A 15-month-old female patient born at term, small for gestational age, the second daughter of non-consanguineous parents was referred to the Bambino Gesù Children Hospital for macroscopic hematuria due to a large renal neoplasm in a solitary pelvic cake kidney.
Laboratory tests showed mild renal failure (creatinine 1.37 mg/dl, BUN 46 mg/dl), normocytic anemia (Hb 7.5 g/dl; MCV 77 fl), hyperuricemia (8.4 mg/dl) and increased LDH (1963 UI/dl). Hypertension (both diastolic and systolic blood pressure exceeding the 90th percentile) required pharmacological treatment.
Physical examination revealed growth retardation (both weight and height lower than 3rd percentile), abnormal skin pigmentation (both café au lait spots and hypopigmentation), elfin facies with epicanthus. Echocardiography showed a mitral valve insufficiency. The patient also had right-convex scoliosis and ribs anomalies. A clinical suspect of FA was formulated and a DEB-test was performed which showed multiple spontaneous and DEB-induced chromosomal breaks per cell. Radiologic tumor assessment confirmed the presence of a renal neoplasm (78.1 × 42.2 × 62.8 mm) (Additional file : Figure S1a) with bilateral lung metastases (Additional file : Figure S1b).
Neoadjuvant chemotherapy was started, according to SIOP WT 2001 protocol, obtaining a partial response on both primary tumor (44 × 33 × 22 mm) (Additional file : Figure S1c) and metastatic lesions. Despite dose-adapted chemotherapy, chosen considering chromosomal fragility and according to renal function, the child experienced a grade-IV hematological toxicity and respiratory failure requiring admission to the intensive care unit. Afterwards, tumorectomy was performed, sparing residual renal functioning tissue. Histologic analysis confirmed a grade-III nephroblastoma, according to SIOP 2001 classification []. Post-surgical chemotherapy was resumed until completion of the protocol. At that point, a single residual lung metastasis was present and therefore resected by thoracotomy with no significant complications. Follow up confirmed stable remission with a mild chronic renal failure.
At the age of 35 months the child was seen with headache and vomiting at the emergency room. A brain computed tomography (CT) scan showed a left cerebellar hemispheric lesion exerting significant mass effect on the fourth ventricle. Cranio-spinal magnetic resonance imaging (MRI) confirmed a localized rounded heterogeneously enhancing mass with intralesional cystic components and perilesional edema (Fig. a-f). Cytologic evaluation of the cerebrospinal fluid resulted negative for neoplastic cells. Gross total resection of the lesion was performed.
Histology showed a neoplasm with an expanded lobular architecture, due to the reticulin-free zones rich in neuropil-like tissue. Such zones contained a population of small cells with rounded nuclei diagnostic of a desmoplastic/nodular medulloblastoma (Fig. ) without C/N-myc amplification evaluated by FISH analysis. Due to previous clinical history and to the persistence of a mild chronic renal failure, a tailored chemotherapeutic regimen with Carboplatin and Vincristine was chosen. Despite the low dose of chemotherapy employed, the patient presented a significant toxicity after the first course of treatment including pancytopenia (WHO grade IV), sepsis and deterioration of renal function that slowly recovered in 3 months. Considering this relevant toxicity no further treatment was offered.
At a follow-up MRI, 17 months after the previous surgery for MB, a midline cerebellar mass was detected (Fig. a-d). Complete surgical resection was performed, and histology showed a large cell neoplasm with vesicular nuclei, prominent nucleoli and variably abundant eosinophilic cytoplasm consistent with large cell/anaplastic MB (Fig. ). FISH analysis showed N-myc amplified medulloblastoma cells (Fig. ). One month after surgery, a local recurrence with leptomeningeal dissemination was documented.
Considering the toxicity shown during previous treatments, an evaluation of target molecular expression on the tumor was performed. Based on the evidence of expression of P-mTor, a personalized treatment with rapamycin [] associated with intrathecal liposomal cytarabine [] was started. Despite therapy, patient died of relapse and disease progression two months after the diagnosis of the second MB at 55 months of age.
Based on published data, the onset of MB after a WT in this FA patient raised the suspicion of a biallelic mutation in FANCD1/BRCA2. To confirm this hypothesis, we performed a genetic analysis of FANC1/BRCA2 on patient’s DNA extracted from both from peripheral blood and MB1 cells, which revealed the presence of compound heterozygosis for BRCA2 frameshift mutations.
Gene-specific BRCA2 analysis, including sequencing of all translated exons and adjacent intronic regions of the BRCA2 gene, was performed on the DNA samples. Both the truncating and novel genetic variants were confirmed by sequencing two different blood samples on both DNA strands. Sequencing was performed using an ABI PRISM DyeDeoxy Terminator Cycle Sequencing Kit and an ABI 3100 Genetic Analyzer (Thermo Fisher Scientific, Waltham, MA USA). Reference sequence for BRCA2: Genebank, NM_000059.1. By this mean, we revealed a compound heterozigosity for two distinct framshift mutations: the already described c.658_659delGT (p.Val220Ilefs) mutation on BRCA2 exon 8, and a previously unknown c.2944_2944delA (p.Ile982Tyrfs) mutation on BRCA2 exon 11 (Fig. )a and b, both of which are predicted to lead to truncated BRCA2 proteins. Genetic testing of the parents confirmed they both were heterozygous carriers; in particular, the father carried the c.658_659delGT mutation, while the mother carried the c.2944_2944delA mutation (Fig. ). Further analysis of the pedigree suggested the segregation of the mutations in the paternal grandfather and in the maternal grandmother, not affected by cancer. The original donor of the new mutation could be the mother’s maternal grandfather affected with pancreatic cancer, which belongs to the spectrum of FA/BRCA-associated tumors (Fig. ). Overall, the genealogical chart was characterized by a low occurrence of tumors both in paternal and maternal families and in particular by the absence of breast and ovarian cancer cases (Fig. ). Analysis of the MB1 tumor tissue from the affected child revealed heterozygosis for both alleles, thus suggesting both of them are selected for in tumor development.
We performed gene expression analysis of both hemispheric MB1 and vermian MB2 by real-time quantitative PCR (RT-QPCR). We used TaqMan Low Density Array custom designed with TaqMan assays (Life Technologies - Thermo Fisher Scientific, Waltham, MA USA) for genes of interest for medulloblastoma subgrouping, according to Northcott 2012 [, ], while we used single TaqMan assay (Life Technologies - Thermo Fisher Scientific, Waltham, MA USA) for all other shown mRNA analyses []. Gene expression analysis on samples was performed using a ViiA7 sequence detection system according to the manufacturer’s instructions. RNA of normal human cerebellum (7 adult samples from 25- to 70-year-old subjects were purchased from Biocat (Heidelberg, Germany), Ambion (Life Technologies - Thermo Fisher Scientific, Waltham, MA USA) and BD Biosciences (San Jose, CA) [].
Unsupervised clustering and heatmaps were generated using the analyzed transcript levels expressed as Delta Ct values as input. We used Spotfire software (TIBCO Software, Inc. CA, USA) to cluster the samples and to generate the heatmaps, as previously described [, ].
The results showed a clear Sonic-hedgehog (SHH) molecular subgroup for MB1 (Fig. a and Additional file : Figure S2) while MB2, though characterized as SHH-MB, was found to express genes associated with group 3 and 4 MBs (such as GABRA5, KHDRBS2 - Fig. ).
Further analysis showed gene expression differences between the two MBs. Gli1, the transcription factor of the Hedgehog (Hh) pathway, was highly expressed in MB1, together with all its downstream targets (PTCH1, PTCH2, IGF2, HHIP, SFRP1, CCND1) (Fig. ); while MB2 showed lower levels of Gli1 and its target genes (Fig. ). Conversely, Gli2 was highly expressed in MB2 (Fig. ), while CCND2 was expressed at very low levels (Fig. ). Of note, N-myc amplification was only found in MB2 (Fig. and Fig. ). Moreover, differences were found in the expression of stem cell/differentiation genes: MB2 was characterized by low expression of lineage differentiation genes (ZIC1, BMP2, GFAP, GABRA6) (Fig. ) accompanied by expression of stemness genes, such as PROM1 and C-MYC (Fig. ), when compared to MB1.
Genes associated with chromatin modifications, such as histone methylases/demethylases and polycomb (EZH2, KDM6B, KDM6A, BMI1) and the homeobox transcription factor OTX2 [], were also evaluated. Indeed, large cell/anaplastic MB2 showed higher levels of EZH2, OTX2 and KDM6B and lower levels of KDM6A and BMI1 (Fig. ).
Finally, hemispheric localization of MB is rare in infancy, while is common in adulthood. Moreover, despite the common activation of Hh signaling, infant, childhood and adult SHH MBs have been demonstrated to be clinically, transcriptionally, genetically and prognostically distinct [, ].
Thus, we investigated the gene expression pattern of MB1 and MB2, compared to adult, childhood and infant sporadic SHH-MBs. We analyzed a panel of genes by RT-QPCR among the top 250 reported to be differentially expressed in the three classes of ages []. Our data are consistent with those reported by Kool 2014 that identified two major clusters mainly separating infant from childhood and adult SHH MBs. Moreover, our analysis showed that hemispheric MB1 (diagnosed under 3 years of age) clustered with adult/childhood MBs (Fig. ), while vermian MB2 (diagnosed after 3 years of age) clustered with infant SHH MBs (Fig. ).
This analysis allowed us to better define features of MBs in FA. We identified a new pathogenetic germline BRCA2 mutation in FA; both MBs belonged to SHH molecular subgroup with a more “aggressive” phenotype in MB2, and, finally, we documented that MB1 shared similarities with sporadic adult SHH-MB, such as hemispheric localization and gene expression pattern.
In our patient, the first manifestation that led to the diagnosis of FA was the onset of WT.
WT and MB in FA have been reported in few cases and are associated with mutations of FANCD1/BRCA2 and more rarely with mutations of FANCN/PALB2 [, ]. Based on this evidence, we investigated BRCA2 mutational status and confirmed the presence of biallelic truncating mutations in the FA patient. The c.658_659delGT mutation occurring on BRCA2 exon 8 had been previously reported in hereditary breast/ovarian cancer cohorts (see in example []) and is one of the most frequently occurring in FANCD1/BRCA2 mutated FA cases []. The second truncating mutation, the previously undescribed c.2944_2944delA (p.Ile982Tyrfs), occurs on BRCA2 exon 11. The segregation analysis among the available relatives allowed us to assign the two mutations as of paternal and maternal origin, respectively. The absence of breast and ovarian cancer cases in the pedigree could appear surprising, at first. However, both paternal and maternal sides of the tree were characterized by a relatively small number of potential female carriers. Indeed, the c.658_659delGT allele was inherited by the patient via two male carriers (father and grandfather) and the only female member on this line (affected by gastric cancer) was not available for segregation analysis. The c.2944_2944delA allele, possibly coming from the mother’s maternal grandfather affected with pancreatic cancer, reached the patients via a 64 years old grandmother and a 36 years old mother, a female carrier of rather young age compared to 43 and 54 years, the mean ages of breast and ovarian cancer diagnosis, respectively, recently reported in a very large cohort analysis []. The preponderance of male relatives in this side of the tree further hindered any possible speculation on the role of the c.2944_2944delA on breast and ovarian cancer predisposition.
Complete BRCA1 or BRCA2 loss is lethal in mice []. This is likely to be the case also in humans, since no biallelic BRCA2 mutations occurring 5′ to exon 7 have been reported in FA patients so far, while monoallelic truncating mutations from exon 2 to exon 7 have been frequently associated with breast/ovarian cancer susceptibility. In three out of four FA patients, the c.658_659delGT mutation occurred in association with a truncating mutations of exon 11 []. This is also the case for the patient described here, in which the c.658_659delGT mutation is associated with a truncating mutation of BRCA2 exon 11, the previously undescribed c.2944_2944delA (p.Ile982Tyrfs) mutation. Overall, these data suggest that BRCA2 truncation downstream of exon 7/8 is probably hypomorphic, but still compatible with life especially in association with exon 11 truncated BRCA2 forms. However, as already noticed by Meyer, homozygous or compound heterozygous exon 11 mutations have not been reported in FA patients despite the relatively high frequency of these alleles. Together with the report of the recurrent miscarriages in Jewish BRCA2 mutation carriers [], this suggests that biallelic exon 11 BRCA2 mutation may also be incompatible with life. More definitive answers on this topic may come from directly addressing this issue in specifically modeled mice.
MB in FA patients reported in the literature typically show cerebellar hemispheric localization and desmoplastic histology, as we observed in MB1 (Table ). Cerebellar hemispheric MBs are frequently desmoplastic and belong to the SHH subgroup, especially in adults []. Hemispheric location is consistent with the results from MB mouse models that have shown SHH-MB origin from committed granule neuron precursors (GNPs) of the cerebellum. Teo et al., reported hemispheric involvement in 9 of 17 (53 %) SHH-MBs, regardless of age at diagnosis []. In Perreault study [], SHH lesions rarely invaded the brain stem, consistent with a prior study that reported brain stem infiltration by WNT, but not by SHH tumors [].
Gene expression analysis of our MBs allowed us to clearly define that both MB1 and MB2 belonged to SHH subgroup.
Biological explanation of the association between FA and SHH-MB has been analyzed in different papers. Frappart et al. first showed that BRCA2 loss affects neurogenesis and promotes MB growth, using a mouse model harboring neural tissue-restricted BRCA2 inactivation []. They also identified PTCH1 (a gatekeeper gene often inactivated in MB) as a critical target in all DNA repair-deficient MB.
Indeed, defective DNA repair mechanisms render FA cells prone to DNA interstrand crosslinks (ICLs) caused by both endogenous (e.g. reactive aldehydes) and exogenous agents (e.g. alkylating chemotherapeutic drugs) [, , , ]. The FA pathway is activated by an ICL during the S phase: the replication fork is stalled and FA core complex is recruited (FANCA, B, C, E, F, G, L, and M). Then, FANCL ubiquitinates the FANCD2-FANCI (ID2) complex, essential for nucleolytic incisions and translesion synthesis repair events. The complex then “unhooks” ICL, allowing homologous recombination repair by FANCD1/BRCA2, FANCJ/BRIP1, FANCN/PALB2, FANCO/RAD51C, and FANCS/BRCA1 (Fig. ).
Huang et al. reported that conditional knockdown BCCIP (BRCA2-interacting protein with a role in homologous recombination and chromosome stability) in concomitance with p53 deletion caused rapid development of MB in the external granular layer, triggered by SHH pathway activation [] via the inactivation of the Ptch1 gatekeeper tumor suppressor []. As reported above, biallelic PALB2/FANCN mutation carriers show a cancer spectrum comparable to those with biallelic BRCA2/FANCD1, characterized by early onset AML and embryonic tumors, including MB and WT []. This observation strengthens the role of BRCA2 in medulloblastomagenesis, since FANCN (also known as ‘partner and localizer of BRCA2′, PALB2) is well known to co-localize with BRCA2 in the nucleus []. Interestingly, BRIP1/FANCJ maps on 17q chromosome, a region frequently deleted in MBs []. Thus, deleterious mutations in one of the members of the homologous recombination machinery could lead to MB onset (Fig. ). This feature may provide the rationale for new therapeutic approaches for MB, as also suggested by Bayrakli et al. []. Platinum compounds or similar drugs, inducing growth arrest by ICL-stalled- DNA replication fork, could be combined with agents which take advantage of the incapacity of HR-deficient neoplastic cells to face up this stall (e.g. enzyme poly-ADP-ribose polymerase I) []. Indeed, PARP- inhibition has already been shown to sensitize childhood glioma, medulloblastoma and ependymoma to radiation [].
It has been reported that MBs do not change subgroup at the time of recurrence and that SHH tumors more frequently have tumor bed recurrence than metastatic dissemination [–]. Even though we cannot completely rule out that the second MB was not a distant relapse from the first one, in our patient, the occurrence of MB2 with a different localization, a more aggressive histology, and distinct gene expression patterns could be suggestive for a second tumor. We hypothesize that Hedgehog signaling activation could have been triggered in two distinct cells of origin. Indeed, MBs have long been known to arise in GNPs in the external granule layer (EGL) and, more recently, GNPs derived from cochlear nuclei of the brainstem []. SHH-dependent MBs may also arise from neural stem cells (NSCs) of the subventricular zone (SVZ). The different tumor location and expression levels of stemness/differentiation genes sustain this assumption. MB2 was characterized by higher levels of EZH2, which trimethylates histone 3 lysine 27 (H3K27me3), concurrently with down regulation of the lysine demethylase 6A (KDM6A), which removes the same repressive mark on chromatin (Fig. e). Both these events converge on shutting off oncosuppressor/differentiation genes and contribute to the maintenance of a more “cancer stem-like” phenotype [, ].
It has been reported that pediatric and adult SHH-MBs are clinically and molecularly distinct [, ]. In a data analysis based on Whole Genome Sequencing Kool et al. reported that the molecular differences among infant, childhood and adult SHH-MBs reside not only at the transcriptional level, but also in DNA methylation [].
In our report, we found that the hemispheric, desmoplastic, myc-not amplified SHH MB1 was more similar to other adult/childhood SHH-MBs, while the vermian, large cell/anaplastic, N-myc amplified MB2 was more similar to infant SHH-MB. The hypothesis of different cells of origin stands also for such differences between adults and infants SHH-MBs.
Lastly, the suspect of SHH-MB in FA could direct the therapy toward a tailored approach, based on the use of PARP inhibitors or/and SHH inhibitors. However, giving the specific genetic background (BRCA2), it is highly unlikely that these tumors have PTCH1 or SMO mutations making them sensitive to the ‘upstream’ Hedgehog inhibitors targeting SMO. It is more likely that they have activated the SHH pathway more downstream at the level of MYCN and probably also GLI2 amplification (as probably in our MB2). Indeed, as Kool et al. have shown in their recent paper, these tumors are resistant to these ‘upstream’ Hedgehog inhibitors []. Inhibitors that target downstream components of the Hh pathway are under pre-clinical evaluation [] (e.g. Gant61 [], Glabrescione B []).


