The patient was a 28-year-old Japanese male who had been diagnosed with XLA soon after his birth. He had been receiving IgG replacement therapy since he was an infant. Regarding his previous infectious history, he had chronic sinusitis, which twice required surgery, episodes of chronic upper respiratory infections, cellulitis progressing to osteomyelitis, tympanomastoiditis, and meningitis resulting in cerebral hemorrhage. Each episode was refractory to antibiotic therapy and potentially fatal. He was referred to our hospital for the possible indication of allo-SCT. The diagnosis of XLA was confirmed by the direct sequencing of BTK gene mutations []. He had an HLA-identical elder healthy brother. After a thorough discussion with pediatricians specializing in hematology, immunodeficiency, and transplantation, we decided to perform allo-SCT from his elder brother. The risks associated with allo-SCT were explained to the patient and his family including the donor. Written informed consent was obtained from the patient and his family. HLA of the patient and his elder brother, the donor, was HLA-A*02:01/24:02 B*40:01/51:01 C (not tested) DRB1*11:01/14:03, and the blood type of both was A+.
We used a RIC regimen consisting of fludarabine (FLU) at 30 mg/m2/day for 6 days (days −10 to −5), cyclophosphamide (CY) at 50 mg/kg/day for 2 days (days −4 and −3), 3 Gy of total body irradiation (TBI), and rabbit anti-thymocyte globulin (ATG, Thymoglobulin, Sanofi) at 1.25 mg/kg/day for 2 days (days −2 and −1). In order to prevent anaphylaxis by ATG, methylprednisolone (mPSL) was administered at 2 mg/kg on days −2 and −1. Prophylaxis for graft-versus-host disease (GVHD) consisted of the continuous infusion of cyclosporine (CsA) starting at a dose of 0.3 mg/kg/day from day −2 and oral mycophenolate mofetil (MMF) starting at a dose of 30 mg/kg/day from day 2. The target blood concentration of CsA was set at 500–550 ng/mL up to day 20, 350–500 ng/mL on days 20–35, and thereafter switched to oral CsA. Peripheral blood stem cell (PBSC) mobilization using granulocyte colony-stimulating factor (G-CSF) was performed as described previously []. Briefly, leukapheresis was performed twice on days 4 and 5 of the G-CSF administration. PBSCs were freshly transplanted on days 0 and +1. The total dose of PBSCs contained 6.66 × 108 nucleated cells/kg and 4.77 × 106 CD34+ cells/kg. After transplantation, the patient received G-CSF from day 5 to the day of neutrophil engraftment.
The clinical course of allo-SCT was shown in Fig. . Hematopoietic engraftment was rapidly achieved, with an absolute neutrophil count of >0.5 × 109/L on day 11 and platelet count of >50 × 109/L on day 25. The donor chimeras of CD3+ and neutrophil fractions in PB were 100 and 68.2 %, respectively, on day 3 using an informative short tandem repeat (STR)-PCR technique, and 100 % donor chimerism was confirmed in the CD3+ and neutrophil fractions on day 10. Since there was no evidence of GVHD, MMF was discontinued on day 23. Stage 1 skin GVHD developed on day 44, which disappeared after slightly increasing the dose of CsA. Weekly IgG replacement was discontinued on day 43. He was discharged on day 75 and has been doing well without any infectious episodes until the last day of the follow-up on day 500.
Lymphocyte recoveries during the admitted and long-term follow-up periods were shown in Figs. and , respectively. CD19+ cells, which were undetectable before allo-SCT, started to increase in number 10 days after allo-SCT and continued to increase for more than 1 year. On the other hand, CD3+ cells decreased by an order of 101/μL and recovered by an order of 102/μL. Regarding comparisons of CD3+ and CD56+ cells, CD56+ cells were dominant until day 250, with the number of CD3+ cells thereafter increasing to more than that of CD56+ cells. Regarding comparisons of CD4+ and CD8+ cells, CD8+ cells were always more dominant than CD4+ cells.
The recovery of immunoglobulins attracted our interest in this case. IgA and IgM, which were undetectable before allo-SCT, rapidly increased by day 20 (Fig. ). Since the blood type of the patient and donor was A+, we followed the titer of anti-B antibodies and found that it appeared as early as on day 10. IgG levels decreased after the discontinuation of IgG replacement and gradually recovered from day 350 (Fig. ). Regarding antibodies to several viruses, all anti-viral IgG, except for EB virus-virus capsid antigen IgG (EBV-VCA IgG), disappeared after the discontinuation of IgG replacement (Table ). All anti-viral IgM remained negative before and after allo-SCT. A seasonal vaccination to influenza was performed on day 148, with neither anti-influenza type A nor type B being positive after the vaccination.
We then examined data related to allergies. The radioimmunosorbent test (RIST), which reflects the total amount of IgE, was undetectable on days 2 and 46 but became positive on day 393 after allo-SCT. Among the various allergens tested, only the radioallergosorbent test (RAST) to orchard grass, to which the donor had a high titer of RAST, slightly increased after allo-SCT (day 46) (Table ). The donor has seasonal hay fever to orchard grass, whereas the patient has no symptoms of hay fever.
We also performed functional tests. BTK protein expression levels and B-cell functional responses were evaluated on day 279 (Fig. ). Similar BTK expression levels in monocytes and B-cells were observed between the patient and healthy control as expected. In order to investigate B-cell functional responses, an in vitro proliferation assay (Fig. ) and immunoglobulin production assay (Fig. ) were performed. B-cells from the patient showed sufficient proliferation after a CD40L and IL-21 or CD40L and CpG stimulation. Effective immunoglobulin production and class switching were also observed after a CD40L and IL-21 or CpG stimulation. In order to assess T-cell and B-cell neogenesis, we monitored data for TRECs, cjKRECs, and sjKRECs (Fig. ). sjKRECs, which serve as an indicator of B-cell neogenesis, became positive 16 days post-SCT, increased to 6300 copies/μg DNA at 42 days, and were maintained at a high level thereafter. B-cell recovery was superior to the previously reported time course of sjKRECs post-hematopoietic stem cell transplantation (HSCT) []. The recovery of TRECs was slow, but became detectable 1 year post-HSCT. The patient achieved immune reconstitution with a normal immune cell configuration judging from a flow cytometric analysis of PBMCs (data not shown).
XLA is a congenital humoral immunodeficiency caused by BTK gene mutations. A standard treatment for XLA is regular IgG replacement, through which a long life expectancy may be achieved []. However, some patients develop chronic infectious episodes despite IgG replacement and have a shorter life expectancy [, ]. Theoretically, allo-SCT is a curative option for XLA; however, the risk of treatment-related mortality has been a barrier to allo-SCT being performed for XLA. The first case series of allo-SCT for XLA was reported by Howard et al., in which six XLA patients received transplants from their HLA-matched siblings without a preconditioning regimen, based on findings obtained in XLA model mice, X-linked immunodeficiency (xid) []. In contrast to xid, stable donor engraftment was not achieved in human cases, and resulted in no harm, but to no benefit. Abu-Arja et al. recently reported successful allo-SCT in a patient with XLA and AML, in which they used a myeloablative conditioning regimen because it is the standard treatment for AML []. They suggested the use of a RIC regimen in the case of allo-SCT for XLA. In the present study, we described a case of allo-SCT for XLA using RIC (Table ).
Due to the benign nature of XLA, a discussion on preconditioning is critical. Baron et al. previously reported the findings of a phase II multicenter randomized study comparing non-myeloablative allo-SCT with either FLU plus 2 Gy of TBI (FLU-TBI) or 8 Gy of total lymphoid irradiation plus ATG (TLI-ATG) []. The TLI-ATG regimen reduced the 2-year cumulative incidence of moderate/severe chronic GVHD to 17.8 % and increased the 4-year cumulative incidence of relapse/progression to 50 %. These findings indicate that the suppression of chronic GVHD by ATG ameliorates graft-versus-leukemia (GVL) effects and further relapses, thereby offsetting the benefit of low GVHD by a high relapse rate and resulting in the same overall survival rate in malignant diseases. Since XLA is a benign disease and has no GVL effects, the use of ATG may be beneficial to allo-SCT for XLA. As an example of a regimen for adult non-malignancies, Bacigalupo et al. employed FLU/CY/ATG with or without low-dose TBI to treat acquired severe aplastic anemia []. They demonstrated that the rejection rate was high in older patients without TBI, and some centers in Europe have introduced low-dose TBI. Although the regimen of busulfan, FLU, and ATG may be another option, a high graft failure rate (21 %) was reported for children with non-malignant disorders and chronic myelogenous leukemia []. Arai et al. previously demonstrated the significance of high-dose cytarabine added to CY/TBI for bone marrow transplantation (BMT) and peripheral blood stem cell transplantation (PBSCT) for myeloid malignancy []. In contrast to the findings obtained for cord blood stem cell transplantation, no additional benefit was observed in BMT or PBSCT, which did not justify the addition of cytarabine to the regimen in this case. Regarding GVHD prophylaxis, although the combination of CsA plus methotrexate (CsA/MTX) is the current standard for SCT from HLA-identical sibling donors, MMF in combination with a calcineurin inhibitor, tacrolimus, or CsA has recently been highlighted for its potential in achieving rapid hematopoietic recovery and mild mucosal toxicity []. A head-to-head comparison of MMF in combination with CsA (CsA/MMF) and CsA/MTX was performed by Piñana et al., in which they showed that CsA/MMF suppressed acute and chronic GVHD to the same extent as CsA/MTX and also reduced the incidence of mucositis more than CsA/MTX after RIC PBSCT []. Lai et al. more recently reported the beneficial outcomes of a combination of CsA, MTX, and MMF (CsA/MTX/MMF) []. It has not yet been established whether prolonged neutrophilia and strong immunosuppression by CsA/MTX/MMF counterbalances SCT for benign immunodeficiency disorders. Based on these findings, we prefer to use a RIC regimen consisting of FLU, CY, ATG, and 3 Gy of TBI followed by prophylaxis for GVHD consisting of CsA and MMF for adult patients with non-malignant disorders, such as aplastic anemia or paroxysmal nocturnal hemoglobulinemia, which may lead to stable donor chimerism without severe regimen-related toxicity []. We applied this regimen to our XLA case in order to minimize toxicity and achieve the permanent reconstitution of the immune system.
In spite of the advances in SCT techniques described above, the indication of allo-SCT for immunodeficiency disorders needs to be carefully considered in each case. Wehr et al. summarized multicenter experiences in allo-SCT for common variable immunodeficiency (CVID) []. The reasons for selecting allo-SCT included lymphoma (24 %), severe infections (12 %), and complex immunological dysfunctions such as cytopenia and inflammatory organ involvement (60 %). Although allo-SCT in patients with CVID was beneficial in most surviving patients, high mortality was associated with GVHD and infectious complications. The indication of allo-SCT for XLA is also difficult to define due to conflicting findings on the mortality rate of XLA patients []. Although most XLA patients may experience a nearly normal life [], Abolhassani et al. reported that 26.8 % of patients died during a follow-up period of 20 years []; the hospitalization rate for patients was significantly higher than alive patients. The cause of death among the 11 patients was mainly end-stage of chronic lung disease in addition to one case of meningitis. According to a national survey conducted in Japan, the 5-year survival rate of allo-SCT for aplastic anemia from related donors was more than 80 %. Due to advances in the SCT technique, repetitive episodes of hospitalization and/or central nervous system lesions may facilitate allo-SCT as a treatment option for XLA.
Before discussing immune reconstitution in this case, the possible impact of ATG needs to be considered from qualitative and quantitative aspects. Two kinds of rabbit ATGs are commonly used in SCT conditioning: anti-Jurkat T-cell line globulin (thymoglobulin) and anti-thymocyte globulin Fresenius (ATG-F). ATG-F was previously reported to affect the reconstitution of not only T-cells but also B-cells []. Since we used thymoglobulin in this case, its impact on B-cells was considered to be minimal. Admiraal et al. found a relationship between the dose of ATG and immune reconstitution in pediatric SCT. The commonly used dose regimen of thymoglobulin in SCT is 10 mg/kg worldwide. They found that the area under the curve of ATG increased, the achievement of successful immune recognition (defined as CD4+ T-cells >0.05 × 109 cells per liter in two consecutive measurements within 100 days) decreased, and successful immune reconstitution by day 100 was associated with an increase in overall survival caused by reduced non-relapse mortality and relapse-related mortality []. Fu et al. showed that the incidence of late-onset hemorrhagic cystitis after haploidentical SCT was higher in high-dose ATG (thymoglobulin 10 mg/kg) than in low-dose ATG (thymoglobulin 6 mg/kg) []. Since we previously demonstrated that even a low dose of ATG, thymoglobulin 2.5 mg/kg, was sufficient to control GVHD at an acceptable level in the Japanese population based on our experience of more than 500 cases of haploidentical SCT [], we used thymoglobulin 2.5 mg/kg in this case and considered the effects of ATG on T-cell recovery to have also been minimized.
In our case, CD19+ cells in PB rapidly increased in number after allo-SCT, and this was accompanied by IgA and IgM production. Moreover, anti-B antibody production, as an example of specific antibody production, was observed as early as on day 10. Although the total amount of IgG in PB spontaneously recovered, the titer of virus-specific antibodies, except for EBV-VCA IgG, disappeared after the discontinuation of IgG replacement. A vaccination for influenza virus was unsuccessful in the first season after allo-SCT. Thus, pathogen-specific immune responses had not fully recovered 1 year after allo-SCT. This may be explained by T-cell reconstitution not being thoroughly achieved, as shown by the TREC analysis (Fig. ). Nevertheless, the patient has been doing well without any infectious episodes, which had previously occurred and were life-threatening. Another interesting result was the possible transfer of immune or allergic responses from the donor. In this setting, the donor had a high titer of RIST and RAST to some allergens. The recipient exhibited a slight increase in RAST to orchard grass on day 46, implicating the transient transfer of allergic immunity.


