L, and CK-MB 2.2 ng/mL. Electrocardiogram (ECG) revealed ST depression in leads I, II, and V4-6. Cardiac enzyme values obtained about six hours later suggested the evolving nature of MI: 0.07 ng/mL, creatine kinase 33 U/L, and CK-MB 3.5 ng/mL. The last set of cardiac enzymes collected 18 hours from the initial presentation were troponin 1.12 ng/mL, creatine kinase 73 U/L, and CK-MB 15.9 ng/mL.
Transthoracic echocardiogram (TTE) showed concentric left ventricular hypertrophy with left ventricular ejection fraction (LVEF) 55%. Coronary angiogram (Figure ) revealed 70 to 80% in-stent restenosis at the left anterior descending coronary artery (LAD). Obtuse marginal branch of left circumflex coronary artery (LCX) also had a complex 90 to 99% stenosis with in-stent restenosis at the ostium. In the right coronary artery (RCA), 60 to 70% stenosis just distal to the posterior descending artery (PDA) was noted.
In view in-stent restenosis in multiple coronary vessels and evolving nature of MI, an urgent five-quintuple CABG was chosen over percutaneous intervention with stent placement. Bilateral internal mammary arteries (IMAs) and left greater saphenous vein (GSA) were harvested via median sternotomy and endoscopy, respectively. CABG consisted of left IMA to the main LAD, right IMA to the obtuse marginal branch of LCX and first diagonal branch of the LAD (with inflow into the RIMA graft from LIMA), and left GSA to the second diagonal branch of the LAD and the PDA of the RCA.
Following the operation, the patient was transferred to critical care unit in stable condition. The patient showed an uneventful postoperative course and was discharged on day 6 of hospital admission. At one-month follow-up, CT angiography confirmed patency of the grafts. The patient also reported complete resolution of angina and dyspnea.


A 78-year-old male was brought to our department with the complaint of painful, progressive, and nonhealing ulcerated lesion of the tongue for 2 months. He did not give any history of fever, night sweats, cough, decreased appetite, or significant weight loss. There was no history of change in voice or choking. He did not give history of traumatic episode preceding the development of that wound. He denied any history of similar lesions in the past. He was a known case of hypertension taking antihypertensive medications. Besides having hypertension he denied history of other systemic illnesses including pulmonary tuberculosis. He admitted to smoking and drinking alcohol occasionally. The rest of his medical and surgical history was unremarkable. His past dental history was not significant. There was no history of TB in his family members. He was repeatedly treated in a local hospital with topical antiseptics and oral antibiotics (ampicillin plus cloxacillin and metronidazole) and analgesics but the lesion did not subside so he was referred to our hospital for the further management.
On general examination he was thin built with general conditions being fair, while, on examination of oral cavity, there was an indurated ulcer measuring 1.0 cm × 0.5 cm on the left lateral border of tongue on the anterior two-third part of tongue (). It was tender with irregular border. It did not bleed on touch. The remaining part of the tongue was normal in texture and color. Mobility of tongue was normal. It was not deviated to either side on protrusion. He had poor orodental hygiene along with sharp tooth adjacent to the ulcerated lesion although the multiple teeth were absent. There were no palpable cervical lymph nodes and no similar ulcers in any other body parts.
Provisional diagnosis of traumatic ulcer was made as the possibility of ulcer due to repeated trauma by the sharp tooth could not be ruled out based on the physical examination alone. As we thought it could be due to chronic trauma by the sharp looking teeth although he was unaware of any traumatic episode. Dental consultation was done as the patient had poor oral hygiene along with loss of multiple teeth and the remaining teeth having sharp edges. Dentist did the coronoplasty of adjacent sharp cusp, and since the ulcer presented for more than two months they took incisional biopsy containing ulcerated lesion along with the normal looking margin being taken under local anesthesia and the specimen was sent for histopathological examination (HPE). The patient was also given oral antiseptic gel for local application and given an appointment for oral prophylaxis. Patient then presented to Department of Otorhinolaryngology with the HPE report. Microscopically the lesion revealed the stratified squamous epithelium with granulomatous inflammation containing Langhans type giant cells, epithelioid cells, and foci of caseous necrosis, strongly suggestive of tuberculosis ().