A 45-year-old male presented to our clinic suffering from a four-month history of abdominal pain. Further questioning revealed that he had eaten hunted rabbit meat on numerous occasions and unintentionally ingested three lead pellets. The physical examination revealed tenderness in the right iliac fossa, but no signs of peritonitis. The lead levels were analyzed, since lead poisoning was considered in the differential diagnosis. All laboratory parameters, including lead levels, were normal, and the patient was afebrile. Plain abdominal films and a barium enema revealed foreign bodies in the right lower abdominal quadrant (). Since the lead pellets were thought to have migrated extraluminally, we removed them with laparotomy under fluoroscopic guidance. The foreign bodies were found in the appendix vermiformis. An appendectomy was performed. Pathologically, three lead pellets were embedded in the appendix and there were signs of intramucosal inflammation (). The patient was discharged on postoperative day 2 without complications. Three months later, he had recovered completely.


A 28-year-old male presented to the emergency department with severe fatigue and inability to move his limbs since 6 hours. He had a history of severe, nonbloody diarrhea (10–20 times/day) with frequent vomiting since 2 days. On examination, he was severely dehydrated, with a heart rate of 130 beats per minute, blood pressure of 80/50 mmHg, and temperature of 38.6°C. There were severe muscle weakness and muscle tenderness. Abdomen examination showed a superficial generalized tenderness.
Laboratory work-up showed deranged renal functions with blood urea nitrogen (BUN) 106 mg/dL, serum creatinine (Cr) of 5.32 mg/dL, and BUN : Cr ratio of 20.2. His urine osmolality was low (259 mosmol/L) and serum osmolality was high (290.1 mosmol/L) with urine/plasma osmolality ratio of 0.8 and urinary spot Na+ of 81 mmol/L. Urine analysis tested positive for pigmented casts. His serum creatinine phosphokinase (CPK) level was significantly high and has almost doubled after 6 hours ( and ).
His ECG showed sinus tachycardia and the PR interval was strikingly depressed and prolonged (). His cardiac markers were markedly elevated ( and ). An emergency bedside echocardiography was done to look for evidence of acute myocardial infarction given the patient's presentation with shock and elevated cardiac marker. His echo showed generalized hypokinesia of the left ventricle wall with preserved left ventricular systolic function and normal cavity size. There were no regional wall motion abnormalities ().
The patient got admitted to the intensive care unit. He was resuscitated with intravenous fluid therapy along with intravenous antibiotics. A central venous catheter and a urinary catheter were inserted to monitor the fluid balance and delivering IV medications. Patient was started, after sending cultures, on empirical antibiotic therapy with Metronidazole, Meropenem, and Levofloxacin. He needed 17 liters of fluid to maintain his hemodynamics.
His stool analysis showed numerous pus cells, and his subsequent stool culture was positive for Salmonella enteritidis and negative for Rotavirus Ag, Adenovirus, and Clostridium difficile toxin antigen. Salmonella enteritidis was also grown in blood cultures. Arterial blood gas (ABG) analysis showed significant anion gap metabolic acidosis with calculated serum anion gap of 16 which was significantly high.
The patient responded well to the medical management. As his cardiac markers showed a downward trend, no additional cardiac medications were given during his in-hospital stay. His renal parameters, CPK, and cardiac enzymes showed a downward trend during the next 4 days. He was discharged home on the fifth day. Two weeks later, follow-up echocardiography and ECG were normal and cardiac markers showed normalization (). He was advised to do regular checkups at the cardiology clinic looking for long-term complications such as cardiomyopathy. To date, the patient is doing well and leading a normal life.