An 83-year-old Asian man was referred to the ophthalmology department by an optometrist for the evaluation of an asymptomatic pigmented lesion on the conjunctiva of the left eye. The patient’s medical history included ocular melanocytosis and ocular trauma that resolved spontaneously six months prior to presentation. On examination, a well-defined 10 × 5 mm pigmented nodule was seen on the superior medial conjunctiva of the left eye. The surrounding conjunctiva was also diffusely pigmented superficially. A clinical diagnosis of CM within an area of PAM was made. Excisional biopsy of the nodule and map biopsies from the flat-pigmented lesion were obtained in order to rule out any malignancy.


A 44-year-old male patient had been on regular hemodialysis three times per week, with 4-hour sessions since December 2003. The etiology of his renal failure was unknown and the patient had no systemic disease when hemodialysis was started.
Anamnesis revealed no family history of a serious disease 4 year before coronary bypass surgery for coronary artery disease was performed. The initial iPTH value of the patient measured at the beginning of hemodialysis was 74.5 ng/L () and his clinical and laboratory findings for renal osteodystrophy were within acceptable limits. His follow-up parameters showed progressively increasing values of iPTH, along with Ca and P. In our patients, kidney transplantation is a good choice. But in our country, a large part of it is made via a living donor. Our patient does not have a living donor and cadaver donor cannot be found. Following phosphate control, calcitriol, paricalcitol and cinacalcet treatment have started. The level of iPTH in start of the cinacalcet in 2010 was 2121. Cinacalcet was first administered at 30 mcg/day in April 2010 for one month, at 60 mcg/day for another month, and when PTH values did not decrease sufficiently at 90 mcg/day for one year unit such time parathyroidectomy occurred.
CaxP values of the patient were consistently above 72 and the patient clinically suffered severe and widespread musculoskeletal pain during this period. Parathyroid MRI was performed when iPTH values went above 2000 ng/L, parathyroid glands were found to be significantly hyperplastic; however, parathyroid scintigraphy was normal. Lesions were 18x21 mm, 14x10 mm and 24x16 mm in size. In April 2011, painful, erythematous skin lesions were detected over and around the external malleolus of the right foot. In the next two months, erythematous skin lesions gained a necrosed character and spread into the malleolar and posterior tibial region and back of the ankle in both extremities. In the lower extremity, Doppler USG the arteries were found to be open and the patient received hyperbaric oxygen therapy for 30 sessions via the recommendation of the dermatology department. The patient showed no clinical signs of recovery and despite anti-biotherapy, debridement and protective measures, the skin lesions got infected and presented as intolerable, painful wounds. The patient was diagnosed with CUA and hospitalized for parathyroidectomy. All parathyroid glands were removed after having checked quick PTH intraoperatively ().
A small amount of parathyroid tissue was intramuscularly auto-implanted into the right forearm when intraoperative value of the PTH was <300 ng/L. Skin lesions showed fast improvement in further follow-ups (). On the 13th postoperative day, the iPTH value was 396.60 ng/L. Three months after parathyroidectomy, iPTH value was measured as 1197 pg/ml. After 6 months of medical treatment, iPTH was found as 970 ng/L and we decided to remove the implanted parathyroid tissue from the right forearm. Following surgical excision, the mean iPTH value was measured 430 ng/L.


We report the case of a 34-year-old man who presented to our emergency department complaining of a severe, diffuse, and throbbing headache. The headache had started two weeks before and shown a progressive worsening with a gradual increase in intensity during this period. The pain was immediately exacerbated when the patient assumed an upright position but was partially relieved after approximately five minutes of recumbency. Common analgesics brought no relief. The patient also complained of nausea, vomiting, photophobia, the sensation of neck stiffness from headache onset, and episodic double vision during the previous two days. He denied having a history of previous headache, recent head or neck trauma, or invasive procedures. There was a personal medical history of psoriasis and asthma, but he was asymptomatic at the time. He attended the gym on a daily basis and he had played tennis on the day before the headache onset. On the fourth day of symptoms, the patient resorted to going to the emergency department of a local hospital, where a brain computerized tomography (CT) was requested. The exam did not show any abnormal findings, and the patient was discharged with symptomatic analgesics.
The physical and neurological examination on admission to our emergency department were remarkable only for a left sixth nerve paresis and severe photophobia.
A brain magnetic resonance imaging (MRI) scan was performed and revealed diffuse pachymeningeal enhancement, a decrease in ventricle size, cerebellar tonsil descent, and subdural fluid collections, findings which were compatible with SIH ().
MRI myelography was then requested. A low cerebrospinal fluid (CSF) opening pressure (5 cm H2O) was confirmed during the procedure and a spread of CSF in the epidural space was observed, extending from L3 to the cervical region, entering the intrathecal space at C7, suggesting a CSF leak located at this level ().
A conservative approach was initially tried, consisting of bed rest, hydration, analgesia, and caffeine intake. After two weeks without clinical improvement, it was decided to proceed with an EBP. Since the CSF leak was located at a cervical level and the literature suggests that these cases are less likely to resolve with a blind EBP, we chose to perform a targeted CT-guided EBP. It involved a CT-guided injection of 10 mL of autologous blood with 2.5 mL of iodinated contrast targeted at the D2-D3 epidural space, with a satisfactory blood spread into the epidural space between C1 and D6 ().
On the day after the targeted EBP was carried out, there was a pattern change in the headache, with a worsening in the supine position, which was suggestive of intracranial hypertension. An urgent CT-scan did not show any new findings, indomethacin was prescribed, and the patient was asymptomatic after three days of treatment. Brain MRI performed one month later revealed a complete resolution of the imagiological features and the patient remained without headache recurrence after 30 months.


A 57-year-old female presented with left-sided leg pain and swelling after a two-stage complex spine operation. The patient was suffering from chronic back pain, right leg pain, and neurogenic claudication. On evaluation, she was found to have degenerative scoliosis as well as central and foraminal stenosis. Initially, the patient underwent an L3-S1 anterior lumbar interbody fusion, followed by a second stage L3 to the sacrum posterior spinal fusion and extraforaminal nerve root decompression two weeks later. Informed patient consent had been obtained prior to her treatment.
In the second stage of the procedure, we used a commercially available electromyographic (EMG) intraoperative monitoring system. Using electromyography monitoring is routine practice for lumbar spinal fusions in our department. Disposable EMG needles were inserted after the area was cleaned with alcohol wipes. These needles are 22 mm in length and longer than standard acupuncture needles and other EMG monitoring systems (typically 13-14 mm long). This needle length was used as part of one our vendor's monitoring packages and unrelated to the patient's body habitus. The needles were secured in place using tape. During the procedure, there was no need to reposition any of the needles due to dislodgment or other technical issues. We removed the needles at the end of the procedure while the patient was still in the prone position. The patient had an uneventful immediate postoperative period except for mild hypotension and was discharged home three days after the procedure.
At a routine follow-up clinic visit at nine days after the second stage procedure, the patient reported a few episodes of fever up to 101oF. She also complained of bilateral leg swelling with pain and heaviness on both sides. She reported that elevation of both legs did not help her symptoms. Due to ongoing leg pain and swelling, ultrasonography (US) of both legs was performed, which excluded deep venous thrombosis. In the three week period following her second stage surgery, her leg pain and swelling deteriorated to the extent that she was unable to move her left leg. Physical examination of her legs at this time showed evidence of bilateral non-pitting edema, which was more pronounced in the left leg. There was no evidence of erythema or purulent discharge at this visit. A repeat lower extremity US did not show any evidence of deep venous thrombosis.
Her left leg swelling increased and she required readmission almost 29 days after her second stage surgery. At this time, she also developed significant hyponatremia (124 mEq/L). On this presentation, she was normothermic with bright erythema from the knee to groin with extension to the pelvis. She showed blotchy red areas in both feet. The erythematous area of her left leg was tender on palpation. She denied use of any antibiotics prior to this admission. C-reactive protein was elevated to 33 mg/L on this presentation. US and CT of both legs showed areas of un-opacified muscle, inflammation, and possible fluid collection in the left thigh. The CT findings are demonstrated in Figures -.
Her clinical presentation, laboratory data, and CT imaging raised a concern about a deep soft tissue infection. She was taken to the operating room urgently for aspiration of left thigh purulent fluid and excision and debridement of left thigh necrotic fascia and muscle. During this procedure, 900 cc of purulent fluid were drained and the vastus lateralis muscle was found to be necrotic. A wound vac (negative pressure wound therapy) was applied at the end of the procedure. Broad-spectrum antibiotics, which included vancomycin, clindamycin, and Zosyn (piperacillin and tazobactam), were started immediately. Her antibiotic therapy was changed to Unasyn (ampicillin sodium/sulbactam sodium) after tissue cultures grew Bacteroides fragilis. Following the fasciotomy, she developed a psoas abscess followed by a lumbar spine wound dehiscence, both of which required further debridements. After further debridement of the left hip, flank, pelvis, retroperitoneum, and left leg, the wound was closed as a separate procedure.