Chest X-ray did not reveal any evidence of active or old Koch's infection. Sputum for acid fast bacillus (AFB) of three early morning samples was negative on Ziehl Neelsen stain. Complete blood count was within normal limit. His erythrocyte sedimentation rate (ESR) value was 20 mm/hr. Serum biochemistry and renal function tests were within normal limits. Serological investigation for human immune deficiency virus (HIV) was negative. Mantoux test was not performed as the histopathological findings were strongly suggestive of tuberculosis. An enquiry was made in the family whether they had any symptoms of pulmonary tuberculosis or any other chronic illnesses. No one in the family had any form of TB in the past. They denied symptoms such as chronic cough, night sweats, loss of appetite, or significant weight loss. They were all vaccinated with BCG as per the expanded programme on immunization (EPI) schedule of Nepal. In the absence of any symptoms no further investigations were ordered for them. Mantoux test was not done as well. Because every child gets BCG vaccination at birth in our country, that can yield positive Mantoux result because of the vaccination. As the sputum for AFB was negative in the patient the chance of spread is minimum to others.
The patient was referred to directly observed treatment, short course (DOTS) clinic after having histopathological diagnosis of TB. He was then started on antitubercular therapy (ATT). The ulcer gradually started fading once drug therapy was started (ATT). The patient felt symptomatically better after the start of ATT; and the tuberculous ulcer healed completely by the 2 months of ATT containing Isoniazid, Rifampicin, Pyrazinamide, and Ethambutol (). The patient was then advised to continue ATT containing Isoniazid and Rifampicin for another 4 months. At the end of total 6 month's ATT course there was no evidence of residual ulcer at the primary site. We emphasized oral hygiene maintenance and advised the patient to follow up at dental outpatient department. As the patient came from a remote place in the hilly region of central Nepal, he did not seek any dental consultation as he was told that he had TB.


A 13-year-old girl was admitted to Children’s Hospital No.2 in Ho Chi Minh City in Vietnam on 31st August 2016 because of fever for seven days. On admission, she was totally alert and had a low grade of fever. The examination found no focal neurologic deficits. Her total blood count showed that white blood cell (WBC) and platelet counts were 11,000/μL and 182,000/μL, respectively. C-reactive protein level was 3 mg/L. On the 8th day (the day after admission) of her disease course, she recovered from fever but first began to complain of no passage of urine. She was found to lose the sensation of urinating and have urinary retention. She then needed insertion of the indwelling urinary catheter. On the 9th day (the 2nd day of admission), the serologic test revealed that serum dengue IgM was positive. Serum PCR dengue was negative. Laboratory tests of liver and renal functions and electrolytes did not show any particular abnormality. On the same day, she could not move her legs, began to lose her consciousness and showed signs of confusion. The neurological examination then found that she became lethargic and quadriplegic with no abnormal sign of cranial nerves. She had normal ocular fundus, opened her eyes with painful stimulation, answered her name and then drifted back to sleep. Muscle strength and tendon reflexes of the upper extremities were 2/5 and 2+, respectively, with the weakness of upper limbs (UL). The sensory functions were nearly intact. The muscle strength and tendon reflexes of the lower extremities were 0/5 and 2+, respectively, with complete paraplegia of lower limbs (LL). Bilateral (B/L) Hoffmann and Babinski tests were positive. Cerebrospinal fluid (CSF) collected on 10th day showed pleocytosis (61 cells/mL); elevation of protein, 1.68 g/L; glucose, 0.43 g/L; chloride, 138 mmol/L; lactate 4.23, mmol/L. Her CSF was positive for ELISA dengue IgM but negative for ELISA Japanese encephalitis virus IgM. PCR Zika virus in blood and in urine was negative. Magnetic resonance imaging (MRI) of the brain and spinal cord did not show any particular abnormality ( and – Figs). An electromyogram showed that motor and sensory functions were normal on both UL and LL ( and Figs).