Our patient is a 67-year-old Hispanic male who presented to our hospital for the chief complaint of progressive worsening of shortness of breath of 3 weeks duration and was admitted for acute respiratory distress due to interstitial lung disease of unknown etiology. His medical history includes coronary artery disease, status postpercutaneous coronary intervention in 2010, hypertension, hyperlipidemia, and diabetes mellitus type 2. He has a significant smoking history of 20 to 30 pack-years and a significant history of alcohol drinking consuming 12 cans of beer per day for 30 years. He has quit smoking and drinking for 10 to 15 years. He works as a janitor and has no significant occupational exposure to asbestos or silicone.
Six months prior to the day of admission, the patient had complaints of dry cough for which he visited his primary care physician and was prescribed over-the-counter cough suppressants with no relief. The patient had a chest X-ray done at this time which showed mild hazy changes in bilateral lung fields (). The patient continued to have dry cough and eventually developed progressive shortness of breath with no dyspnea at rest. The patient continued to ignore his symptoms until few weeks prior to the day of admission he had significant shortness of breath to the point to which he could not walk to the bathroom in his house. Concerned of this he came to the hospital for further evaluation.
In the ED, the patient was brought in by his daughter and he had significant shortness of breath during ambulation which caused him to rest after every few steps. His initial SpO2 on room air was 77% and he was put on 3-litre O2 on nasal canula and his SpO2 improved to 93%. His blood pressure was 134/76 mm of hg, heart rate was 78/min, and respiratory rate was 22/min. On physical examination the patient was awake, alert and oriented, his neck was supple with no jugular venous distension, his heart sounds were audible with no murmurs or gallops, and auscultation of his chest revealed bilateral breath sounds with significant velcro rales on all the lung fields bilaterally. Abdomen was soft and nontender and the patient had no focal neurological deficits. Examination of his extremities revealed no pedal edema but grade 3 clubbing of his finger nails. The patient denied fever, chills, hemoptysis, orthopnea or paroxysmal nocturnal dyspnea, recent travel, or sick contacts.
Chest X-ray in the emergency department showed reticular and hazy markings throughout the both lungs, being worse compared to the previous chest X-ray (). A CT scan of the chest showed extensive honeycombing and bronchiectasis of both lungs which were markedly worse when compared to a CT scan done 4 years ago (). X-rays of both hands and wrists showed early inflammatory arthropathy but the patient denied any joint pain (). 2D echocardiogram showed ejection fraction of 59% with mild mitral regurgitation and no pulmonary hypertension, which was not consistent with CHF.
Concerning his chest X-ray and CT scan findings, ILD was now the working diagnosis. The differential at this time was idiopathic versus rheumatoid arthritis. Laboratory data showed elevated erythrocyte sedimentation rate 98 (N 0–20), elevated C-reactive protein 17.4 (N ≤ 7.0), elevated rheumatoid factor 275 (N ≤ 10), and elevated cyclic citrullinated peptide >250 (N < 20). To exclude causes of falsely elevated rheumatoid factor, hepatitis C Ab was done which was negative. ANA and DsDNA were both negative.
The complete blood count, electrolytes, and renal and liver functions were within normal limits. Lung biopsy was avoided due to the complications of an invasive procedure.
A diagnosis of interstitial lung disease of the usual interstitial pneumonia (UIP) variant due to rheumatoid arthritis was made. The patient was given intravenous solumedrol 40 mg TID which was tapered and changed to oral prednisone 60 mg daily upon discharge. During his hospital stay he was on nasal O2 3 litres and had episodes of desaturation on ambulation; hence he was discharged with home oxygen. He was advised to continue the rest of his medications for his comorbidities and to follow up with his primary care physician and pulmonologist as outpatient. Eventually the patient was referred to a tertiary care center for lung transplant. The patient is currently on the waiting list for his lung transplant.


In March 1998, a healthy 8-year-old boy fell on a concrete soccer field while playing at school, fracturing his left lateral incisor through the frontal impact of his maxilla on the ground. The patient reportedly suffered a small cut in the superior labial mucosa, slight bleeding at the gingival sulcus, and local pain and numbness of the anterior maxillary teeth. At an emergency dentistry service, the fractured tooth was provisionally restored by covering the exposed dentin with resin-modified glass-ionomer cement. The parents were recommended to monitor the pulpal conditions of all involved teeth, and the pain almost disappeared after 3 days. However, 10 days later, spontaneous tooth pain of the central and lateral maxillary incisors at night led the patient's parents to seek endodontic care for the child.
Clinical inspection verified the fracture of incisal edge and mesial angle of tooth 22, with loss of structure at the enamel and dentin but without pulpal exposure. According to Miller's scale (within 0–3), the dental mobility scores of teeth 12 and 22 were rated as 1-2. These teeth did not respond to cold vitality testing using frozen cotton pellets Endo-Frost (Coltène/Whaledent, Langenau, Banden-Württemberg, Germany), but slight tenderness to vertical percussion was recorded. Radiographic analysis (Eastman Kodak Company, Rochester, NY, USA) revealed no fracture lines on the root structures or increased periodontal ligament spaces apically; thus, the possibility of a luxation injury was rejected (). The other anterior teeth were asymptomatic. A root canal treatment was chosen for tooth 12. Calcium hydroxide apexification was planned for tooth 22, due to the presence of a widened root canal and an immature open apex (). The written consent was provided by the parents after the procedures were explained.
In a first session, absolute isolation of the operative field was achieved by using a rubber dam and clamps held on the premolars teeth. Coronal pulp chamber accesses were made with a diamond bur 1014# (KG Sorensen, São Paulo, SP, Brazil) in a high-speed hand piece irrigated with an air-water spray. Despite the vitality signals previously described, the access was initially made without anesthesia to confirm the pulp condition in situ. During the procedures, the patient related a mild sensitivity. Afterwards, mepivacaine HCl 3% (Mepivalem, Dentsply Pharmaceutical, Catanduva, SP, Brazil) was employed, but without vasoconstrictor to avoid a probable transient ischemia. However, the pulp tissue was found to be ischemic and without bleeding, confirming the diagnosis of pulp necrosis in both teeth ().
Root canal therapy to tooth 12 was conventionally accomplished in two visits. Canal patency was achieved with a Senseus FlexoFile Endodontic Instrument 10# (Dentsply/Maillefer, Johnson City, TN, USA). The working length was established 0.5 mm short of apex, and instrumentation was performed with a manual step-back technique. The canal was alternately irrigated with 1% sodium hypochlorite (AFER, Ponta Grossa, PR, Brazil) and 0.9% sodium chloride (Segmenta Farmacêutica, Ribeirão Preto, SP, Brazil). The apical preparation was performed up to 40# by using a K-type file (Dentsply/Maillefer), and the canal was thoroughly dried with multiple paper points. In a second session, the canal was obturated with a zinc-oxide eugenol-based sealer Endoseal (Ultradent Products, Inc., South Jordan, UT, USA) and gutta-percha cones (Dentsply/Maillefer), using the cold lateral obturation technique ().
In the first visit, apexification of tooth 22 was simultaneously performed according to guidelines of the International Association of Dental Traumatology []. The pulp chamber and canal were irrigated with 1.0% sodium hypochlorite (AFER) to neutralize a probable septic content due to dentin exposition during fracture. A Senseus FlexoFile Endodontic Instrument 25# L25 mm (Dentsply/Maillefer) was used to confirm the absence of fissures or fracture into the root. Then, the odontometry was radiographically determined. Instrumentation of the canal was executed by removing the necrotic remaining pulp tissue, shaping the canal walls, cleaning under constant irrigation with 1.0% sodium hypochlorite (AFER) and 0.9% sodium chloride (Segmenta Farmacêutica), and drying with sterile absorbent paper points (Dentsply/Herpo, Petrópolis, RJ, Brazil).
A paste of calcium hydroxide manipulated at an adequate density with propylene glycol vehicle and iodoform (Biodinâmica Química e Farmacêutica, Ibiporã, PR, Brazil) was placed into the canal. The condensation and filling of material were completed with the aid of a small spatula and lentulo carrier 25# L25 mm (Dentsply/Maillefer). Appropriate filling was radiographically confirmed. shows the slight extrusion of the material into the periapical tissues. The tooth was temporarily sealed with zinc-oxide eugenol-base cement TempBond (Kerr Corp, Orange, CA, USA). After 24 h, the patient did not complain of pain or discomfort. The calcium hydroxide dressings were replaced after 1, 3, 6, and 8 months. The canal entry was covered with resin-modified glass-ionomer cement (GC Corporation, Tokyo, Japan).
At 1 month, the initial restoration was removed and a new one was constructed with resin-based composite Z100 (3M-ESPE, Saint Paul, MN, USA). Within 3 months, the initial formation of mineralized apical barrier was radiographically observed. Exposure to calcium hydroxide was ended after 8 months, when the complete formation of a barrier was observed. After 4 months, the endodontic treatment was finished (Figures and ), and the coronal pulp chamber access was properly restored by using a resin-based composite Z100 (3M-ESPE). The patient did not come for controls and only returned to the office to change his aged restoration. Then, the long-term outcome was verified clinically and radiographically 13 years () and 14 and half years (Figures and ) after treatment. Moreover, the success of treatment was proved by means of a cone beam computerized tomography (CBCT) performed after 16 years and two months of the end of treatment. shows the complete apexification and formation of periapical bone.