A 4-month-old female infant, who weighed 3.57 kg and was 54.6 cm in height, was hospitalized because of the diagnosis of severe subglottic stenosis. At birth, she was diagnosed with 22q11.2 deletion syndrome with multiple anomalies, including thymic aplasia, aortic arch interruption, ventricular septal defect, atrial septal defect, and subvalvular aortic stenosis. Eight days after birth, when she weighed 2.77 kg and was 46 cm in height, she had surgery of the right pulmonary artery banding under general anesthesia. This anesthesia management allowed easy intubation (Cormack-Lehane Grade I) with a cuffed endotracheal tube (3.0 mm inner diameter (ID)). She was extubated at the pediatric intensive care unit (PICU) without any complications the next day after surgery. Three weeks later, she had secondary radical surgery of the aortic arch and intracardiac repair under general anesthesia with intubation with a cuffed endotracheal tube (3.0 mm ID) without any problems. After the second surgery, she was under artificial ventilation in the PICU. On the 5th postsurgical day, she was extubated and placed under bubble continuous positive airway pressure (bCPAP). However, after extubation, she had stridor in her respiration and had difficulty weaning from bCPAP for the next 3 days. At the 7th postsurgical day, an otolaryngologist performed nasolaryngeal optical fiberscopy, and she was diagnosed with right vocal cord paralysis. Six weeks after surgery, she was discharged from the hospital and was placed at home care. However, 6 weeks after discharge, at 4 months old, she was rehospitalized because of respiratory distress with the constriction situation at the time of crying and reduced suckling force at breastfeeding. Blood arterial gas analysis showed hyper apnea and metabolic alkalosis as follows: pH, 7.45; PaO2, 67.8 mmHg; PaCO2, 54.9 mmHg; base excess, 11.7; lactate level, 1.0 mEq/L; and SaO2, 95.4% at room air. Severe subglottic stenosis with an estimated diameter of 2.3–2.5 mm in the narrowest portion of her larynx was diagnosed by computed tomography (). Emergent tracheostomy was then planned under general anesthesia, and the method of induction of anesthesia was discussed.
Because the patient just maintained spontaneous ventilation with depression of epigastric intercostal, there was a high risk of “cannot intubate cannot ventilate” during induction of anesthesia under the method of being either awake or anesthetized during induction. Therefore, in advance of the procedure of tracheal intubation, we decided to keep her under spontaneous ventilation and performed extracorporeal cardiopulmonary support under regional anesthesia with light sedation (). Venoarterial extracorporeal cardiopulmonary support with cannulation by the open cut method was performed by cardiac surgeons in case of resuscitation with cardiac support. She was sedated with dexmedetomidine (0.7 µg/kg/h), ketamine 1.0 mg (0.5 mg, 2 shots), and midazolam 0.2 mg (0.1 mg, twice). Total heparinization followed by arterial and venous cannulation of the extracorporeal circuit to the right femoral artery and right femoral vein was then performed under local anesthesia with 1% lidocaine (1.7 mL). Additional administration of ketamine (0.5 mg, 2 shots) and midazolam (0.1 mg, once) was performed after the extracorporeal circuit was started and oxygenation of arterial blood was attained by evaluation using pulse oximetry. Semiawake tracheal intubation was carried out with an uncuffed endotracheal tube (2.5 mm ID). Although slight resistance was felt at the time the tip of the endotracheal tube passed through the narrowest region of the subglottis, the tube was successfully placed in an appropriate position with a depth of 8.5 cm from the infant's mouth. A total of 5 mg rocuronium bromide was administered intravenously and respiration of the patient was under the control of positive airway pressure ventilation. Ten minutes after tracheal intubation, extracorporeal cardiopulmonary support was stopped and decannulation and neutralization of heparin with protamine were carried out. Tracheostomy was successfully performed by an otolaryngologist in the next 20 min. The anesthesia time was 3 hours and 8 minutes and the extracorporeal cardiopulmonary support time was 19 minutes. The patient was admitted to the PICU for postoperative management.


A 36-year-old female in her third pregnancy came to our hospital at 8 weeks of gestation for a routine prenatal check. The couple and their previous children's past and family histories were unremarkable. Ultrasonographic examination at 8 weeks of gestation was unremarkable, with a crown-rump length (CRL) of 15.9 mm. At 11 weeks of gestation, although the CRL was 49.6 mm corresponding to gestational age, fetal hydrops was evident on ultrasonography (). Since screening for immune hydrops and congenital infections were negative, a transvaginal ultrasound was performed the following week for further evaluation. At 12 weeks of gestation, appropriate fetal growth was observed with a CRL of 60 mm; however, fetal hydrops was still present. The couple was counseled on the different etiologies of fetal hydrops; however, at this point the cause was not clear.
At 13 weeks of gestation the biparietal diameter (BPD) was measured to be 27.4 mm, corresponding to the 95th percentile. From this week on macrocephaly was observed and a narrow thorax was suspected on subsequent ultrasonographies (). At 16 weeks of gestation, amniotic fluid examination showed a normal karyotype (46XX); however, a routine and a four-dimensional ultrasound revealed shortening and bowing of the long bones (femur length (FL) 11.6 mm) (Figures and ) with no subsequent improvement. As a result, a fetal skeletal disease, specifically TD, was strongly suspected. At 20 weeks of gestation, the FL was 1.18 cm, compatible with less than the 5th percentile. Also, the BPD was 5.3 cm, corresponding to more than the 95th percentile. During genetic counseling, a molecular analysis was suggested to the parents in order to make an accurate prenatal diagnosis of TD; however, they opted not to pursue this exam and decided on termination of the pregnancy, instead. The patient was then hospitalized and underwent mechanical cervical dilation. The following day gemeprost (PGE1) was administered intravaginally every three hours. A 400 g female fetus was delivered dead at 20 weeks and 2 days of gestation (). All limbs were noted to be extremely short with redundant skin folds. Macrocephaly was evident. A narrow bell-shaped thorax with short ribs and a protuberant abdomen were noticed; however, the skull and facial characteristics were within normal limits. Skeletal radiography showed telephone receiver-like curved femurs and humeri accompanied by irregular metaphyses, an H-shaped platyspondyly, and curved clavicles (). No cloverleaf skull deformity was observed. These characteristics confirmed the diagnosis of TD type I.


A 60-year-old man presented with few days of jaundice, generalized fatigue, and dark urine. On admission, he had a bilirubin level of 836 μmol/L (normal < 24), direct bilirubin of >580 μmol/L (normal < 5), ALP of 235 U/L (normal 40–130), GGT of 340 U/L (normal < 60), AST of 236 U/L (normal < 45), ALT of 75 U/L (normal < 45), albumin of 21 g/L (normal 38–52), and serum creatinine of 135 μmol/L (normal 60–105). His creatinine 6 months earlier had been 80 μmol/L.
He had been taking flucloxacillin 500 mg daily intermittently for 3 months to treat skin folliculitis. He stopped the antibiotics 6 weeks prior to his presentation. There was no history of substance or alcohol abuse. He was on no other regular medications.
On Examination. He was afebrile and had BMI of 30, BP of 125/80, and heart rate of 70/min. His JVP was +2 cm above the sternal angle, with mild peripheral oedema, clear chest on auscultation, and nontender liver extending 3 cm below the costal margin.
The screen for viral and metabolic causes of hepatitis was unremarkable. An abdominal CT with contrast showed hepatomegaly with diffuse fatty changes but no biliary dilatation. The serum bilirubin continued to rise reaching a peak of 881 μmol/L on day 8. A liver biopsy was performed and showed panacinar steatosis, moderate steatohepatitis (NAFLD score 5/8), portal fibrosis, and cholestasis. An ERCP was normal. The diagnosis was flucloxacillin-induced hepatitis.
The patient's serum creatinine continued to rise and peaked at 581 μmol/L on day 16 despite adequate hydration and avoidance of nephrotoxins. In addition, the patient had persistent severe hypokalemia with serum potassium levels consistently <3 mmol/L despite the potassium replacement. Arterial blood gas was not suggestive of renal tubular acidosis with serum bicarbonate level of 26 mmol/L and pH of 7.46.
On day 3, his urine sodium was 33 mmol/L, urine potassium 42 mmol/L, and urine osmolality 420 mmol/kg. The transtubular potassium gradient was >10 and the serum potassium at the time of specimen collection was 2.7 mmol/L indicating renal cause for his hypokalemia. The urinary protein/creatinine ratio was slightly raised at 39 mg/mmol (normal < 23) and otherwise bland urine sediment. The urine output averaged 1.5 L per day from the day of admission.
A renal USS showed normal sized kidneys at 128 mm and 125 mm with no obstruction, normal echotexture, and perfusion; a renal biopsy was performed.