From her clinical course and laboratory tests, she was diagnosed as ADEM following dengue infection without warning signs. For treatment of ADEM, high dose of methylprednisolone (30mg/kg/day) for five days was given, beginning on the 3rd of September. The oral low dose of prednisone (1 mg/kg/day) was then used for four weeks. Her alertness improved gradually. On the fourth day of methylprednisolone course, she opened her eyes responding to voice, oriented and answered word by word correctly. Although urinary retention remained, her muscle strength of upper and lower extremities increased to 4/5 and 2/5, respectively. After two weeks of oral prednisolone, limbs weakness was significantly improved and after four weeks, sphincter function was back to normal. She was nearly intact with the proximal part of her legs had a mild weakness when she was discharged from the hospital after four weeks of admission (five weeks since fever onset).


A 36-year-old male patient was admitted to our clinic because of gait disorder, diplopia, and speech disorder. The patient experienced these symptoms for two weeks. The past medical history of the patient was unremarkable, and the family history was negative for neurological disorders. Oral aphthous ulcerations had been presented for approximately three months.
The patient’s neurological examination revealed the presence of cerebellar-type dysarthria, truncal ataxia, wide-based ataxic gait, dysmetria, dysdiadochokinesia, and hyperreflexia in all his extremities. Body temperature was 36,0 °C. MR image showed mesencephalic lesion with oedemaas a hyperintense area (arrowheads) (). Contrast uptake was not seen in the MRI. Uveit was not found in the patient’s ophthalmic examination. Human leukocyte antigen B51 (HLADR B1) was found. The markers of collagen tissue disease were negative. Hematological markers, such as fibrinogen, antithrombin, and protein C and S were also in normal ranges, excluding ischemic stroke. Factor V Leiden, prothrombin G20210A gene mutations and MTHFR enzyme were not detected. Transthoracic and transesophageal echocardiography and carotidartery doppler were normal. The plasma Vit B (12), folic acid, and homocysteine levels were normal. Finally, the case was diagnosed as NBD.
At the beginning of therapy, intravenous (IVP) methylprednisolone (1g/day) was administered for five days. The patient’s all neurological deficits improved within two weeks, and the patient was discharged.
The follow up determined that genital aphthous ulcerations had developed within three months. A relapse of NBD was not seen in this patient, and recurrent corticosteroid and any drugs were not used. However, one year after NBD was diagnosed, the patient consulted an orthopedic surgeon for bilateral hip pain. MR image of both hips showed well-demarcated areas of osteonecrosis (arrowheads) in both femoral heads and bone marrow oedema in the right femoral head (). The patient underwent surgery; there were no complications perioperatively, and the patient was discharged.