A 46-year-old woman was admitted in 2010 for investigation of hypercalcemia discovered during recurrent nephrolithiasis. Her family history was noteworthy with cardiac arrhythmia in two dead sisters and nephrolithiasis in another sister. Her son was diagnosed with MD at the age of 24 years. Five years ago, an arrhythmia was diagnosed and required the implantation of a pacemaker. She was noted to have a bilateral cataract. She complained of muscle weakness, diffuse myalgia, and palpitation. The weakness was gradually progressive in arms. Physical examination revealed percussion myotonia and the typical emaciated face of MD, hollow cheeks, drooping jaw, a peripheral neurogenic syndrome, and multinodular goiter. There was no exophthalmia. The electrocardiogram was normal. Hypercalcaemia was confirmed 2.83 mmol/L. There were no symptoms directly attributable to hypercalcemia. Other laboratory tests showed serum phosphate 1.2 mmol/L, urinary calcium 0.153 mmol/kg/day, creatinine level 52 μmol/L, alkaline phosphatase 97 IU/L (normal range: 45–245 IU/L), parathormone 362.5 pg/mL (normal range: 15–65 pg/mL), thyroid stimulating hormone TSH 0.02 mIU/L (normal range: 0.34–5.6 mIU/L), FT4 21.17 ng/mL (normal range: 6.09–12.2 ng/mL), and negative anti-thyroperoxidase antibodies. Cervical ultrasound revealed a multinodular goiter with isoechogenic homogenic nodules with clear border and cystic cavities (8∗6 mm). The 99mTc-MIBI scintigraphy localized a lower right parathyroid adenoma. The electromyography (EMG) showed myotonic discharges. The bone mineral density (BMD) was normal. The clinical data, the family history of MD and arrhythmia in 2 sisters, EMG data, and endocrine disturbances were strongly suggestive of MD associated with hyperthyroidism and primary hyperparathyroidism (PHP). The patient was treated with benzylthiouracil, propranolol, and vitamin E. Euthyroidism was obtained after 2 years and the antithyroid drug was stopped. Four years later, MD is still in remission, and the alkaline phosphatase levels, serum creatinine and calcium, urinary calcium, and BMD are normal during follow-up.


Patient 31 was a 45-year-old woman with a diagnosis of metastatic breast cancer since 2003. Given the progression of her disease, pain became a major morbidity. On this admission, she presented with severe upper abdominal pain that had worsened in the previous 2 days. She reported that pain intensified with movement or touching of the affected area. During EM, she lay on her bed. In the room were two medical attendings and the EM practitioner. On initial assessment, the patient stated that her abdominal pain was improved to a score of 6 of 10 since admission but that she had significant (7 of 10) mid-lower back pain. The practitioner placed his hands approximately 10 inches above her right upper abdomen for approximately 20 seconds without touching her. Immediately afterward, she rated the abdominal pain to be 0 of 10. He addressed her lower back by placing his hands several inches over her umbilicus, after which she reported a pain score of 0 of 10. The practitioner asked her about the location of the cancer and did further work on the liver area. The patient was reassessed 15 minutes later and reported a sustained relief from pain in both areas.


Patient 24 was a 72-year-old woman who presented to the emergency department with bilateral worsening knee pain, inability to walk, and inability to bend her knees. She had been told that she needed bilateral knee replacements, but her cardiac status contraindicated surgery. The patient arrived with her husband, who was sympathetic to her pain and frustrated by her inability to ambulate and the ineffectiveness of her pain medication. Before EM, her pain was 10 of 10 in both knees. She had less than 5 degrees of active range of motion. Passive range of motion was 3.5 degrees in the left knee and 0 degrees in the right knee. After the session, her pain was 0 of 10, and she had full active range of motion in both knees. She stood up and walked with a cane, smiling. Her husband applauded and said that he hadn't seen her do this in many years.


We report a case of a 70-year-old white male, with a status after uncomplicated aortic valve replacement for severe aortic stenosis, who presented with melena and hypotension, returning to the hospital the same day of discharge. He reported a 15-pound weight loss over a few months. His past medical history was significant for a 60-pack-year smoking history and severe aortic stenosis. On physical examination, he was pale, tachycardic, and hypotensive, but he responded well to resuscitation. Esophagogastroduodenoscopy (EGD) revealed a seven-centimeter ulcerated submucosal mass in the fundus of the stomach without active bleeding (), and biopsy was not attempted. Imaging of the chest and abdomen revealed a 7 × 4 cm mass in the gastric fundus with no evidence of locoregional extension or distant metastasis (). He was taken to the operating room and it was found that the mass was locally invading the left hemidiaphragm. He underwent a partial left diaphragmatic resection, total gastrectomy, D1A lymphadenectomy, reconstruction with Roux-en-Y esophagojejunostomy, and a feeding tube jejunostomy. Histological and immunohistochemical analysis revealed an infiltrating moderately differentiated gastric squamous cell carcinoma (SCC) with direct invasion to the adjacent diaphragm striated muscle, with free margin resection, and one perigastric lymph node was positive for metastatic disease for a T4, N1, and M0 disease. Immunohistochemistry was positive for cytokeratin 5/6, p63 and negative for CD117, CK20, and p16. Three months after surgery, he was started on adjuvant radiation therapy and chemotherapy with capecitabine and oxaliplatin. He developed recurrent disease in the peritoneum and multiple liver metastases were found on positron emission tomography scan (PET). He received sorafenib, but he presented severe fatigue and the dose was decreased and eventually stopped. Carboplatin plus irinotecan was started 16 months after surgery due to progression of liver metastases. Twenty months after surgery, imaging showed progression of disease and 5-fluorouracil and gemcitabine were started with no response. Subsequently, he had progression of disease and expired 27 months after surgery.


A 59-year-old male with a history of recently diagnosed hypertension presented to the emergency department with sharp epigastric abdominal pain that radiated to the back and chest associated with nausea and nonbloody vomiting. He was started on hydrochlorothiazide (HCTZ) by his primary care physician ten days previously. The patient denied fever, chills, diarrhea, and dysuria. Past medical history was significant for occasional alcohol use. On physical examination, the patient showed abdominal tenderness in the upper quadrants and hypoactive bowel sounds. Vital signs were temperature 36°C, blood pressure 130/80 mm Hg, heart rate 127 beats per minute (bpm), respiratory rate 18 breaths per minute, and oxygen saturation of 99%. White blood cell (WBC) count was elevated at 16.1 × 103 cells/μL with 80 percent neutrophils, lipase 6312 U/L, glucose 178 mg/dL, alkaline phosphatase 69 U/L, alkaline transaminase 84 U/L, albumin 4.5 gm/dL, blood urea nitrogen 18 gm/dL, creatinine 1.32 mg/dL, and hemoglobin 16.1 g/dL. The patient underwent a computed tomography (CT) scan which showed peripancreatic edema and mild pancreatic fluid which was consistent with pancreatitis. The patient was put on a clear diet with aggressive intravenous (IV) fluid hydration. Blood cultures were negative. It was determined that his condition was most likely induced by HCTZ, and the medication was discontinued. His mental status deteriorated and he was transferred to the intensive care unit (ICU). A repeat abdominal CT scan done on the third day of his hospital stay showed increased ascites and peripancreatic edema with necrosis of the pancreatic head. The patient was placed on IV vancomycin and meropenem. The WBC increased to 25.7 × 103 cells/μL. By the sixth day, the patient's condition improved. A third CT scan of the abdomen was done on the eighth day of the hospital stay and showed a decrease in peripancreatic ascites from the previous CT scan and the appearance of peripancreatic fat stranding. On the ninth day of his hospital stay, the patient developed swelling of the scrotum and penis. An ultrasound done the next day showed that both testes were within normal limits and there was a large hydrocele bilaterally (). There were no varicoceles or testicular masses. Good blood flow was observed for both testicles. Oral Lasix 40 milligrams twice daily was added to the medications to manage the swelling. Urinalysis was unremarkable. Echocardiogram showed normal ejection fraction with no signs of congestive heart failure. Over the next eight days, the hydrocele and swelling gradually diminished. On the eighteenth day, the patient was discharged home in stable condition.


A 36-year-old lady presented to the Emergency Department with a five-day history of progressively worsening right knee pain. She denied any trauma and had no other past medical history. Physical examination revealed a mild pyrexia of 38.2°C, a moderate sized effusion, warmth of the joint, tenderness on palpation, and an arc of movement of 20 degrees. Her respiratory, cardiac, abdominal, urological, and neurological systems were normal. Blood tests showed a raised white cell count (WCC) of 17 × 109/L, C-reactive protein (CRP) of 132 mg/L, and erythrocyte sedimentation rate (ESR) of 78 mm/h. Aspiration of the knee joint produced 25 mls of straw-coloured fluid but no organisms or crystals were isolated on microscopy. Blood and urine cultures were unremarkable and the patient underwent an arthroscopic knee washout later that day. Intraoperative samples were negative for organisms and she was discharged pain-free 2 days postoperatively without antibiotics.
Six weeks later, the patient presented again to the Accident and Emergency Department with worsening symptoms and raised inflammatory markers. WCC was again raised at 22.7 × 109/L, CRP at 184 mg/L, and ESR at 83 mm/h. Repeat knee aspiration showed no organisms or crystals. The patient underwent a second arthroscopic washout and was placed on intravenous flucloxacillin and benzylpenicillin (1 gram and 1.2 grams QDS, resp.) for seven days prior to discharge on oral penicillin (1 gram QDS) for a total of 6 weeks.
After further 4 weeks, she re-presented with identical symptoms. Inflammatory markers had not changed since the previous admission. A third knee aspiration produced 85 mls of straw-coloured, turbid fluid that again was not purulent in appearance. This time, some aspirate was placed into standard blood culture bottles (aerobic and anaerobic) in addition to regular sterile containers and microscopy was performed on all 4 samples.
Inoculation of the aerobic blood culture sample for 2 weeks on blood agar in a CO2 enriched atmosphere allowed the growth of a Gram-negative coccobacillus. This was identified as Kingella kingae (a nonmotile, nonfermenting, weakly oxidase-positive, catalase-negative, and urease-negative organism which produces beta-haemolysis on blood agar) [] which was sensitive to gentamicin and ciprofloxacin only. The patient underwent an open knee washout and was started on 6 weeks of oral ciprofloxacin. There were no further acute presentations. One year after presentation, the patient complains of some residual pain and a loss of 20 degrees of joint flexion.