A 70-year-old male, with no family history of melanoma, but with multiple atypical nevi, came for off-protocol follow-up in September 2013 (). The patient first presented in 1981, at the age of 37, with malignant melanoma on the lower back and the following year another two primary melanomas were diagnosed on the lower back. Unfortunately, no histology on these melanomas is on record, but they are described in old case files. The patient had a 19-year period without recurrence or new tumours but presented again in 2001 with SSMM on the back, level 4, Breslow depth of 1 mm, and negative sentinel node biopsy. Over the next 12 years, the patient was followed up according to the protocols of the time and diagnosed with seven new primary melanomas, four invasive and three in situ melanomas (). In 2013, the diagnosis of a thick melanoma on the back required sentinel node biopsy. However, the lymphoscintigraphy did not demonstrate any hot spots and sentinel node biopsy could not be performed. The patient underwent a PET-CT-scan instead, which showed suspicious areas in the colon and a slightly enlarged spleen. Additional work-up did not explain the slightly enlarged spleen, but an adenocarcinoma of the sigmoideum was diagnosed and operated. The patient was genetically tested but found not to be carrier of either of the two high-risk genes CDK4 and CDKN2A.


A 22-year-old female presented to the hospital with a history of progressive dyspnea, fatigue, and chest and neck tightness. She had a history of antiphospholipid syndrome, Budd-Chiari Syndrome, and end stage renal failure. On physical examination, the patient was cyanotic with a heart rate of 125 beats/min, respiratory rate of 22/min, blood pressure of 82/50 mmHg, and oxygen saturation of 86% on room air and 95% on 15 liters nonrebreather oxygen mask.
Chest computed tomography (CT) angiography was performed to rule out pulmonary emboli. The exam was performed using IV iodinated contrast (Xenetix) via right antecubital vein with a power injector. Images were acquired in helical mode using multidetector CT scan (GE discovery, CT 750 HD) with slice thickness of 0.625 mm. Axial, coronal, and sagittal reconstructions and multiplanar reformats (MPR) were performed. The exam showed complete nonopacification of the SVC and left brachiocephalic vein. The upper azygos vein was distended and not opacified as compared to the opacified inferior part. There were extensive collaterals draining into the right atrium through coronary sinus and some appeared to drain directly into the right atrium. Furthermore, the exam showed numerous strongly enhancing multiple hilar, mediastinal, and pericardial venous plexus around the bronchi, pulmonary arteries, and pulmonary veins with subtle early filling of the central pulmonary veins as compared to peripheral segments leading to the left heart chambers and aorta with early opacification (). There was no filling defect to suggest pulmonary embolism. The exam revealed multiple collateral venous pathways, such as the azygos and hemiazygos veins, internal and lateral thoracic veins, and vertebral venous plexus.
Echocardiography with limited views was performed with saline injection via the right antecubital vein and revealed echo bubble in both sides of the heart, more on the left side, suggestive of venous connection to left atrium. Lung perfusion scan with Tc-99m MAA was performed and showed focal tracer uptake at the region of the brain, stomach, and both kidneys indicating right-to-left shunt (). Cardiac magnetic resonance imaging (MRI) was requested to assess and quantify the shunt. There was a sluggish flow of the pulmonary artery branches in the phase contrast necessitating reduction in the velocity encoded gradient echo from 150 cm/sec (routinely used for arteries) to 100 cm/sec (routinely used for veins). The average velocities of the MPA, RPA, and LPA were reduced and measured 5.45 cm/sec, 6.37 cm/sec, and 7.76 cm/sec, respectively. The net forward volume to body surface area was 7 mL/m2 for the MPA and 15 mL/m2 for the ascending aorta with a Qp/Qs ratio of 0.5. An attempt to assess the pulmonary veins was initiated; however, the patient was unable to complete the exam.
Conventional venogram was performed by the cardiologist and confirmed SVC complete obstruction at the SVC/RA junction and narrowing of the IVC with the narrowest diameter measuring 6.6 mm. The patient then underwent successful SVC and IVC dilatation and stenting. The patient was extubated immediately following the procedure and was clinically stable with normal oxygen saturation on room air and complete resolution of her cyanosis.


A 2-month-old girl from the southeastern part of Turkey presented with failure to thrive (birth weight unknown; 2-month-old weight in 10th percentile, length in 25th percentile, head circumference in 3rd to 10th percentiles), irritability, and diarrhea for the last 20 days and was found to have pallor, petechial rash, and no head control upon physical examination. She was the 6th child of first-degree cousins from the 8th gestation, and family history revealed that a sister of hers had died at 1 year of age with diarrhea and vomiting and a brother had died at 3.5 months with bleeding. Liver and renal function tests were unrevealing. Urinalysis revealed absence of proteinuria. Bone marrow aspiration indicated megaloblastic changes in the erythroid and myeloid lineages and vacuolization in the myeloid lineage. Serum vitamin B12 level was found to be 351 pg/mL (normal range: 200-860); however, serum homocysteine was 40 µmol/L (normal: 5.5-17) and urinary methylmalonic acid level was twice the normal value. She was given erythrocyte and platelet transfusions on the first day of admission and intramuscular hydroxocobalamin was initiated at 1000 µg/day with a possible diagnosis of transcobalamin II deficiency. The hemogram findings on the day of vitamin B12 treatment initiation were as follows; RBC: 2.6x1012/L, Hb: 7.4 g/dL, Hct: 21.3%, MCV: 80 fL, WBC: 3.8x109/L, platelets: 61x109/L, absolute neutrophil count (ANC): 0.3x109/L, and absolute lymphocyte count (ALC): 3.4x109/L. By the 6th day of admission the diarrhea subsided and on the 10th day of admission the hemogram results improved to Hb: 8.9 g/dL, Hct: 24.4%, MCV: 78.5 Fl, WBC: 33.2x109/L, platelets: 125x109/L, and ANC: 22.3x109/L. Leukocytosis developed in the absence of an infection after the initiation of vitamin B12 treatment and subsided to the normal range in 2 weeks. Hydroxocobalamin dosage was continued intramuscularly on alternating days for the 2nd week and weekly after the 3rd week. Folic acid at 1 mg orally was added to the treatment. Molecular analyses revealed c.1106+1516-1222+1231del in a homozygous state, which was a deletion of 5304 bp beginning 1516 bp into intron 7 and ending 1231 bp into intron 8, causing deletion of all of exon 8 and a frameshift to produce a premature stop 4 codons into the new reading frame. During the follow-up, the family was learned to have attempted to cease the treatment by their own intention and the patient had similar attacks of pancytopenia and diarrhea. Both attacks resolved after reinitiation of hydroxocobalamin. The patient was also detected to have β-thalassemia trait (HbA2 6%) during outpatient visits due to MCV values as low as 65.2 fL after initiation of vitamin B12 in the absence of iron deficiency. She is currently alive and asymptomatic at 4 years of age.


A 28-day-old boy from the 1st gestation of a couple of first-degree cousins presented with failure to thrive, poor feeding, and vomiting. He was from the Central Anatolia region of Turkey. Hemogram results revealed pancytopenia. Antibiotic treatment was started empirically. He received transfusions several times, and the bone marrow examination was remarkable for megaloblastic changes and vacuolization in bone marrow precursors. Serum vitamin B12 was 623 pg/mL (normal: 200-860). Cyanocobalamin (1000 µg) was initiated intramuscularly with a possible diagnosis of transcobalamin II deficiency. Signs and symptoms declined after cyanocobalamin initiation. Folic acid was added to the vitamin B12 treatment. The control for bone marrow aspiration after vitamin B12 initiation revealed the disappearance of megaloblastic changes and vacuolization in the myeloid lineage. The molecular analyses was ordered and revealed c.1107-347_1222+981del in 364. This complex mutation appears to be a 1444-bp deletion that includes exon 8. There was also a 364-bp insertion. He is currently alive at 6.5 years of age under weekly intramuscular cyanocobalamin.


A 2-month-old girl, from the 1st gestation of a couple of first-degree cousins, presented with diarrhea, vomiting, and fever for 1 week. Body weight and length were below the 3rd percentile for age. Hemogram results revealed pancytopenia. Bone marrow examination revealed megaloblastic changes. Sweat test by pilocarpine iontophoresis was ordered for the diarrhea and results were positive, with a sweat chloride of 87 mEq/L. Molecular testing for cystic fibrosis for the common 21 mutations in Turkey was negative. Serum vitamin B12 was within normal laboratory limits, whereas urinary methylmalonic acid level was 16.45 mmol/mol creatinine (normal: 0-10). Molecular study revealed homozygous c.106C>T p.Q36X. A C-to-T substitution at nucleotide 106 resulted in a premature stop codon. She was started on intramuscular cyanocobalamin at 1000 µg/day on the 13th day of admission; by the 16th day of admission, she was discharged after resolution of symptoms with hemogram findings of Hb: 10.1 g/dL, WBC: 20x109/L, MCV: 89 fl and platelets: 850x109/L, with continuation of treatment twice weekly. Oral folic acid was also initiated. The sweat test was repeated during that period and was normal. She is currently alive at 5 years of age and asymptomatic under weekly cyanocobalamin treatment.


A 3-month-old boy of Turkish origin from Cyprus presented with failure to thrive and poor feeding. Blood and bone marrow examination revealed pancytopenia, hypersegmentation, and megaloblastic changes in the myeloid lineage. Serum homocysteine and vitamin B12 levels were 46 µmol/L (normal: 5.5-17) and 677 pg/mL (normal: 200-860), respectively. Cyanocobalamin was initiated intramuscularly and the pancytopenia resolved. Molecular analyses revealed c.1106+1516-1222+1231del in a homozygous state. The mutation was the same as that found in Case 1.


A 9-year-old male patient was diagnosed with clinical stage I HL with the mixed cellularity (MC) histopathological subtype and had received local RT of 40 Gy to the neck region. He relapsed 3.5 years later with clinical stage IV disease and was given 6 cycles of C-MOPP and 4 cycles of maintenance C-MOPP, for a total of 10 cycles. A fibrosarcoma developed in the radiation area 8 years following the initial treatment ( 1), then followed by papillary thyroid carcinoma diagnosed at 16 years and a right-sided retrobulbar meningioma at 30 years later consecutively. The patient was treated according to his neoplasms and he is alive at the present time.


A 15-year-old male patient was diagnosed with clinical stage I HL with lymphocytic predominance (LP) and received 3 cycles of C-MOPP and 40 Gy RT to the neck region. A thyroid nodule developed 27 years after the initial treatment. Surgical excision was performed and the histopathological diagnosis was follicular adenoma of the thyroid gland. The patient is presently alive with no symptoms.


A 10-year-old female patient was diagnosed with clinical stage II HL of the nodular sclerosis (NS) type and received nitrogen mustard, vinblastine, and local RT (40 Gy) to the neck region. She developed a mediastinal relapse 4 years after the initial treatment and was given cyclophosphamide (CTX), vincristine (VCR), and adriamycin (ADM) (four cycles) and C-MOPP (two cycles), and mediastinal RT at a dose of 37 Gy. She further developed a benign thyroid nodule 14 years later, which was excised. An invasive ductal carcinoma appeared in her left breast 30 years after the initial chemoradiotherapy. After the diagnosis of the breast carcinoma, the patient did not return and was lost to follow-up.