An 84-year-old Caucasian female with a past medical history of hypertension, hypothyroidism, and chronic low back pain presented for an exacerbation of her low back pain. Before her hospitalization, she had been managing her low back pain with opioid analgesics and physical therapy at a skilled nursing facility for the prior four weeks. She was scheduled to see Neurosurgery in the outpatient setting, but her back pain became more severe. It progressed to the point that she could no longer sit nor ambulate without being in severe pain. Her back pain worsened with any movement, particularly while flexing forward, and radiated down the posterior aspect of the right leg in the S1 dermatome. She denied any numbness or tingling, and no saddle anesthesia or any acute bowel or bladder changes were noted. The extent of pain was truly debilitating, requiring hospitalization. She underwent a workup that included a magnetic resonance imaging (MRI) scan of the lumbar spine, which did not reveal any significant finding, and an MRI of the abdomen and pelvis, which revealed a severe bilateral SIF with grade 2 anterolisthesis of S1-S2 (Figure -). A subsequent computed tomography (CT) scan revealed bilateral L5 transverse process fractures, diffuse bone demineralization, and comminuted SIFs through the bilateral sacral ala with malalignment at the S1-S2 level (Figure -). Bone scintigraphy (Figure ) was obtained of the bony pelvis, which demonstrated an H-shaped increased uptake in the bilateral sacral ala and the anterior aspects of the sacrum. This situation would typically disable a patient and, in this age group, likely contribute to mortality. Surgical intervention was recommended to prevent further debilitation and aid in a return to former ambulatory status. Following the surgical intervention, she could ambulate on postoperative Day 1, with only mild discomfort. She returned to the skilled nursing facility to finish her rehabilitation and regained most of her preinjury level of function. She was ambulating independently and with no pain at her six-week postoperative follow-up. She experienced no complications from the surgery, nor did she experience the common complications of prolonged immobility associated with SIFs.
The surgical decision-making was complex, and several factors had to be considered. First, the author did not feel a sacroplasty was sufficient to fixate the sacral alar fractures and address the S1-S2 unstable anterolisthesis. Additionally, although commonly performed, sacroplasties are not FDA-approved and are considered “investigational.” Iliosacral screw fixation is another surgical technique to treat sacral fractures. The author was concerned about the patient’s bone quality and about the fact that a simple screw fixation would not be strong enough to stabilize the fractures adequately. With bilateral alar fractures in the sagittal plane and a dislocation of S1-S2 in the horizontal plane, the surgeon was looking for the strongest construct possible; yet, he wanted a less-invasive option to minimize surgical time and morbidity.
The lead author decided to perform a bilateral iliosacral fixation using the triangular titanium implants (iFuse implants from Si-BONE, San Jose, CA) commonly used for minimally invasive sacroiliac (SI) joint fusions. The shape of these implants is felt to be superior to standard threaded screws. The design of these implants also allows for the passage of a kyphoplasty needle (Kyphon Express from Medtronic, Dublin, Ireland) through the central cannulation. This permits the direct injection of polymethylmethacrylate (PMMA) through the iFuse implant into the sacral ala, providing additional fracture augmentation and implant strength.
The patient was positioned in the standard prone position on a Jackson operating table. She was prepped from hip to hip. A C-arm was used to mark the one-inch skin incision bilaterally, following the posterior sacral line on lateral fluoroscopy. After the skin had been incised, Steinmann pins were placed through the lateral ilium across the SI joint and into the sacral ala. After each pin had been placed, a three-dimensional image was obtained using the O-arm (Medtronic, Dublin, Ireland) to assess the pin position and make sure it crossed the alar fracture line. Next, the drill-guide was placed over the pin, resting on the lateral ilium. The implant length was then measured, and the implant trajectory was drilled over the pin. After the drilling, a triangular channel was created using the implant broach. The iFuse implant (Si-BONE, San Jose, CA) was then inserted and tapped into position. Three implants were placed on each side. Two implants were intentionally placed above the S1-S2 interspace, and the third inferior implant was placed below the transverse fracture line. After the implants were placed, a Kyphon Express needle (Medtronic, Dublin, Ireland) was placed through the central cannulation of each implant. Approximately 2 ml of PMMA was injected into the medial ala through each implant under live fluoroscopy. Several times during the cement delivery, a C-arm radiograph was obtained to make sure the cement did not undergo extravasation nor violate the S1 neuroforamen. This created a solid construct, fixating the sacrum securely to the ilium. The intraoperative C-arm fluoroscopic radiograph is shown in Figure .