We present a 32-year-old Caucasian female with a past medical history of pseudotumor cerebri (ventriculoperitoneal shunt in place) and morbid obesity managed with Roux-en-Y gastric bypass. Two years after gastric bypass, necrosis of the distal pouch, stomach, and duodenum occurred, necessitating surgical debridement with abdominal reconstruction. She subsequently developed chronic malnutrition and short gut syndrome requiring long-term total parenteral nutrition through a peripherally inserted central catheter (PICC). Due to ongoing chronic pancreatitis, a pancreatic-auto-islet cell transplant with splenectomy was performed.
Five months following the pancreatic-auto-islet cell transplant, she was hospitalized three times during the same month with fever and abdominal pain. Hospitalization one Fevers were documented up to 101.2°F with a mild leukocytosis (11,400 cells/mm3). Blood cultures were positive for α-hemolytic Streptococcus (Table ). The PICC line was removed and replaced before discharge. Hospitalization two Fevers were documented up to 100.8°F with a leukocytosis of 21,000 cells/mm3. Blood cultures were negative. Computed tomography (CT) imaging of the abdomen and pelvis did not demonstrate a source for the fever or leukocytosis. Nutritional support was maintained through enteric tube feeds, and at the patient’s preference a PICC line was again replaced for daily fluid infusion. Hospitalization three Fevers were documented up to 103°F for 3 days, with a leukocytosis of 14,300 cells/mm3. Blood cultures from the PICC line and peripheral draw grew α-hemolytic Streptococcus and Achromobacter spp. on two consecutive days. No fluid collections or intra-abdominal abscesses were found on CT imaging of the abdomen and pelvis. A chest radiograph and transthoracic echocardiogram were normal. The α-hemolytic Streptococcus and Achromobacter spp. (Table ) were treated with 14 days of piperacillin–tazobactam.
In clinic, following the third hospitalization, this patient reported daily fevers up to 104°F that started 1 day after being discharged from the hospital (while on piperacillin–tazobactam). She reported head and neck pain with a sore throat, which increased in severity during the febrile episodes. Mild fever of 100.9°F was present. Physical exam was normal, including the oropharynx and skin exit site of the PICC line. Outpatient workup included blood cultures, viral studies, and fungal blood tests (all were negative) (Table ). High-resolution chest CT revealed extensive tree-in-bud infiltrates (Figure ). The following day she reported high fevers and was admitted to the hospital for an expedited work up.
During hospitalization four there were no documented fevers. Bronchoalveolar lavage was non-diagnostic with negative cultures and cytology. The morning of hospital day five, the patient developed acute chest pain, dyspnea, mild hypotension, and hypoxia. Intravenous fluid and oxygen supplementation were administered. Echocardiogram showed new marked right ventricular dilatation with severe right ventricular dysfunction. Due to concerns for pulmonary emboli (PE), intravenous heparin therapy was initiated. CT pulmonary angiogram was negative for PE. That afternoon she was found unresponsive in pulseless electrical activity arrest. The patient died despite extensive resuscitation efforts. Mycobacterium mucogenicum eventually grew from the PICC line culture drawn from hospital day one. The cause of death at autopsy was attributed to complications from pulmonary microcrystalline cellulose emboli with associated foreign body granulomatosis (Figure ).


A 23-year-old female, gravida 1, and para 0 at 31 weeks of gestation was transferred to our cardiothoracic intensive care unit (CTICU) for further management of her aortic valve endocarditis. Her past medical history included intravenous drug use (currently on methadone maintenance), hepatitis C discovered during this pregnancy, bipolar disorder, and depression with multiple prior suicide attempts. Of note, the patient also had a root canal two weeks prior and was started on ampicillin for a dental abscess.
She initially presented to an outside hospital one week earlier with severe right thigh and groin pain, which had progressed to the point of inhibiting ambulation. A right lower extremity Doppler study revealed an occlusive thrombus in the deep femoral artery. She was started on therapeutic enoxaparin and transferred to a second hospital, where a transthoracic echocardiogram (TTE) revealed large vegetative lesions on all 3 leaflets of the aortic valve, including a mobile vegetation measuring 0.8-1-cm on the ventricular side of the valve (Figures
–). Mild to moderate aortic insufficiency was present. Blood cultures grew yeast but had not yet speciated upon transfer to our hospital. Amphotericin B was initiated and, after an initial infusion reaction, she was able to tolerate subsequent doses with premedication. Micafungin was added until speciation of the yeast was final. She remained hemodynamically stable requiring no inotropic or pressor support.
Anticoagulation was withheld despite her thrombus due to concern for cerebral embolic infarction and risk of hemorrhagic conversion in the setting of mobile aortic endocarditis. A magnetic resonance angiogram (MRA) of the brain was obtained to rule out a mycotic aneurysm, given that her endocarditis was known to be fungal in nature. The MRA showed a 2.2 mm aneurysm of the anterior communicating artery. An ophthalmologic exam was negative for fungal endophthalmitis. She received betamethasone and magnesium sulfate for fetal lung maturity and fetal neuroprotection, respectively. A fetal ultrasound demonstrated normal growth and activity of the fetus.
After a multidisciplinary meeting involving the CTICU intensivists, obstetrics, cardiothoracic surgery, cardiology, neurology, neurosurgery, obstetric anesthesiology, and obstetric and CTICU nursing teams, it was decided to proceed with delivery of the baby via Caesarean section followed by an aortic valve replacement (AVR) the following day. The decision to separate the procedures by approximately 12 hours was made out of concern for uterine bleeding after the Caesarean section with the full heparinization required for the AVR. It was decided that the risk of significant uterine bleeding, possibly necessitating a hysterectomy, would be too high in a 23-year-old woman.
The following day, the patient underwent a successful Caesarean delivery of a healthy baby under general endotracheal anesthesia. Her trachea was extubated so that she could spend time with her newborn. The following morning, she underwent a bioprosthetic AVR and a right femoral artery thrombectomy. Her blood cultures eventually speciated to Candida parapsilosis, as did intraoperative cultures.
It was decided that the patient would need long term antifungal therapy for her endocarditis and fungemia and that a peripherally inserted central catheter (PICC) was indicated. Initially there was a great deal of hesitation to place a PICC and possibly discharge her with one, given her history of intravenous drug abuse. Although there was no evidence of recent intravenous drug use, both on physical exam and on multiple urine toxicology screens, ethics and psychiatric consultations were obtained. After much deliberation, it was decided that PICC placement should not be withheld from her if it was medically indicated.
Discussions concerning whether the patient needed further brain imaging or intervention at some point for her aneurysm also took place. However, on further review of the MRA, the neurology service decided that based on its appearance and location the aneurysm was most likely congenital and not mycotic. Thus, no further imaging was warranted.
Postoperatively, the patient experienced considerable postsurgical pain that was difficult to control initially, likely due to her increased opiate requirements. In addition to her maintenance methadone dosing and a hydropmorphone PCA, she was maintained on fentanyl, ketamine, and dexmedetomidine infusions, which were gradually able to be weaned off over the next few days as her pain improved. The ketamine and dexmedetomidine infusions provided a multimodal and narcotic sparing approach to her opiate tolerant pain. She was eventually discharged from the CTICU on postoperative day 3 and from the hospital on postoperative day 17.


An 11-month-old African-American female presented to neurology due to seizure-like activity. She was a former term infant with a birthweight of 3.714 kg. At presentation she weighed 9.6 kg (56th%) and was 77 cm (89th%) tall. During her evaluation, a glucose value of 38 mg/dL (1.998 mmol/L) and bicarbonate of 24 mmol/L were noted.
During a subsequent fasting challenge, her serum glucose decreased to 32 mg/dL (1.776 mmol/L) within 5.5 h. The results of the critical sample are presented in Table . Specifically, her insulin level was appropriately low, while her beta-hydroxybutyrate (BOHB) was minimally elevated, and free fatty acids were inappropriately within the normal range. Additionally, her growth hormone was low. All other laboratory results including ammonia, *urine organic acids, *serum amino acids, and *acylcarnitine profile were normal (*drawn in the fed state). A glucagon stimulation to assess glycemic response at the time of hypoglycemia was attempted but was unsuccessful. Based on the critical sample results, she was thought to have growth hormone deficiency and was started on growth hormone therapy. She was discharged after several inpatient days with improved glucose levels.
In the interim, the insulin-like growth factor-1 (IGF-1) (prior to growth hormone therapy) resulted at 105.7 ng/mL (approximately the 80th% for age and sex), and insulin-like growth factor binding protein-3 (IGFBP-3) was 2800 ng/mL (above the mean for age and sex). While at home, she was noted to have a glucose of 19 mg/dL (1.0545 mmol/L) despite growth hormone therapy. Given the severity of her hypoglycemia, she was readmitted for further assessment. An arginine/clonidine growth hormone stimulation test done after discontinuation of growth hormone revealed a peak growth hormone level of 7.9 ng/dL (radioimmunoassay). In the setting of continued hypoglycemia despite growth hormone therapy, her critical sample obtained at her initial admission was reviewed and determined to be concerning for CHI. Therefore genetic studies for CHI were sent (Athena Diagnostics, Worcester, Massachusetts).
While genetic studies were pending, diazoxide treatment was initiated and titrated to 15 mg/kg/day divided three times daily. However, she continued to have hypoglycemia. After one week of diazoxide therapy, octreotide was added. Octreotide was increased to 15 mcg/kg/day, with subsequent improvement but not resolution of hypoglycemia. Frequent feeds and uncooked cornstarch were implemented to avert hypoglycemia. Her hyperinsulinism was deemed diazoxide-unresponsive and diazoxide was discontinued.
Mutational analysis confirmed a diagnosis of CHI as three variants in ABCC8 were identified (Table ). The R1215W variant was found to be paternally-inherited while the W739C and R1393L variants were maternally inherited. The paternal change was a known mutation described previously (at Children’s Hospital of Philadelphia) in a patient with diffuse disease. In this previously described patient, the inheritance pattern was thought to be recessive, given a normal maternal ABCC8 gene copy. In our patient, the significance of the maternal variants was unclear as they had not been previously described in CHI cases. Therefore, for our patient, we were unable to predict focal versus diffuse disease pathology based on mutational analysis alone.
Our patient was transferred to Children’s Hospital of Philadelphia for an 18-fluoro L-3, 4-dihydroxyphenylalanine positron emission tomography (18-F-DOPA-PET) scan. There was no focal uptake of isotope by the pancreas (Fig. ), which suggested, but did not confirm diffuse disease. A pancreatic biopsy was subsequently recommended in order to further delineate her pathology, but was declined by the family. A gastrostomy tube was placed for enteral dextrose administration (overnight glucose infusion rate (GIR) of 7 mg/kg/min).
Over several months, the child has continued to have intermittent, daily hypoglycemia despite adjustments of her treatment regimen. The GIR of her fluids has been gradually increased. Her current treatment regimen at age 3 years consists of octreotide 20 mcg/kg/day divided three times daily and overnight dextrose (14 h, GIR of 9 mg/kg/min) through her gastrostomy tube. She continues to have daytime hypoglycemia [glucose <70 mg/dL (3.885 mmol/L)]. Speech delay that was noted shortly after diagnosis persists despite therapy. Considering her disease and failure of medical management, a near-total pancreatectomy may be necessary to achieve normal blood glucose levels. Other treatment options that are also being considered include continuous glucagon via an insulin pump [, ] and continuous octreotide via an insulin pump []. These treatments have not been pursued based on parental requests.