A 13-year-old male patient was diagnosed with clinical stage III HL with MC histopathology and he received 40 Gy RT to the neck region and C-MOPP plus maintenance C-MOPP (a total of 10 cycles). A swan-like neck developed 12 years after the treatment (). An EMPNST () developed 30 years after the initial treatment. Although the patient received four cycles of iphosphamide and ADM combination chemotherapy, he died with progression of his malignant disease 6 months after diagnosis.


A 3-month-old girl was admitted to the hospital with respiratory difficulty, tachypnea and forced respiration with retractions, which had been noticed in an ordinary pediatric control. She was the first child of unrelated, young, and healthy parents without familial history of neuromuscular disorders or sudden infant death syndrome. The baby had been born by caesarean section at 34 weeks gestation due to intrauterine growth retardation (IUGR), decreased fetal movements, and abruptio placentae diagnoses. She weighed 1,550 g at birth (< 10th percentile), with an Apgar score of 8/10, and presented neonatal respiratory distress immediately after birth, requiring mechanical ventilation and pulmonary surfactants for 3 days.
On admission at 3 months, pulmonary auscultation revealed severe bilateral hypoventilation with crepitus. Chest X-ray suggested bronchiolitis and she received corticoids and oxygen without improvement. The disease progressed to severe respiratory insufficiency, requiring mechanical ventilation. Repeated efforts to wean her from ventilator resulted unsuccessful.
Limb weakness with distal to proximal progression appeared shortly after the onset of respiratory insufficiency, with marked generalized hypotonia, areflexia, bilateral equinovarus foot deformities, and Achilles contractures. Tongue fasciculations were absent.
Serologic and biochemical parameters, including creatinine kinase levels and cerebrospinal fluid analyses were normal. Results from other tests performed for infective and metabolic conditions were unrevealing.
On electrophysiological examination, sensory potentials were abolished in the lower limbs and fingers. The only recordable potential was that of the median nerve (amplitude 2.6 µV, SCV 21 m/s) (). Concentric needle examination revealed severe partial denervation in all examined muscles of the upper and lower limbs. Complete denervation of the left hemidiaphragm was demonstrated.
Electroencephalogram, brain magnetic resonance imaging (MRI), and cardiologic studies did not show abnormalities. Genetic analysis for Survival Motor Neuron (SMN1) gene was negative. Electron microscopy of skin and biochemical assays in cultured fibroblasts ruled out metachromatic and globoid cell leukodystrophies.
Muscle and nerve biopsies were performed at 5 and 10 months of age. At 5 months muscle biopsy was nearly normal. However, sural nerve biopsy at that age demonstrated significant decrease in myelinated fiber density (A) with no evidence of inflammation. At electron microscopy examination, no onion bulbs or axonal cluster formation were present. Microtubules and neurofilaments were normal. Giant axons, metachromasia, or lysosomal storage were absent (B).
Electrophysiological examinations at 11 months of age demonstrated complete denervation in the most distal muscles (tibialis anterior, gastrocnemius, and foot muscles) and severely reduced interference pattern in the most proximal ones (vastus lateralis, deltoid, and facial muscles) (). At that age, marked atrophy of both type I and type II fibers was found in muscle biopsy (C) with fibers showing prominent nuclei and increased oxidative activity, clearly demonstrative of a neurogenic process (D) showing features of immature fetal phenotype ().
Despite therapeutic efforts, the condition of the child rapidly deteriorated, resulting in complete paralysis of limbs and trunk. In the end stage of the disease, tracheostomy and gastrostomy were required, and the baby developed recurrent pulmonary, urinary, and systemic infections. Autonomic manifestations subsequently occurred, including neurogenic bladder and cardiac arrhythmia. The child died of respiratory failure at 23 months of age. Permission to perform a necropsy was obtained.
Post-mortem examination revealed bilateral pneumonic consolidation and pleural effusion. The spinal cord showed a reduced anterior spinal root diameter and prominent loss of motor neurons in the anterior horns (A), extending from the cervical to the lumbar region. The remaining motor neurons displayed chromatolysis and pyknosis (B). In DRG, significant neuronal loss was observed (C), better depicted with S100 immunohistochemistry. The overall size of nerve cells was small with abundant clusters of satellite cells’ nuclei (Nageotte nodules). No abnormalities were present in the brain and midbrain motor nuclei.
Severe axonal depletion was found in sural (D) and sciatic (E) nerve samples, with less than 50 – 60% of preserved fibers and prominent endoneurial fibrosis. Fibers showed thin myelin sheaths without signs of active demyelination or remyelination. Non-myelinated fibers were morphologically normal and basal lamina did not show abnormalities. Onion bulbs, axonal sprouts, or inflammatory infiltrates were absent.
Muscle samples from the limbs, diaphragm, and intercostal muscles showed large groups of atrophic fibers with frequent nuclear clumps, massive adipose infiltration, and fibrosis, particularly in the diaphragm (F).
Further genetic studies were performed. Automatic sequencing of all 15 exons and flanking regions of IGHMBP2 on 11q13-q21 revealed a compound heterozygous mutation R147X/C496X ([], case no. 15). These mutations were demonstrated in the father and the mother respectively.
Some years later, the mother became pregnant and underwent prenatal diagnostic tests in a chorionic villi biopsy at 11 weeks’ gestation, with her written informed consent. Prenatal molecular analysis in DNA extracted from chorionic villi samples proved the second fetus to be single heterozygote, harboring the paternal mutation. The pregnancy was continued, and a healthy girl was born at term and remains unaffected at 5 years of age.


A 37-year-old African-American male with past medical history of HIV (detected in 2001; transmitted by heterosexual intercourse; latest CD4 count 320 cells/mm3 with undetectable viral load; compliant with highly active antiretroviral therapy (HAART); no opportunistic infections in past) and nephrolithiasis presented to emergency department of our hospital with progressively worsening epigastric pain and nausea for one week. Pain was constant and was rated severe and radiated to his back. The patient denied hematemesis, hematochezia, or diarrhea. However, he reported weight loss of 12 lbs in last 2 months but denied night sweats. There was no history of recent travel, sick contacts, or illicit drug use. Vital signs were notable for tachycardia of 120 beats/minute and low-grade fever of 38.8°C. The physical examination revealed epigastric tenderness with no rebound. Initial laboratory evaluation showed elevated levels of lipase 629 IU/L (33–200), amylase 250 IU/L (30–110), lactate dehydrogenase (LDH) 936 IU/L (313–618), and C-reactive protein 3.6 mg/dL (0-1), with normal liver and renal function tests. White cell count was 3.8 × 109cells/L (3.8–9.8 × 109), hemoglobin was 13.2 g/dL (13.5 to 17.5), and platelets were 139 × 109 cells/L (150–450 × 109). Cardiac troponins came out negative with unchanged EKG. Preliminary diagnosis of acute pancreatitis was made. Subsequently, abdominal computed tomography (CT) demonstrated multiple, well-defined, peripancreatic, soft tissue masses to left of the uncinate process (), posterior to the pancreatic tail, and near the hepatic hilum (). The peripancreatic masses were found to be compressing the body of pancreas, causing acute pancreatitis in our patient. Furthermore, there was partial compression of the portal vein with multiple surrounding portal venous system collaterals.
Differential diagnoses included lymphoma, mycobacterium avium complex (MAC), disseminated fungal infection, and tuberculosis (TB). The case was discussed in the multidisciplinary tumor board. It was concluded that, due to the advanced disease, tissue diagnosis will be difficult employing surgery or interventional radiology. Thereafter, an uneventful endoscopic ultrasound (EUS)-guided fine-needle aspiration biopsy of one of the masses was performed, and preliminary pathology suggested lymphoma. Cancer antigen 19-9 (CA 19-9), carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), and serotonin levels were within normal limits. Sputum AFB culture and QuantiFERON-TB Gold (QFT) were negative ruling out TB. Fungal cultures and isolated bacterial cultures for MAC also came out negative. Total body scan showed subcentimeter bilateral mediastinal and axillary lymphadenopathy. Histopathology analysis revealed diffused infiltration of large B-cells with plasmablastic (cells with rounded nuclei, coarser chromatin, and smaller two to three nucleoli) and immunoblastic morphological features (cells with vesicular enlarged nuclei and single prominent nucleolus). A high proliferative index with frequent apoptosis and focal necrosis was demonstrated. Immunohistochemistry of the peripancreatic specimen revealed neoplastic cells positive for BOB1, MUM1, and EBER-ISH, partially positive for CD79a, and negative for CD20, CD56, CD138, CD3, CD5, AE1/AE3, and HHV8, most consistent with plasmablastic lymphoma. A bone marrow biopsy was performed for staging purposes. It revealed normocellular marrow with maturing trilineage hematopoiesis with no evidence of excess blasts or lymphoma. Furthermore, lumber puncture cytology was negative for malignant cells and CSF flow cytometry did not show any abnormal cells; based on these findings, the patient was deemed as stage III.
Subsequently, epigastric pain improved with oral opioids and other pancreatitis-related symptoms resolved with the symptomatic treatment. The patient was discharged from the hospital with oncology out-patient follow-up. Therein, he was initiated on cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy. Central nervous system prophylaxis was achieved by employing intrathecal chemotherapy. Filgrastim (G-CSF) was administered twenty-four hours after CHOP cycles and was continued daily for seven days. Our patient tolerated the treatment well, with no significant interactions with HAART for his HIV-infection, and achieved remission after six cycles of chemotherapy. Contrast-enhanced CT at the level of pancreas 3 months after initiation of CHOP treatment demonstrated near complete resolution of previously seen soft tissue masses (). The patient has been disease-free for over a year now without any additional specific therapy.