A 39-year-old pregnant woman with Klippel-Trenaunay syndrome (KTS) and associated pelvic varicosities delivered her child by emergent cesarean section following placental abruption due to a large retro-placental clot. She had a provoked prior pulmonary embolism (PE) at age 16, a few days after an unspecified abdominal surgery for KTS. An inferior vena cava (IVC) filter was placed at that time for secondary prevention of PE. She was on warfarin for two years and it was then stopped as her PE was provoked. Her antenatal course was uncomplicated. She received low dose aspirin (81 mg) and 40 mg of low molecular weight heparin (LMWH) daily throughout her pregnancy. Prophylactic LMWH was resumed six hours after delivery. She reported mild pleuritic chest pain shortly following the delivery. On postoperative day two she complained of acute severe shortness of breath, palpitations, lightheadedness, and sudden worsening of the pleuritic chest pain.
On examination, the patient was afebrile, with a heart rate of 126 beats/min, a respiratory rate of 14 breaths/min, a blood pressure of 110/85 mm Hg and an oxygen saturation of 94% on room air. She was alert, oriented and in mild respiratory distress. Also noted was tachycardia without murmur, tachypnea with bilateral and equal breath sounds, non-tender extremities without asymmetric edema, and no gross neurologic deficits.
Hemoglobin was 10.1 g/dL, platelets 119,000/mm3, white blood cells (WBC) count 7,100/mm3 and bicarbonate 21 mmol/L. Troponin I was elevated at 1.27 ng/mL (normal <= 0.04 ng/mL). An electrocardiogram showed a S1Q3T3 pattern. A transthoracic echocardiogram showed right ventricular dilatation with reduced systolic function and positive McConnell’s sign (Video ).
Upper and lower extremity venous duplex studies were negative for deep venous thrombosis (DVT). A chest computed tomography angiogram revealed extensive bilateral pulmonary emboli, as seen in Figure .
Given the extent of the clot burden, evidence of right heart strain, and positive biomarkers of cardiac injury, the patient was transferred to the intensive care unit. She was immediately transitioned to therapeutic LMWH and dosed with warfarin. She was not given thrombolytics due to her recent Cesarean section. She continued to do well clinically and was gradually transitioned to the outpatient setting.
Lower extremity venous ultrasound, as above, was negative for DVT. We hypothesize that the large retro-placental clot was the cause of the PE. KTS is known to have aberrant, anomalous, and collateral venous systems. Our patient had many pelvic and uterine varicosities. The clot may have traversed those channels and reached her pulmonary circulation by by-passing the IVC filter. Contrast magnetic resonance imaging would have best delineated the patient’s venous system, but since she was pregnant when the imaging was completed, her pre-natal magnetic resonance imaging scan was non-contrast. Hence, it is uncertain if the anomalous venous system is the culprit. Additionally, we cannot rule out the IVC filter being the source of the clot, especially since it was placed 23 years prior.


A 63-year-old Caucasian male with was initially diagnosed with angiosarcoma of the nose in October 2011 and underwent rhinectomy with negative margins followed by 3 reconstructive operations using a forehead flap. The patient also had a medical history of chronic lymphocytic leukemia which was untreated and being observed. In September 2012, the patient noticed two new lesions, one on his left cheek and the other on his right submandibular region and surgical resection occurred to remove these lesions in December 2012. Adjuvant treatment ensued with nab-paclitaxel dosed at 100 mg/m2 weekly on a 28-day cycle starting in February 2013 for 2 cycles. In November 2013, CT of the chest and abdomen demonstrated multiple new hepatic lesions (Fig. ) and the patient was started on clinical trial with evofosfamide (TH-302) and received 4 cycles of treatment. The patient progressed on study and was referred to interventional radiology where he underwent bilobar radioembolization with Yttrium-90. Repeat CT examination following Yttrium-90 radioembolization demonstrated post treatment changes without significant decrease in size of the hepatic lesions (Fig. ). However, in December 2014 the patient developed a new right jaw mass and was started on another cycle of nab-paclitaxel.