A 28-year-old man was transferred to our institution with a diagnosis of AML ( and ). He presented with signs of infection (fever and cough) and a remarkable swelling on the neck with slight rubor and tenderness. Computer tomography (CT) demonstrated bilateral massive lymphadenopathy with necrosis. His AML turned out to be chemoresistant as he failed three induction courses (). Further leukemia-directed treatment was therefore discontinued, and the patient succumbed within short of infections.


A 68-year-old Caucasian woman, with active tabagism (40 pack-years), obstructive sleep apnoea syndrome under continuous positive airway pressure (CPAP) via nasal mask, and hypothyroidism secondary to a partial thyroidectomy in 1979, was investigated by her practitioner for fatigue in 2010. The current treatment at that time was aspirin 100mg per day, levothyroxine 100μg per day, and lorazepam 1mg per day. Her family history was negative for any hematologic malignancy.
A hemoglobin (Hb) level of 177g/L and hematocrit (HCT) level of 55% was found, with slight leukocytosis at 12.3G/L, but there was no other abnormality found on her blood smear, especially no left deviation or myelemia. Therefore it was initially interpreted as secondary erythrocytosis.
In 2012 a rise in her Hb level was noted and she was seen at our institution for further investigation. Her test results indicated a Hb level of 180g/L, a HCT level of 55%, a leukocytes count of 16G/L with normal differentiation, a thrombocytes count of 294G/L, and a reticulocytes count of 67G/L. Her arterial blood gas levels were: partial pressure of oxygen in the arterial blood (PaO2) of 8.8kPa, partial pressure of carbon dioxide in the arterial blood (PaCO2) of 4.7KPa, carboxyhemoglobin at 8.6%, a pH of 7.42, and a base excess of -1.2mmol/L with oxygen saturation at 95%. Her lactate dehydrogenase value was 527U/L (normal value: <450U/L), with her liver test results showing normal function. Her erythropoietin and ferritin values were low at 2.3U/L (normal value: 8 to 22U/L) and 16μg/L (normal value: 30 to 300μg/L), respectively. In this context, polycythemia vera was suspected, but could not be confirmed by molecular biology analysis as she was negative for the JAK2 V617F mutation. Interestingly, her vitamin B12 level was very high at 1,703pg/mL (normal value: 185 to 1,060pg/mL).
Her blood marrow biopsy revealed a slight hypercellularity with discrete hyperplasia and slight atypia of megakaryopoiesis, normal erythropoiesis with discrete signs of dyserythropoiesis without hyperplasia, and normal myelopoiesis. These abnormalities were aspecific and not suggestive for a MPN. Based on hyperleukocytosis and a high vitamin B12 level, we searched for the BCR-ABL1 fusion gene, which was surprisingly positive. Her bone marrow conventional cytogenetic analysis revealed a female karyotype with the presence of the Philadelphia chromosome (t (9; 22) (q34; q11.2)) in 85% of metaphases.
An interphase fluorescence in situ hybridization (FISH) analysis confirmed the BCR-ABL1 rearrangement in 88.5% of interphases analyzed. In light of these results we diagnosed a BCR-ABL1-positive CML, in chronic phase, with a low risk Sokal score (0.62). Given the presence of the Philadelphia chromosome (t (9; 22) (q34; q11.2)), we did not search for exon 12 mutations.
We started a therapy of imatinib mesylate (daily dose of 400mg) on 13 April 2012, and she showed relatively good tolerance. Under treatment, she obtained a complete hematological response at three months, including rapid disappearance of her erythrocytosis (see Figure ), normalization of absolute neutrophil count (see Figure ) with complete cytogenetic response and major molecular responses being observed at six months (see Figure ). These responses were considered optimal according to European LeukemiaNet criteria 2010 and 2013 [].


An 80-year-old woman presented to our institution with odorous discharge from an opening in her swollen right thigh. In the previous 4 years, her right thigh had swollen up. Three months prior to her visit, an opening formed spontaneously at the medial aspect of the thigh, and jelly-like material began to ooze steadily. Two months before her visit, an odorous discharge began to exude from the opening. Physical examination revealed fluctuation in the right lower quadrant of the abdomen, the medial aspect of the right thigh, and the posterior aspect of the right calf.
Fourteen years previously, the patient had undergone an operation for an intra-abdominal mass at another institution. The operation record mentioned a bilateral salpingo-oophorectomy with massive adhesiolysis and excision of a large 20 × 19 × 18-cm mass in the retroperitoneal space. There was no mention of the appendix in the record, and the patient had not undergone appendectomy before the operation. The pathological record reported a mucinous borderline left ovarian tumor with extensive pseudomyxoma ovarii and severe tubo-ovarian adhesion. Although the patient had noted progressive abdominal expansion with dull pain in the right lower quadrant 8 years previously, diagnostic studies such as computed tomography (CT) and ultrasonography (US) [] were not performed.
A magnetic resonance image of the right thigh showed a fluid-containing lesion in contact with the surface and an opening in the medial compartment. In addition, there was a multiloculated, lobulated lesion mainly involving the anterior and medial compartment of the thigh and extending distally along the fascia of the hamstring muscles (Fig , ). A magnetic resonance image of the calf also revealed a similar lesion chiefly involving the posterior compartment along the deep fascia (Fig , ). An abdominal CT scan showed a large multiloculated cystic mass occupying the right retroperitoneal space and extending to the right thigh (Fig ). There were no definite abnormal findings on the chest CT scan. Together, these imaging studies revealed extension of the lesion from the abdomen to the calf. The patient’s initial blood tests revealed abnormal results including a white blood cell (WBC) count of 11,820/mm3, 87.5 % segmented neutrophil, an erythrocyte sediment rate of 96 mm/h, 5.89 mg/dL C-reactive protein, 178 mg/dL fasting blood sugar, 4.5 g/dL total protein, 2.4 g/dL albumin, and 50 U/L aspartate transaminase. The urine analysis and sediment examination noted abnormal results including leukocytosis, a positive occult blood, and WBC and red blood cell count of 30 to 49 and 20 to 29 per high-power field.
Immediately after admission, we started intravenous antibiotic administration, which included 2.25 g of piperacillin and tazobactam four times a day and 1 g vancomycin once every 96 h. Two weeks after admission, a suspected infected portion of the thigh lesion was excised, and tracks connecting from the thigh to the peritoneum were ligated. After the operation, administration of 2.25 g of piperacillin and tazobactam four times a day was continued. Staphylococcus epidermidis grew when mucinous material obtained intra-operatively from the lesion was cultured. Pathological examination of the excised specimen demonstrated acellular mucinous materials with a carcinoembryonic antigen-positive immunoreaction (Fig ).
Two weeks after the first surgery, follow-up blood test results demonstrated improvement of the infectious condition in the thigh. The WBC count, segmented neutrophil, erythrocyte sediment rate, C-reactive protein, fasting blood sugar, total protein, albumin, and aspartate transaminase were 4640 /mm3, 51.8 %, 11 mm/h, 1.09 mg/dL, 112 mg/dL, 5.7 g/dL, 2.9 g/dL, and 24 U/L, respectively. On urine analysis and sediment examination, the WBC and red blood cell count were 1 to 3 and 4 to 9, respectively, per high-power field.
A second operation was performed for all the lesions from the abdomen to the calf by a collaborative team of orthopedic surgeons and gynecologists. No bowel obstruction was observed, and the appendix was not seen. A large volume of mucinous material was suctioned from the abdominal lesion (Fig ). Multiple intra-muscular and interfascial connections between the abdomen and lower extremity were observed at the level of the inguinal ligament (Fig ). Cytoreductive surgery with peritonectomy was performed for the intra-abdominal lesion. The lower extremity lesion was marginally removed; it had a thin capsule and was mostly composed of mucinous material (Fig ). Four hours after the operation, the patient underwent cardiopulmonary resuscitation following a hypovolemic shock due to massive intra-operative bleeding. She recovered with proper management without any acute sequelae.
Five days after the second surgery, no bacterial growth was observed in a culture of intra-operatively obtained mucinous material. Pathological examination showed low-grade mucinous carcinoma peritonei with the lining epithelium in the intra-abdominal lesion (Fig ) and only acellular mucinous material in the lower extremity lesion (Fig ). The patient’s postoperative course was uneventful, and she was discharged 2 weeks after the definitive operation. Thereafter, she sent us the pathology slides from 14 years previously, which were re-examined by pathologists at our institution. They revealed pseudomyxoma ovarii (Fig ). The patient did not report any abdominal symptoms or swelling in the lower extremity at the most recent follow-up, which was 2 years after the final operation. She was able to walk with a cane, and the Musculoskeletal Tumor Society functional rating for the lower extremity was 73 %.
The origin of PMP is still controversial. PMP is currently thought to be associated mainly with mucinous epithelial neoplasms of the appendix [–]. However, several convincing cases have been published with a different primary organ of origin, such as the ovary, urachus nest, or colon [, ]. Because our patient had not undergone an appendectomy before the operation in 1999 and there was no mention on the appendix in the operation record, we could not confirm the appendix as the origin of PMP on histological grounds. Despite the previous pathological report, the ovaries were normal and did not appear to be the origin of the tumor based on the review of the previous slides. We, therefore, assume that the appendix was the organ of origin in this case.
PMP usually manifests with tumor deposits throughout the entire peritoneal cavity. This characteristic pattern of dissemination can be explained by the redistribution phenomenon, which is associated with the intra-peritoneal fluid current and gravity []. In the end stage of disease, PMP engulfs the entire peritoneal cavity. Intestinal movement becomes limited because of an excessive amount of mucinous tumor mass, and bowel obstruction becomes imminent. Patients ultimately die of cachexia when untreated [, , ].
CT and US have been reported to be useful in detecting PMP [, , ]. While CT remains the gold standard for diagnostic imaging, US is inexpensive, readily available, well tolerated, and can identify most common PMP findings such as ascites and omental caking. Our patient did not have any diagnostic examination despite abdominal symptom, and a relapse was diagnosed barely after development of the lower extremity lesion.
In 1995, Ronnett et al [] described three distinct categories of PMP, namely, diffuse peritoneal adenomucinosis (DPAM), PMCA, and an intermediate/discordant subtype (PMCA-I/D) on the basis of pathological findings. They reported that 5-year overall survival rates of 75 % in DPAM, 50 % in PMCA-I/D, and 14 % in PMCA when the same surgeon treated PMP tumor patients uniformly. Recently, Chua et al. [] examined the outcome of nearly 2300 patients from 16 institutions worldwide who were treated uniformly over an 18-year period and confirmed the paramount importance of the histopathological subtype with respect to outcome. Five-year overall survival rates were 81 % for DPAM, 78 % for hybrid tumors, and 59 % for PMCA. Multivariate analysis showed that the PMCA subtype was an independent predictor of poor overall survival.
Although the intra-peritoneal lesion in this case was diagnosed as low-grade PMCA and optimal treatment was not performed for a long time, our patient did not report any symptoms associated with bowel obstruction. Despite a huge lesion, her clinical course was modest over a long period, and death by cachexia was avoided. We assume that the extension of the intra-peritoneal lesion to the lower extremity acted as an expansion of the peritoneal cavity and prevented such an outcome. When PMP is progressing, the characteristic visceral and mesenteric sparing of PMP becomes visible intra-operatively and is related to a favorable prognosis after surgery [], as in our case.
The proper treatment for PMP remains uncertain; however, the combination of aggressive cytoreductive surgery and hyperthermic intra-peritoneal chemotherapy seems to improve the outcome []. Nevertheless, extensive surgical resections to achieve complete tumor eradication are associated with high morbidity and mortality rates and may decrease the quality of life without any survival benefit, particularly in cases of extensive high-grade diseases [–]. In contrast, less aggressive surgery may be optimal in cases of extensive low-grade disease, as in the extremity lesion of our patient if the benefit compensates for surgical morbidity []. Chemotherapy may cause side effects, particularly surgical complications, as a result of bone marrow toxicity []. As in the case of peritoneal lesions, we had to consider balancing treatment benefit and morbidity in the extremity lesion. A wide excision encompassing large areas of muscle and parts of neurovascular structures could have rendered the extremity nonfunctional, especially with adjuvant treatments. In addition, it may have caused more severe hypovolemia. Even if we had chosen more aggressive management with careful support from anesthesiologists, it would have been difficult to achieve R0 margin because the mucinous contents and thin capsule extended from the abdomen to the calf. The first surgery had already contaminated the thigh area. The advanced age of the patient also added complexity; therefore, we performed less extensive surgery without any adjuvant treatment for the extremity lesion.
Although the cause of PMP extension to the lower extremity has an important clinical significance, we could not explain why the extension occurred only in this case. The fluidity of mucinous contents and the gravity might have contributed to the formation of the lower extremity lesions as an extension of tuberculous psoas abscess into the thigh. Further studies to elucidate the mechanism are required.