A 21-year-old woman presented to the Emergency Service with pain and swelling of the right knee after twisting the knee while playing sport. The physical examination showed an effusion in the knee, sensitivity on palpation, and an inability to reach full extension. A direct radiograph showed a free bone fragment lateral to the lateral femoral condyle (Figures and ). Computed tomography (CT) showed an osteochondral defect in the patella inferomedially and a free fragment at the level of the lateral femoral condyle (). Obviously, the flake fracture was due to patella dislocation. The free fragment measured 25 × 16 mm; the bone was 4 mm thick and the cartilage was 3 mm thick. An intra-articular hematoma was aspirated and a long leg splint was applied with ice compression and elevation until surgery.
Spinal anesthesia was administered and, with the patient in a supine position, a pneumatic tourniquet was applied to the right leg. With a medial parapatellar incision, an arthrotomy was made and the osteochondral defect was explored. A 100-mL hematoma was drained and the joint was washed with saline. The patellar chondral defect and the ends of the fracture fragment were debrided (). The fracture was then reduced and osteosynthesis was applied with two headless compression screws (). Medial retinaculum was repaired primarily because it was incised during medial arthrotomy. The tight lateral side was loosened and when the patella appeared stable, the surgical procedure was terminated. After inserting a drain and applying a dressing, the operation was ended.
The patient was put in a long leg splint postoperatively. On the second day, the splint was exchanged with immobilizing brace, full weight-bearing was permitted, and quadriceps exercises were started. After 2 weeks, the degree of flexion was increased gradually and, in the 6th week, the brace was removed and open-chain exercises were continued. Four months postoperatively, full healing was seen clinically and radiologically and there was full-joint range of movement.
Five months postoperatively, the patient complained of stiffness in the knee and mild pain. The physical examination detected a feeling of friction under the anterior patella at early degrees of flexion. The patient's Knee injury and Osteoarthritis Outcome Score (KOOS) was 71; the score was limited mainly because of loss of function during high level activities. CT showed full healing at the osteotomy line (). It was thought that friction caused by the headless compression screws in the patellofemoral joint had led to cartilage destruction, so we decided to remove the screws. Intraoperatively, the fragment was stable and the cartilage surface was intact, but screws were palpable below the cartilage, so both screws were removed. There were no signs of screw loosening. Postoperatively, quadriceps strengthening exercises were started. Two months later, the final follow-up radiographs were evaluated as normal (), the joint range of movement was full, all of the complaints had resolved, and the KOOS was 91.


In March 2012, a healthy 50-year-old Caucasian male sustained a traumatic bifocal pertrochanteric and distal third shaft fracture of the left femur that was treated by another surgeon with a cephalomedullary long nail distally fixed with 2 screws. After 2 months, in May 2012, during the rehabilitation period, he suffered from the displacement of the fracture because of the loosening of the distal screws. He underwent a new operation by the same surgeon to reduce the displaced fracture and replace the distal screws. Six months after the last surgery, the fracture was still unconsolidated and he underwent pulsed electromagnetic fields and extracorporeal shockwaves therapy without success.
On February 2013, he referred to our department for persistent thigh pain and lameness that forced him to walk with a cane. The radiographic examination showed a hypertrophic nonunion of the distal femur (), refractory to the conservative treatment, which has been given an indication for surgical treatment. No limitation of the knee and hip range of movement was recorded. The limb was shortened to 3 cm.
Our first surgical choice was the revision of the nail and the bone reconstruction with a corticoperiosteal pedicled flap from the medial femoral condyle.
Before the surgery, a CT angiography is performed to study the vascularization of the distal femur. The antibiotic preoperative profilaxis with gentamicin 160 mg (1 hour before the surgery) and cefazolin 2 g (just before the surgery) is administered.
The patient was placed in supine position with the hip and knee slightly flexed and externally rotated. A tourniquet is inflated at the proximal thigh. The removal of the intramedullary nail and screws was performed through the previous surgical access and the recipient site was prepared by debriding the bone, excising all scarred tissues and reaming of the femoral canal. A longitudinal incision was made on the medial side of the distal third of the thigh. The vastus medialis was reflected anteriorly, whereas the tendon of the adductor longus was retracted posteriorly, exposing the medial femoral condyle and its periosteal blood supply (). The dominant vessel was identified and dissected to its source. The design of the graft was outlined on the periosteum. The periosteum was cut with an electrocautery. Large vessels were ligated with hemoclips or absorbable suture threads. Then, using an osteotome or an oscillating saw, the outer cortex was cut and lifted, hammering slightly from the periphery towards the center (Figures and ).
Simultaneously, the nail was removed from the femur bone and the recipient site was prepared by debriding the bone, excising all scarred tissues. The fracture was reduced and the osteosynthesis was performed by an anterograde intramedullary nail; the graft was overturned and wrapped around the nonunion and fixed with transbone stitches (). A radiograph was performed at the end of the procedure ().
Subcutaneous enoxaparin sodium (4000 UI) was administered as soon as the recovery of full weight bearing took place. Wound inspection was done on the first and third postoperative days. Knee and hip mobilization, quadriceps exercises, and touch-toe weight bearing were started from the third postoperative day using a frame or crutches. The patient was discharged after 7 days from the surgery and stitch removal was done on the 15th postoperative day. The patient was followed at monthly intervals up to six months, then at three monthly intervals up to one year, and then every six months up to the last follow-up. Radiological assessment was done by taking serial X-rays as needed.
Progressive to complete weight bearing was allowed on the 35th postoperative day after the appearance of callus on radiographs. The patient reached the complete weight bearing on the 60th postoperative day. We considered union to have occurred at 3.5 months of follow-up when radiologically anteroposterior and lateral radiographs showed bridging of at least three of the four bony cortices and clinically the patient was able to walk full weight bearing without any pain.
At the 20 months of follow-up, there was not recorded pain or excessive intoeing/out-toeing walking and the limb was shortened to 1.5 cm compared to the opposite leg. The radiographs showed complete union of the distal femur (). The patient was completely satisfied with the procedure.


An 83-year-old woman with Alzheimer's disease was brought to the hospital after an overdose of medication. She had mistaken benzodiazepines for candies and taken a one-month supply of the medication. On admission, she was on memantine 20 mg once a day and quetiapine 25 mg twice a day. Her Mini-Mental State Examination (MMSE) was 3. She was admitted for mental status change and vomiting. In the ward, she refused the care especially taking a shower. The patient was agitated and aggressive to nurses with conventional care. When she was provided a shower, it took 300.5 seconds and the patient spent 25% of care time manifesting aggressive behavior. When multimodal comprehensive care—Humanitude—was applied, the duration was 315.6 seconds and no aggressive behavior was observed all through the care episode. In the comparison of percentage of the modalities during care, eye contact was 1.7% in the conventional care and 19.5% in Humanitude, verbal communication was 19.7% and 73.9%, and touch was 0.2% and 60.4%, respectively (). Because of the improvement of her symptom, the dosage of quetiapine was reduced to 25 mg once a day.


A 93-year-old woman with Alzheimer's disease had complained of abdominal pain and was admitted to acute care hospital. Cutaneous abscesses of the abdominal wall were found and intravenous antibiotics were started. Her Activity of Daily Living was totally dependent with advanced dementia, and MMSE was not able to be obtained due to inability to communicate the questions. On admission the patient was on sulpiride 50 mg once a day and risperidone as needed basis. In the ward, she continued to scream and act violently. Nurses had difficulty providing care. She refused to change diapers and became increasingly aggressive to the nurses.
During diaper change, conventional care took 360.7 seconds and the patient spent 24.5% of care time evincing aggressive behavior. When Humanitude care was applied, it took 127.6 seconds to complete the care. There was no aggressive behavior and the patient accepted the care peacefully. In the comparison of percentage of the modalities during care, eye contact was 0% in conventional care and 4.3% in Humanitude care, verbal communication was 27.4% and 42.1%, and touch was 0% and 44.0%, respectively (). After the implementation of the care methodology, risperidone was no more needed.


An 89-year-old woman with Alzheimer's disease was admitted to the acute care hospital because of a urinary tract infection with bacteremia. Her MMSE was 11. Nurses had difficulty providing care. When they attempted to change the diaper with conventional care, she refused aggressively and the delivery of care failed. The attempt ended in 20.5 seconds and 66.3% of the time aggressive behavior was noted. The nurse gave up continuing the care.
When multimodal comprehensive care—Humanitude—was applied, the duration was 241.8 seconds and little (0.26%) aggressive behavior was observed. In the comparison of the modalities, eye contact was 0% in the conventional care and 13.7% in Humanitude, verbal communication was 0% and 48.5%, and touch was 0% and 29.2%, respectively ().


FG, 50 years old working man came to our outpatient headache clinic complaining of recurrent attacks of headaches.
When he was 16 years old he suddenly begun to suffer of unilateral right orbital and sopraorbital severe pain, without radiation. He had usually two attacks per day, each lasting from 30 min to 2 h, every day at the same time: 2 or 3 o’clock a.m. and 2 or 3 o’clock p.m. Throbbing pain was associated with ipsilateral lacrimation, conjunctival injection, ptosis, nasal stuffiness. Restlessness or pacing activity was always present. Patient denied to experienced aura, nausea, photophobia or phonophobia. The attacks were concentrated in cluster lasting about 1 month, usually during summer, when he was young, and preferentially during winter in adult life. He remembered to have had about a cluster period every year in the last decade. He was treated with ergot, flunarizine, injectable sumatriptan.
The patient did not report a family history of headache. He smoked 30 cigarettes per day, drank about five cups of short-coffee per day, and some glasses of wine at dinner. During the pain periods alcohol intake triggered the beginning of the headache. He had suffered of gastric ulceration treated with proton pump inhibitor (omeprazole) and he was taking antihypertensive drugs.
The patient came to our clinic nearly at the end of the cluster period, but complained a new kind of headache, pulsating in quality, located on the left side, left temple, eye, and forehead, with radiation to the nostril associated with lacrimation, nasal congestion, photophobia, and phonophobia. He did not refer restlessness. These headache initially lasted 90 min, starting at 11 p.m., almost every night, rarely he had attack at 4 p.m. In the course of the time the attacks began more frequent: 4–5/day lasting about 30 min. The patient strongly asserted the new headaches were different from his usual previous ones. He was experienced these new headaches from 2 months and drugs he was using for cluster headache (verapamil, injectable sumatriptan) gave no relief, such as other nonsteroidal anti-inflammatory drugs (i.e. nimesulide, ergot). Routine blood tests revealed slight hyperglycemias and hypercholesterolemia. MRI of the head was normal.
Indomethacin, 50 mg taken at night, before sleeping, dramatically interrupted the crisis. The patient stopped the drug because of gastritis; this led to the recurrence of the headache. A this time Indomethacin 50 mg/daily was not enough, and the dose of 50 mg tid was gradually titrated together with increase in gastric protection. In 2 weeks the patient was again pain-free.
Indotest was not performed due to non availability of parenteral indomethacin (Antonaci et al. ) He was in indomethacin for 1 month after the last attack, and he is now headache free from 24 months. The patient gave his informed consent to the writing of this paper.