The patient had noticeable disease progression with interval development of a right tongue mass. Staining of the patient’s tumor tissue with Roche SP142 revealed positive PD-L1 expression a measured by greater than 5% of the tumor cells staining positive. In 2015, based on the positive tumor expression, off-label treatment with pembrolizumab dosed at 2 mg/kg every 21 days was begun. The patient had concurrent radical excision of the right jaw soft tissue angiosarcoma with advanced flap closure. Subsequent restaging CT scans demonstrated a significant response of the liver lesion (Fig. ). After completion of 13 cycles of pembrolizumab he developed autoimmune hepatitis. The immunotherapy was held and the patient was started on prednisone with a step down taper. In March 2016, while on prednisone therapy, he had another CT study of the abdomen/pelvis (Fig. ) that revealed a further decrease in size of the liver disease. Additional body scans and biopsy did not detect any new disease at this time.


A 78-year-old Caucasian female with a past medical history of hypertension presented to the emergency department with complaints of lower extremity weakness for last 2 to 3 months, which has been progressively worsened. The patient denied any numbness, paresthesias, memory loss, trauma, dizziness, tremors, history of seizures, family history of neurological disease, or loss of consciousness. The patient also denied having any bowel or urinary incontinence. She also experienced a 5-pound unintentional weight loss over a 2-month period. She denied smoking, drinking alcohol, or abusing any drugs. Her medications were aspirin 81 mg oral daily and amlodipine 5 mg oral daily. She denied use of any illicit drug or herbal supplement.
On physical examination, vital signs were the following: blood pressure of 139/79 mm Hg, pulse rate of 85 beats per minutes, respiratory rate of 17 breaths per minute, temperature of 98.6°F, and an oxygen saturation of 99% on room air. She was alert and oriented to person, place, and time. Pertinent positive findings on neurological examination showed motor weakness of her lower extremities muscle with power of 3 out of 5 in her proximal lower extremities’ muscles. Her results for manual muscle strength testing increased from 3 out of 5 to 4− out of 5 for her bilateral lower extremities after a sustained 30-second contraction. The sensations were intact to light touch and pinprick. Deep tendon reflexes were 2+ bilaterally at the patella, ankle and 1+ bilaterally at the biceps and triceps, and Babinski’s sign was down-going bilaterally. There were no cerebellar signs. Cranial nerve examination was intact II-XII. There was no involvement of extraocular muscles or respiratory compromise. The remainder of the systemic physical exam was unremarkable.
Laboratory work showed no metabolic abnormality or signs of anemia. Renal and liver function test were within normal range. Routine chest X-ray showed a 4.3 cm right upper lobe lung mass posteriorly in the supra-hilar region and a 0.8 cm right upper lobe lung nodule (). Subsequent computed tomography (CT) scan of the chest confirmed the lung mass with a maximal diameter of 4.9 cm, most likely a primary lung malignancy with a smaller satellite nodule within the medial apical aspect of the right upper lobe (). A CT scan of the brain showed enhancing lesions within the occipital and temporal regions of brain consistent with metastatic disease. The patient, however, did not have any upper motor neuron signs on neurological exam. Patient’s clinical symptoms were consistent with lower motor neuron involvement at the NMJ, being purely motor with no sensory deficits. CT-guided biopsy of the lung mass revealed invasive adenocarcinoma moderately differentiated. LEMS was the most likely explanation for her proximal lower limb weakness as a paraneoplastic syndrome secondary to adenocarcinoma of the lung. Furthermore, the electromyogram and antibodies test to voltage gated calcium channel were ordered to confirm LEMS. However, understanding the extent of the disease with poor prognosis and patient’s functional status with deteriorating condition, the outcome was discussed with family by the oncology team and the family decided not to proceed with chemotherapy, and opted for palliative care. The patient underwent few session of palliative radiation therapy. Subsequently, the patient was referred to inpatient hospice where the patient died within few days.