The patient was a 32-year-old Caucasian male who was diagnosed in 2004 with mycosis fungoides after developing a pruritic rash. There was no family history of cancer. He was initially treated with topical nitrogen mustard and later received UVB narrow band therapy. In October 2012, the patient presented with a cough, dyspnea, fever, chills, left pleuritic chest pain and significant weight loss. These symptoms were associated with a flare of his skin lesions. A CT scan of the chest demonstrated extensive left cervical, supraclavicular and mediastinal adenopathy, as well as left upper lobe airspace disease. Review of pathology from a left cervical lymph node biopsy from December 2012 revealed complete effacement of the normal architecture by a diffuse infiltration of large and giant pleomorphic lymphocytes characterized by conspicuous nucleoli and large amounts of cytoplasm (Figure a). Immunohistochemical stains showed weak CD45 and strong CD43 expression (Figure b), with strong CD30 expression in the membrane and Golgi patterns (Figure c). The malignant cells expressed cytoplasmic ALK (Figure d) but lacked expression of CD 3, 4, 5 and 8. A T cell lineage was confirmed in the tumor cells of the initial biopsy sample by clonal T-cell receptor gamma gene rearrangement. Identical infiltrates were identified in material from recurrent biopsies of skin and subcutaneous tissue, and from lung and endobronchial biopsies at the time of progression.
After an initial response to four cycles of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy, the disease progressed rapidly while the patient was on therapy. He was started on gemcitabine, dexamethasone and cisplatin (GDP) chemotherapy in preparation for an autologous stem cell transplant but progressed after 3 cycles. The patient then received one cycle of the CD30 antibody–drug conjugate brentuximab, with a response but tolerated the treatment poorly. He was subsequently started on the ALK small-molecule kinase inhibitor crizotinib and tolerated the therapy well with an improved performance status. A fluoro-deoxyglucose positron emission tomography (FDG-PET) scan performed after 3 months of crizotinib showed an improvement in the previously noted airspace disease in the left lung but an enlarging FDG-avid 5.2 cm mass in the apex of the left lung. There was no evidence of disease outside the chest. A CT scan-guided biopsy of this mass was positive for ALK by immunohistochemistry and RT-qPCR using an ALK RGQ RT-PCR Kit (Qiagen, Hilden, Germany). The remaining RNA from the lymph node biopsy was reverse transcribed to cDNA and used in a 5′ RACE PCR followed by Sanger sequencing to identify the ALK fusion partner. Analysis of sequence data revealed a TRAF1-ALK fusion in which 3′ end of exon 6 of TRAF1 was fused to the 5′ end of exon 20 of ALK (Figure ). The mRNA fusion junction in TRAF1 and ALK in the case was identical to that present in the TRAF1-ALK-positive ALCL case reported by Feldman et al. [].
The patient underwent an unrelated-donor stem cell transplant in December 2013 but disease recurred in the left lung within 3 months post-transplant, and failed to respond to the reintroduction of crizotinib and brentuximab. Endobronchial biopsies from lesions in the left and right lungs revealed ALK-positive ALCL. The patient died of progressive lymphoma 6 months post-transplant.
Molecular testing of the patient’s biopsy samples was performed with the consent of the patient using a study assay approved by the BC Cancer Agency Research Ethics Board (H13-01763) and conducted in accordance with the ethical principles of the Declaration of Helsinki.


A 32-year-old Japanese male with no previous medical history was admitted to our hospital for a persistent low-grade fever and purpura lasting for 1 month. A complete blood count (CBC) revealed marked anemia, thrombocytopenia, and hyperleukocytosis (136,130/µL; blasts 97%, neutrophils 0%, lymphocytes 2%, and eosinophils 1%). Bone marrow aspiration from iliac crest were hypercellular with 97.6% lymphoblasts. Cytogenetic analysis revealed that blasts were positive for the Philadelphia chromosome (Ph1) with minor BCR/ABL mRNA transcripts. Therefore, the patient was diagnosed with Ph1-positive ALL.
Combination chemotherapy with dasatinib was immediately initiated as remission induction. On treatment day 27, CBCs had normalized and bone marrow aspiration from iliac crest analysis confirmed complete remission. On treatment day 39, consolidation chemotherapy with daunorubicin, cyclophosphamide, vincristine, prednisolone, methotrexate, and dasatinib was initiated. On treatment day 51, the patient became pyrexial (39.2°C) and reported severe lower back pain. The pain rapidly worsened and radiated to the right axilla. WBC count was 430/mm3, with 8% segmented neutrophils, 2% bands, 80% lymphocytes, and 10% monocytes. We immediately collected blood culture and started empiric antibiotic therapy with meropenem, vancomycin, and liposomal amphotericin B. CT imaging revealed no apparent abnormal findings; however, fluorodeoxyglucose (18F)-positron emission tomography (FDG-PET) revealed increased uptake of FDG in the iliac bones and right side of the sacrum. These findings suggested osteomyelitis of the iliac bone and sacrum and Gram-positive bacteria were detected by needle aspiration biopsy of the iliac bone (Fig. ). Gram-positive bacterium was also found in the blood culture; however, the bacteria could not be identified. For this reason, we tested the blood culture for direct 16S ribosomal RNA (16S rRNA) sequencing and identified C. innocuum 2 days later. The presence of this pathogen was also confirmed by bone marrow culture from iliac crest. As a result of these findings, the patient was treated with piperacillin/tazobactam, metronidazole, and clindamycin. In this case, the causative pathogen was sensitive to ampicillin, piperacillin/tazobactam, meropenem, clindamycin, and metronidazole. Intermediate sensitivity to penicillin G and cefmetazole was observed. Further, the isolated strain was resistant to vancomycin with a minimum inhibitory concentration (MIC) of 8 μg/mL.
Fever gradually resolved over the next 3 weeks, but the lumbar pain persisted. CT imaging identified a small abscess in the iliacus muscle. Therefore, CT-guided drainage was performed. No pathogens were detected in cultures of the abscess fluid or blood. The previously administered antibiotic regimen was consequently deemed effective. After another 8 weeks of antibiotic therapy, the lumbar pain subsided and treatment was terminated. On treatment day 104, the patient was asymptomatic and chemotherapy was reinitiated.


A 69-year old Caucasian lady presented to the emergency department with a two day history of haemoptysis, pleuritic chest pain and dyspnoea. She had a productive cough with thick, yellowish sputum, associated with intermittent low-grade pyrexia and mild weight loss over the past few weeks. There were no significant comorbidities, history of recent travel or positive family history. She was a non-smoker.
Physical examination revealed a septic patient, in apparent distress and extremely short of breath. Observations revealed pyrexia, tachycardia, tachypnoea and hypoxia with oxygen saturations of 93 % on air. Blood tests revealed a raised C-reactive protein of 347.2 mg/L along with a raised white cell count of 28.2 × 109 /L. Differential counts revealed neutrophilia 61.7 %, raised lymphocytes 33.2 % and eosinophilia 7 %. All other biochemical tests including urea and electrolytes, liver function tests and clotting profile were within normal range. She was started on broad-spectrum antibiotic therapy and her sputum sample was then cultured which revealed no significant bacterial growth including absence of acid fast bacilli for tuberculosis, however multiple cysts were seen on microscopy. A suspicion of hydatid disease was confirmed by a positive hydatid complement fixation test of the sputum.
Baseline investigations such as an electrocardiogram and echocardiography were unremarkable.
A plain chest radiograph showed a hydropneumothorax on the right side with the pneumothorax component measuring 16 mm. The left lung was clear. There was a near-complete whiteout of the right hemithorax with sparing of the apex, which was most likely to be a persistent pneumothorax with possible rupture of the hydatid cyst (Fig. ). In order to obtain more clear details of the disease process, a magnetic resonance imaging (MRI) scan of the thorax and liver revealed a complex pulmonary mass, which extended from the right lower lobe of the lung, through the hemidiaphragm and into the posterior aspect of the right lobe of the liver. The intrahepatic component appeared thicker walled and well encapsulated. The thoracic component measured 9.5 cm, the intrahepatic component was 9.6 cm and the overall craniocaudal length was 13.2 cm (Fig. ). There was extensive involvement and rupture of the right posterior diaphragm by the hydatid cyst as it passed into the chest. The mass appeared heterogeneous with a serpiginous internal structure. The chest component appeared more irregular and tubular and was occupying a greater proportion of the lower lobe of the lung, with likely airway involvement. There were further ‘simple’ cysts within the liver and both kidneys. There was a small right pleural effusion, and significantly increased atelectasis in the lower lobe posterior to the hydatid mass.
The patient was then commenced on the anti-helminthics albendezole and praziquantel. A multidisciplinary team consensus determined that the patient required complex surgical intervention to eradicate the fistula and prevent further deterioration. A computed tomography (CT) scan was performed for accurate surgical planning, delineating the margins to ensure complete division (Fig. ). The patient underwent a right-sided thoracotomy and a lower lobectomy. There was extensive evidence of thickened pleura with empyema intraoperatively. The fistulous tract was then identified and over sewn. All remaining cystic lesions were removed and curetted and all defects were closed aseptically. Drains were placed post operatively. Following surgery, the patient’s inflammatory markers for sepsis steadily improved. A CT scan post-operatively demonstrated complete resection of the fistula. She continued on the anti-helminthic medications and remained well at six months post discharge.