Patient 1 was a 72-year-old woman. She complained about chest tightness, dyspnea and trachyphonia for 3 months. She had no fever, cough, expectoration or decompensation during the course of disease, except increased serum ferritin (663.6 μg/L). A contrast enhanced CT images of the chest revealed a well-defined mass of homogeneous attenuation in the superior middle mediastinum, and the mass measured 3.2 × 4.3 cm in diameter. An arborizing-pattern of coarse calcification was seen within the lesion (Fig. ). The mass compressed adjacent trachea, esophagus and superior vena cava. It had similar homogeneous enhancement as the adjacent great vessels on 18-Fluoro-deoxyglucose positron emission tomography (FDG PET)-CT images. Thoracoscopic biopsy was then performed. The oval and fusiform tumor cells were slightly atypia with eosinophilic cytoplasm, and large nuclei with obvious nucleoli and mitoses. Mixture of lymphocytes and neutrophils patchily infiltrated among neoplastic cells. Immunohistochemical analysis showed that the tumor cells were positive with CD21, CD23, CD35 and HLA-DR, focal positive for CD20 and CD163. Patients received radiotherapy alone without surgery, and died of the disease due to metastasis one year after the diagnosis.


Patient 2 was a 51-year-old woman presented with a history of chest tightness, chest pain, cough, expectoration and trachyphonia for 20 days. Serum ferritin was elevated to 234.4 μg/L. A contrast enhanced chest CT images revealed a well-defined 9.1 × 8.7 cm mass of homogeneous attenuation in the right superior middle mediastinum. A peripheral speckle-strip coarse calcification was seen within the lesion (Fig. ,). The mass was excised and sectioned for histological examination. The plump spindle tumor cells were diffusely proliferated and densely arranged with significantly atypia, large nuclei and mitoses. Moreover, significant lymphocytic infiltration was noted. Immunohistochemical staining showed positive expression of CD 21 and CD35 in tumor cells. Patients underwent thoracic resection of the tumor and received radiotherapy after the surgery. Patient died of the disease due to metastasis 10 months after the diagnosis.


Patient 3 was a 53-year-old woman who was admitted for a mediastinal mass found during annual physical examination. An unenhanced chest CT scan revealed a mass of 10.3 × 7.6 cm in the anterior mediastinum, with well-demarcated shallowly-lobulated soft tissue protruding to the left lung around several nodules (Fig. ). The entity was excised for histological examination. The tissue sections showed an intact capsule and fleshy pinkish white surface, bordering with the pericardium and bilateral mediastinal pleura, and several nodules around as well. Microscopically, the spindle tumor cells were in fascicular, swirling or diffusely irregular arrangement mixed with lymphocyte infiltration. Tumor cell nuclei were round, oval or fusiform, vacuolated with granular chromatin (Fig. ). Partial areas showed histological features characteristic of hyaline vascular Castleman’s disease. Moreover, the tumor cells were positive for CD21 (Fig. ) and CD35. The pathological diagnosis was mediastinal FDCS and hyaline vascular Castleman’s disease. Patient underwent surgical resection of the tumor without radiotherapy. Patient is still alive one and half years after surgery.


A 48-year-old male police officer was referred to a chiropractic clinic by a general practitioner for the evaluation of acute low back pain (LBP) of two weeks duration. The patient reported that the LBP had come on after spending a 12-h night shift driving a patrol car. The LBP was described as diffuse and the patient reported sharp pain radiating down the left lateral thigh to the knee. The average pain intensity was rated as 6/10 on a visual analogue scale (VAS), but had progressed to 8/10 VAS at the time of presentation. The symptoms were aggravated by sitting, sleeping on the left side, and inactivity; while standing provided the most relief. The pain was worse in the morning, and improved only marginally during the day. Self-care with heat packs and over-the-counter non-steroidal anti-inflammatory drugs (6 × 200 mg ibuprofen tablets per day) provided only a 2-point reduction on the VAS. The patient denied the presence of any paraesthesia (e.g. pins or needles), saddle anaesthesia, loss or changes in bladder or bowel control, fever, or nocturnal pain. The patient reported an approximately 20 kg reduction in body weight over the past 10 months, which he attributed to dietary changes and uptake of a substantial exercise regimen.
The patient also complained of left-sided headaches in the suboccipital and temporal regions of three weeks duration. The headaches were accompanied by occasional dizziness (clarified to be a feeling of unease) that were aggravated by sustained awkward neck postures. He had a family history of hypertension, type 2 diabetes, and migraines. His grandmother had passed away from bowel cancer. The patient was currently being treated for haemochromotosis, for which he had been managed successfully for 8 years. The rest of the systems review was unremarkable.
The physical examination revealed a marked antalgic posture to the right with limited active lumbar range of motion (ROM) in left lateral flexion and flexion (finger-to-floor reach was noted to be 2 cm above the knees). Coughing, sneezing, and Valsalva manoeuvre reproduced the LBP, but not the leg pain. Straight leg raise was positive for leg and back pain at 40° on the left and negative at 70° on the right. Bragard’s test was positive on the left, while slump test and well leg raise were negative. Deep tendon reflexes were normal (2+) in both upper and lower limbs, except for the patella reflex on the left which was slightly diminished (1+). There was no decreased sensation to pin prick or vibration sense in either the upper or lower limbs; however, sensation to light touch was slightly decreased in the left L4 dermatome. Motor and cranial nerve exams were unremarkable. Blood pressure was 152/92 mmHg and the resting heart rate was 75 bpm (measured in the sitting position).
The left temporal headache and dizziness (uneasiness) could be reproduced by combined flexion and 25° of rotation of the head to the right. The same manoeuvre on the contralateral side was pain free at 50° of rotation. There was marked tenderness to palpation over the left C2/3 zygapophysial joint and the lumbar spinous processes.
On the basis of the clinical presentation, history, and findings of the physical examination, a working diagnosis of posterolateral L3/4 intervertebral disc herniation affecting the left L4 nerve root was made, and a trial of conservative management was suggested to the patient. The patient also received a concurrent working diagnosis of cervicogenic headache. In addition, the patient was recommended to seek further evaluation of his blood pressure.
Conservative management consisted of cryotherapy (ice packs), high-velocity, low-amplitude spinal manipulation to the lumbar region, isometric stretching, and neurodynamic mobilisation techniques (neural flossing). This passive care was complemented by ergonomic advice and a prescribed back extension exercise program. The patient received a total of 6 treatments over a 4-week period. After this treatment regimen the patient reported the LBP to be 1-2/10 VAS, with no pain radiating down the left leg, and that he was able to perform all activities of daily living. Neurodynamic tension tests (e.g. straight leg raise and Bragard’s test) were negative. Lumbar spine ROM was improved (finger-to-floor reach 34 cm below the knees during flexion) and pain free.
The patient was discharged with a 4-week core muscle strengthening program and asked to return for a follow-up consultation after its completion, or earlier if symptoms returned. The patient returned asymptomatic after 4 weeks, and was able to satisfactorily perform the functional core strength tests.
Two months after the last follow-up of the first episode of LBP, the patient presented to the chiropractic clinic with a new episode of acute LBP with pain radiating down the left leg. Similar to the first episode, the patient reported that the LBP had come on after an 8-h shift of driving a patrol car. However, this time the leg pain was radiating down the anterior aspect of the left thigh to the knee. He was taking prescription pain killers as directed by his general practitioner (1–2 tablets of 5 mg oxycodone [Endone, Aspen Pharamceuticals] per 6 h). However, the medication provided minimal relief and the pain was unrelenting, worse at night, and interfering with his sleep. Bladder and bowel function was normal. The physical examination mirrored the initial presentation but for two findings: (1) light touch was decreased in the left L3 and L4 dermatomes, and (2) slump test produced left anterior thigh pain radiating down to the left knee and lateral leg to the foot.
Because the patient now presented with indications of the possible involvement of multiple lumbar nerve roots, severe pain waking him up at night, and not responding to strong prescription pain medication, he was referred for magnetic resonance imaging (MRI) for an evaluation of possible compression of neurological structures at the L2 to L4 vertebral levels.
The MRI revealed a substantial heterogeneous space-occupying lesion with an intramedullary orientation within the filum terminale at the L2/3 vertebral level (see Fig. ). The lesion measured approximately 2.5 cm × 1.2 cm in the craniocaudal and anterior-posterior dimensions, respectively. It appeared predominantly cystic on T2-weighted sequences and contained several fine internal septations. On post-contrast imaging, there was a heterogeneous enhancement of the lesion (predominantly peripheral), with a non-enhancing central aspect indicating a possible haemorrhagic or calcific component. The remainder of the spinal cord and conus medullaris appeared normal. Because the observed lesion most likely represented a myxoapapillary ependymoma, the patient was promptly referred for a neurosurgical consultation.
The patient was scheduled for surgery the day after the neurosurgical consultation. A gross total resection was achieved and radiological adjunctive therapy was not pursued. Although the patient reported resolution of the neurological symptoms immediately after the surgery, low-grade LBP (3/10 VAS), described as a dull ache, still persisted for several weeks post-surgery. The patient received standard, post-surgical rehabilitation with a hospital-based physiotherapist for 6 months post-surgery. In long-term follow-ups at 6 and 12 months post-surgery, the patient reported no pain (0/10 VAS), with only a vague sensation of persistent numbness in the left anterior leg.


A previously healthy, 19-year-old Caucasian man reported to his attending physician a recent odynophagia, left cervical pain, and fever. At this time, he was diagnosed with a nonbacterial pharyngitis (a rapid strep test was negative) and treated with acetaminophen.
Four days later, he was admitted to the Surgical Intensive Care Unit of a French University Hospital because of severe sepsis with persistent fever and asthenia. Physical examination revealed a high fever (39°6), a low blood pressure (78/40 mmHg) with diffuse mottles, and respiratory failure (SpO2 88% while breathing room air) associated with haemoptysis. The ear, nose, and throat examination was normal and a tender induration was found on the left and upper side of the neck. Laboratory test revealed a thrombopenia (14 G/L), a high white blood cell count (14.1 G/L), a moderate acute renal injury (creatinine of 97 µmol/L and urea of 11.5 mmol/L), and an elevated lactate serum of 1.8 mmol/L (normal value < 1.2 mmol/L). A chest and neck computed tomography (Figures and ) revealed a retropharyngeal abscess, an internal jugular vein thrombosis, bilateral lung infiltrates, and pleural effusions. Ceftriaxone associated with metronidazole and gentamicin was introduced right after blood cultures were drawn. Few hours later, severe sepsis regressed after consequent fluid administration and platelet transfusion. Only medical treatment was necessary since the abscess was too profound to reach. Fusobacterium necrophorum and Streptococcus constellatus were found in blood cultures. Initial antibiotic therapy was replaced by high doses of amoxicillin (8 g), clavulanate, and metronidazole. The patient left the unit for the Infectious Diseases Unit four days after admission. Anticoagulant treatment by heparin was initiated on the fifth day when thrombopenia was corrected. Oral anticoagulant was introduced secondarily. Apyrexia was obtained on the seventeenth day. Antibiotic therapy was maintained for three weeks.
One month later, pulmonary nodules had mostly regressed on the lung computed tomography. Recanalization of the internal jugular vein happened only ten weeks after anticoagulant treatment was introduced.