A 57-year-old male with a remote history of a two-stage fasciocutaneous urethroplasty presented with a new penetrating injury to his perineum after falling on a crowbar at work. He was reluctant to see a physician immediately and has delayed his visit by 3 months. By the time of his first visit he had a large perineal abscess and a fistula through which he was voiding since the injury. The patient was immediately admitted to the hospital and underwent incision, drainage, and conservative debridement of the perineal abscess and a suprapubic tube placement. On urethroscopy the urethral lumen could not be visualized beyond proximal pendulous urethra. The patient was managed with wet to dry dressing changes as outpatient until complete closure of the perineal wound.
Three months later he presented for reevaluation with a voiding retrograde urethrogram and attempted voiding cystourethrogram (). The study demonstrated a 5 cm stricture involving most of the bulbous urethra and a persistent urethrocutaneous fistula draining into the perineum. Patient was counseled on available reconstruction and diversion techniques, and had chosen reconstruction. In view of his prior extensive reconstruction with local flaps and subsequent significant trauma to the perineum followed by abscess a reliable local tissue was not available for reconstruction. The plan was to excise the devastated urethral segment and reconstruct it by augmenting the defect with buccal mucosal graft dorsally and composite buccal mucosa-gracilis flap ventrally. The procedure was planned to be performed in two stages to monitor graft survival and contracture before committing to “tubularization.”
Stage 1. After appropriate informed consent was obtained, the patient underwent a general anesthesia, administered IV Cefazolin and Gentamycin, placed in a low lithotomy position, prepped, and draped in a manner allowing access to the perineum and the left inner leg (). The suprapubic tube was removed and a suprapubic cystoscopy was performed with an attempt to pass a guide wire antegrade through the bladder neck into the urethra. The wire had preferentially passed into the urethrocutaneous fistula.
(a) Augmented Perineal Urethrostomy. An inverted Y-incision was carried through the perineum and through the abundant scar. The fistula and the affected urethra were dissected and removed leading to a 6 cm defect (). The proximal and distal urethral stumps were spatulated both ventrally and dorsally and their lumens measured at 24 French. Two 6 × 2.5 cm buccal mucosal grafts were harvested, defatted, and fenestrated (). One graft was quilted on the corpora cavernosa and anastomosed to the spatulated urethral stumps dorsally using 4-0 polydioxanone suture. A perineal urethrostomy was matured by approximating edges of skin to the edges of neourethral plate (). A catheter was placed in the urethrostomy and a tie-over dressing applied over the graft.
(b) Gracilis Prelamination. During the same operation, the left gracilis tendon was identified and a 6 × 2.5 cm elliptical skin defect was created just proximal to the tendon (). The exposed muscle was sutured to the skin edges as previously described by Zinman []. The second harvested buccal graft was quilted on the exposed muscle with 4-0 polydioxanone sutures and a tie-over dressing and an elastic bandage around the leg were applied for one week (). The patient had returned home on postoperative day one and was seen in the clinic at 1-2-week intervals for the graft assessments. Both the urethral catheter and the tie-over dressings were removed at one-week follow-up.
Stage 2. Eight weeks after the first stage, both grafts appeared to have taken well with no signs of a contracture or stenosis of the urethrostomy (). Again, the patient was placed in a low lithotomy position and prepped with access to the perineum and the left inner thigh. The perineal urethrostomy was freed by incising the skin just around the edges of the buccal graft (new dorsal hemi-plate) and dissecting laterally away from the graft (). Both proximal and distal urethral stumps were again calibrated with a bougie at 24 French.
The second incision was made around the buccal mucosa engrafted on gracilis and extended distally and proximally 3–5 cm along the axis of the muscle. The muscle was circumferentially dissected proximally and distally and its tendon transected (). The minor distal vascular pedicles to gracilis were tied and severed. To facilitate the gracilis harvest and its tunneling, another 5 cm incision was made along the course of the muscle equidistant between the perineal incision and the distal gracilis incision. The major proximal vascular pedicle located approximately 10 cm distal to the pubic ramus was preserved. The muscle-graft composite was passed through a wide tunnel into the perineal incision and the BMG edges on the flap (new ventral plate) were approximated apex-to-apex to the edges of the dorsal graft with running 4-0 polydioxanone sutures (Figures –). A 16-French silicone catheter was left in place. The gracilis muscle was sutured to corpora cavernosa as a second layer over the first suture line with a 3-0 polyglactin suture. Both the perineal and the leg incisions were closed in layers and a Jackson-Pratt drain was left in the gracilis harvest bed for one week. The patient returned home one day after the operation and was followed in the office at 1-2-week intervals. He had retrograde and antegrade imaging studies in the office at 3 weeks demonstrating a small contrast extravasation which had resolved by 5 weeks at which point his urethral catheter was removed (). The suprapubic catheter was removed 6 weeks later after a period of successful voiding with tube clamped.
At 8-month follow-up patient was voiding with a maximum flow of 53 cc/sec and a postvoid residual of 51 cc. He has reported no urinary incontinence and no fistulous connection to the perineum itself. He has demonstrated a relatively preserved erectile function with SHIM score decreasing from 21 preoperatively to 18 postoperatively. Through his follow-up patient reported having neither chordee nor pain with erections. As expected, he admitted diminished force of ejaculation (since before his trauma) and minimal postvoid dribbling. On the office cystoscopy at 8-month follow-up the patient demonstrated patent anastomotic sites and a patulous neourethral segment circumferentially lined with healthy appearing buccal mucosa (). The patient has reported working without limitations and has not been having any functional disability or changes in his gate.


Case 1 is a skull from a female estimated at 6–8 years old based on tooth wear. The right maxillary P4 is missing, likely due to the extensive erosion of the alveoli (Fig. a). At the level of the left P4 and M1, the palate shows erosions resulting in porosification and even perforations (Fig. a). The left buccal side of the maxilla show porosification at P3, M2 and M3, whereas perforations at M1 expose the roots (Fig. b).


Case 3 is a skull from a female estimated at 5–7 years old based on tooth wear. The palatal side of the right maxilla shows erosion of alveolar pockets of P4 and erosion of the palate along the molars (Fig. a), whereas the left side has erosions and perforations of the palate (Fig. b). The right buccal side shows severe erosion of the maxilla exposing most of the roots of the molars, and with perforations exposing the roots of the premolars (Fig. c), similar to the left buccal side (Fig. d). The left buccal side of the mandible shows advanced erosion and perforations at the level of molars, and a reduced jaw height (Fig. e). The alveolar pockets at M3 are eroded while the jaw is thickened (Fig. f, g). The right buccal side of the mandible also exhibits erosion at M3 and a reduction of mandibular height (Fig. h).


Case 4 is a skull from a female estimated at 2–4 years old based on tooth wear, i.e. a young animal. The palate bordering the right premolars shows porosification and the alveoli of P4 are eroded (Fig. a). The left and right buccal sides of the maxilla show porosification and perforations which expose the roots of most upper teeth (Fig. b, c).


This 2-month-old boy presented with a tense fontanelle, abnormal head growth, episodes of vomiting, and “sunset” gaze.
Radiographic findings An MRI revealed pronounced supratentorial hydrocephalus and a partially contrast enhancing right-sided posterior fossa tumor with downward herniation through the foramen magnum and lateral displacement of the brain stem (Fig. ).
Operation Intraoperative external drainage of the cerebrospinal fluid (CSF) was established to control the intracranial pressure (ICP). A suboccipital craniotomy was performed in the mid-line. The tumor was microsurgically excised via the fourth ventricle to gross-total resection (GTR) of the tumor. The external drainage was terminated as CSF flow through the Sylvian aqueduct had been observed. Postoperative MRI scans performed in the same anesthetical procedure as the surgery confirmed the GTR (Fig. ).
The histological examination revealed a malignant small cell tumor with several true multilayered rosettes (Fig. a). The rosettes were postitive for vimentin (Fig. b), but negative for GFAP (Fig. c) and synaptophysin. The tumor was also focally positive for cytokeratin. The Ki-67 labelling index was about 90% in the most cellular areas (Fig. d). The tumor was diagnosed as an ependymoblastoma.
The biopsy has been re-examined by an experienced neuropathologist with the same conclusion.
Signs of persistent hydrocephalus reappeared after 3 days, and the patient underwent an endoscopic 3rd ventriculocisternostomy. This procedure did not suffice and a ventriculoperitoneal CSF-shunt had to be inserted after 2 weeks. After careful consideration the boy was given chemotherapy according to the MET-HIT 2000-BIS4 protocol during the following 40 weeks. He had several episodes with serious infections, including shunt infection. Following completion of the chemotherapy and infection controls, a new CSF shunt, now ventriculoatrial, was implanted, 14 months after the tumor resection.
Serial follow-up MRI scans have demonstrated relative normalization in the posterior fossa (Fig. ), without any signs of recurrent neoplastic disease, as well as stable ventriculoatrial shunt function.
Today, this boy is 12 years and he follows a normal school program with some assistance (5 h special teaching a week).
He has minor balance problems, but is playing soccer and he is also doing cross-country skiing.