A 77-year-old Japanese man with a 20-pack-year history of cigarette smoking also had a history of asbestos exposure while working in the construction industry between the ages of 40 and 65. He was admitted to our hospital complaining of coughing, sputum and breathlessness, which had developed gradually. A chest X-ray of his left lung demonstrated an abnormal shadow, and chest computed tomography (CT) revealed left pleural effusion, diffuse pleural thickening and infiltrates with cavitations in the left lung. The levels of all serum tumor markers examined, including carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), squamous cell carcinoma antigen (SCC), neuron-specific enolase (NSE), cytokeratin fragment (CYFRA), and pro-gastrin-releasing peptide (Pro-GRP), were within the normal ranges. Cytological examination of the left pleural effusion detected malignant mesothelial cells, and a preoperative clinical diagnosis of MPM was made. Chest and abdominal CT imaging demonstrated no detectable distant metastasis. Left extrapleural pneumonectomy was performed.
Cross-sectional examination of the resected specimen showed that the left lung was widely covered by diffuse pleural thickening confluent with the multinodular grayish-white solid tumor (Fig. ). The tumor involved both the parietal and visceral pleurae, invading the diaphragm and mediastinal tissues surrounding the thoracic aorta. In the close vicinity of this major pleural tumor described above, an intrapulmonary tumor was found in the lower lobe (Fig. ). This latter tumor had an ill-defined border and a gray-white cut surface. This intrapulmonary tumor had not been demonstrated in the preoperative imaging work-up.
Histologically, these two tumors showed distinct features. The pleural tumor was composed of neoplastic cells growing in a tubulopapillary pattern, or in solid sheets or nests in some areas (Fig. ). Most of the papillae were covered by a single layer of cuboidal tumor cells, and the pseudoglands were lined by similar cells, often with a solid growth pattern. These histologic findings were conclusive of MPM, epithelioid type. On the other hand, the intrapulmonary tumor was composed of neoplastic cells showing lepidic growth in the peripheral portion, and papillary or acinar invasive growth patterns in the central portion (Fig. ). Its stroma varied from fibrous to desmoplastic. These findings suggested a diagnosis of PAC, which is invasive adenocarcinoma, lepidic predominant (lepidic 60 %, papillary 30 %, acinar 10 %) according to Sica’s classification []. The two tumors, MPM and PAC, collided within the same lower lobe of the left lung (Fig. , ). Asbestos bodies were detected rather easily in HE-stained sections of the subpleural or peribronchial non-tumorous lung parenchyma.
Immunohistochemistry (IHC) showed that the cells in the pleural tumor were positive for calretinin and D2-40, but negative for TTF-1 and Ber-EP4 (Fig. , ), being consistent with the diagnosis of epithelioid-type MPM. In contrast, the cells in the intrapulmonary tumor were positive for TTF-1 and Ber-EP4, but negative for calretinin and D2-40 (Fig. , ), thus confirming that the latter tumor was PAC.
The results of our various examinations allowed us to make a final diagnosis of collision tumor consisting of two lesions: epithelioid-type MPM, and PAC. Molecular testing performed on the PAC showed negativity for EGFR, KRAS/NRAS/BRAF gene mutations and ALK fusion protein.


A 25-year-old woman (gravida 0, para 0) presented with a 4-year history of an asymptomatic pelvic mass that had increased in size in the previous few months. The women had an unremarkable medical and gynecological history with a regular menstrual cycle.
Ultrasonography confirmed the presence of a hypoechoic cystic mass of undetermined origin. Further evaluation was performed, including laboratory tests and computed tomography (CT). The serum level of CA 125 was found to be elevated (139.0 U/mL), and a CT scan revealed tumors in both the ovaries. The right ovary showed a 7.0 × 4.5 cm fat-containing cystic mass with internal calcification, and the left ovary showed 16.0 × 14.0 cm fat-containing cystic mass with multiple septa and internal calcification (Fig. ). The radiologic findings suggested that both the ovarian tumors were mature teratomas, and the patient underwent bilateral ovarian cystectomy. Macroscopically, the left ovary revealed a multicystic mass containing viscous sebaceous material and hairs, measuring 20.0 × 12.0 × 7.5 cm. The cystic wall also contained adipose and bony tissue. Similarly, the right ovary showed a cystic mass filled with sebum and hairs, measuring 6.5 × 5.0 × 4.0 cm. Frozen sections of the left ovarian mass were made. On microscopic examination, mature squamous and respiratory epithelium, as well as mesenchymal tissue including the bone, cartilage, smooth muscle, and adipose tissue were observed. In addition, abundant brain tissue, such as glial tissue and choroid plexus, were observed. Through the frozen sections, the left ovarian mass was diagnosed as MCT, and therefore, no further intervention was performed at the time of the operation.
However, formalin-fixed, paraffin-embedded multiple sections of the left ovary revealed an incidental microscopic focus that displayed a monomorphic population of polygonal cells beneath the respiratory epithelium. The focus measured 0.5 cm in diameter and was not observed in the frozen sections. The tumor cells formed cords and trabeculae and had scant, eosinophilic cytoplasm, and round nuclei with mild atypia (Fig. ). Immunohistochemical staining showed positivity for neuro-specific enolase (NSE), synaptophysin, and CD56 (Fig. ). One mitosis was seen per 10 high-power fields, and the Ki-67 proliferative index was 1 % (Fig. ). Therefore, the tumor was classified as low grade. Based on the morphological and immunohistochemical findings, the tumor was diagnosed as a carcinoid tumor (trabecular type) arising from a MCT. The right ovary, on the other hand, had no evidence of somatic type tumors.
The patient received no further treatment. And she had no clinical symptoms associated with carcinoid syndrome including cardiac involvement that might be a major cause of death in this syndrome, so cardiac ultrasound had not performed. Also, no evidence of recurrence or metastasis was detected on abdomen and pelvic computer tomography (CT) after 8 months of follow-up.


A 51-year-old Caucasian woman initially consulted for right visual loss (2/10, with corrective lenses) and central scotoma demonstrated with perimetry. Visual evoked potentials confirmed the altered conduction of the right optic nerve. In the absence of any other obvious neurologic symptoms and signs, optic neuritis was suspected. An initial MRI scan showed right tortuous optic nerve enlargement with a peripherally increased signal on fluid-attenuated inversion recovery (Fig. ) and on coronal T2-weighted fat-suppressed (Fig. ) sequences. Therefore, uniform contrast enhancement (Fig. and ) affected the last third of the nerve.
Three months later, follow-up MRI demonstrated the persistent signal abnormalities on MRI. A comprehensive biological workup including lumbar puncture – initially refused by the patient – showed no abnormal results, and an ONSM was suspected.
SPECT/CT was performed 24 h after injection of 180 MBq [111In]-pentetreotide and showed an intense uptake in the last third of the intraorbital right optic nerve (Fig. and ) corresponding to the contrast enhancement on the MRI scan. After this confirmation, she was referred to the radiotherapy center for stereotaxic radiotherapy. A treatment consisting in 30 sessions of stereotaxic radiotherapy was planned. Our patient received a total of 54 Gy by photons of 6 MeV (1.8 Gy per session), which was well tolerated. The 1-year clinical follow-up was positive with disappearance of the Marcus Gunn pupil sign, better visual acuity (7/10, with corrective lenses), and stability on MRI imaging.
Although meningiomas are common intracranial tumors, ONSMs as a specific subset are infrequent, accounting for only 1–2 % of all meningiomas []. Since morphological imaging techniques have their limitations in differentiating meningiomas from other tumors of the optic pathway [, , , ], an alternative method was added to detect whether this lesion expressed somatostatin receptors. Thus SPECT/CT or positron emission tomography/computed tomography (PET/CT) imaging with somatostatin analog radiotracers are highly effective methods for detection of meningiomas [–].
In accordance with a few studies on ONSMs [, ], the case reported herein showed an intense uptake of [111In]-pentetreotide in the last third of the intraorbital right optic nerve (Fig. , , and ), as well as physiological pituitary uptake (Fig. and ). This radiotracer presents a very high affinity for somatostatin receptor subtype 2 with high sensitivity and specificity, as well as [111In]-octreotide. There have also been reports on using somatostatin to treat intracranial meningiomas and monitor the efficacy of the treatment [].
Consequently, this imaging technique provides good proof so that the exact origin of certain optic nerve tumors can be identified, especially and specifically in cases of very small tumors, in order to avoid biopsy and give the best treatment available quickly. In the majority of ONSMs involving the orbit, complete surgical resection is not possible and the results of surgical decompression are poor, despite the natural progression of diseases with progressive visual loss []. The diagnosis of ONSM is a crucial one, because modern surgical and/or radiotherapy approaches at an early stage may allow total resection and improve the chances of preserving vision [, , –]. For this reason, our patient could be treated with the best adapted procedure, resulting in better visual acuity. This technique with multimodal imaging provided positive identification rapidly, and our patient was spared more permanent visual damage or intracranial growth. A surgical approach was not adapted and presented a risk in this case due to the location and the small size.
This case supports other studies [, ] that have demonstrated a high [111In]-pentetreotide uptake by ONSMs, and shows the importance of making an early and noninvasive diagnosis compared to other orbital lesions, that is, optic nerve gliomas, optic nerve inflammation, non-Hodgkin lymphomas, vascular lesions, and sarcoidosis [, ]. In the present case, it was the most effective method to reverse the initial diagnosis of optic neuritis.


At 35th weeks of gestational age (mother 19-year-old, primigravida), a baby girl was delivered via emergency C/S for intrauterine growth retardation and suspicion of strangulation of eviscerated bowel through anterior abdominal wall defect. Her birth weight was 1900 gms and Apgar score was 9 at 1st minute. On examination she had a ruptured exomphalos sac with parts of stomach, small and large intestines lying outside the abdomen (Fig. 1). Protruded bowel was dusky but improved after resuscitation. There was no thickening or matting of bowel. At operation, there was rupture of exomphalos sac measuring 3x3 cm in diameter. Bowel was reduced easily after milking out meconium through anus and primary repair done with umbilicoplasty. She was kept electively ventilated. On postoperative D-2 baby developed abdominal distension and deterioration of her general condition. An emergent abdominal x-ray revealed pneumoperitoneum. Emergency laparotomy done through supra-umbilical transverse incision showed a stomach perforation of 1x1 cm size at the fundus (Fig. 2). Primary repair of perforation was done after ruling out distal obstruction. Baby was extubated from ventilatory support after 2 days and had a speedy recovery. She was discharged in good clinical condition.