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1.  Solitary breast metastasis from myxoid liposarcoma 
BMC Cancer  2014;14:482.
Background
Metastasis to the breast from nonmammary malignancies is rare, and mostly involves patients in a pre-terminal condition with systemic metastases outside the breast. Lymphoma and leukemia, melanoma, and lung carcinoma are the most common primary malignancies to cause breast metastasis; metastasis of soft tissue sarcoma to the breast is very rare. Here, we report a case of primary lower-extremity myxoid liposarcoma with the development of a solitary metastasis to the breast. To the best of our knowledge, no isolated case reports of solitary breast metastasis by myxoid liposarcoma have been previously reported in the English-language literature.
Case presentation
The patient, a 66-year-old woman, had been previously diagnosed with myxoid liposarcoma of the right thigh. At 21 months after complete surgical resection of the primary tumor with negative margins, a palpable tumor was identified in the patient’s left breast. Needle biopsy revealed the presence of metastatic liposarcoma; positron emission tomography/computed tomography examination confirmed the metastasis as solitary, and no local recurrence of the primary tumor was identified. The patient underwent lumpectomy with negative margins and did not provide consent for adjuvant chemotherapy. As with the biopsy specimen and the total cleavage specimen, myxoid liposarcoma with metastasis to the breast was diagnosed. No recurrence or new metastases were observed five years after resection of the metastatic breast lesion.
Conclusions
We have presented an extremely rare case of a solitary metastatic breast tumor arising from myxoid liposarcoma of the lower limbs. There is no standard treatment for the management of solitary breast metastasis from myxoid liposarcoma. Therefore, treatment should be guided by consideration of an individual patient’s overall condition.
doi:10.1186/1471-2407-14-482
PMCID: PMC4089553  PMID: 24994066
Solitary metastasis; Breast; Resection; Liposarcoma
2.  First evidence of a large CHEK2 duplication involved in cancer predisposition in an Italian family with hereditary breast cancer 
BMC Cancer  2014;14:478.
Background
CHEK2 is a multi-cancer susceptibility gene whose common germline mutations are known to contribute to the risk of developing breast and prostate cancer.
Case presentation
Here, we describe an Italian family with a high number of cases of breast cancer and other types of tumour subjected to the MLPA test to verify the presence of BRCA1, BRCA2 and CHEK2 deletions and duplications. We identified a new 23-kb duplication in the CHEK2 gene extending from intron 5 to 13 that was associated with breast cancer in the family. The presence and localisation of the alteration was confirmed by a second analysis by Next-Generation Sequencing.
Conclusions
This finding suggests that CHEK2 mutations are heterogeneous and that techniques other than sequencing, such as MLPA, are needed to identify CHEK2 mutations. It also indicates that CHEK2 rare variants, such as duplications, can confer a high susceptibility to cancer development and should thus be studied in depth as most of our knowledge of CHEK2 concerns common mutations.
doi:10.1186/1471-2407-14-478
PMCID: PMC4091954  PMID: 24986639
CHEK2; Duplication; Breast cancer; Hereditary cancer; MLPA; Next-generation sequencing
3.  Leptomeningeal metastasis from hepatocellular carcinoma with other unusual metastases: a case report 
BMC Cancer  2014;14:399.
Background
Leptomeningeal metastasis, which results from metastasis of tumors to the arachnoid and pia mater, can lead to the dissemination of tumor cells throughout the subarachnoid space via the cerebral spinal fluid, and frequently with a poor prognosis. The primary tumor in adults is most often breast cancer, lung cancer, or melanoma. Although leptomeningeal metastasis due to cholangiocarcinoma has been reported, to the best of our knowledge there is no cytologically confirmed report of leptomeningeal metastasis from hepatocellular carcinoma.
Case presentation
We herein report a case of leptomeningeal metastasis from hepatocellular carcinoma in a 53-year-old woman with concomitant systemic metastases to the lung, bone, brain, kidney, adrenal gland, subcutaneous tissues, and abdominal pelvis. The neurological symptoms of the patient were relieved after treatment with methotrexate intra-cerebral spinal fluid chemotherapy concurrent with whole brain radiotherapy.
Conclusion
To our knowledge this is the first report of leptomeningeal metastasis from hepatocellular carcinoma confirmed by cytology. Treatment with methotrexate intra-cerebral spinal fluid chemotherapy concurrent with whole brain radiotherapy was effective.
doi:10.1186/1471-2407-14-399
PMCID: PMC4048255  PMID: 24893802
Hepatocellular carcinoma; Metastasis; Leptomeningeal metastasis
4.  FOXP1 and TP63 involvement in the progression of myelodysplastic syndrome with 5q- and additional cytogenetic abnormalities 
BMC Cancer  2014;14:396.
Background
The progression of low-risk del(5q) myelodysplastic syndrome to acute myeloid leukemia is increased when associated with mutations of TP53, or with additional chromosomal abnormalities. However, to date the prognostic impact and molecular consequences of these rearrangements were poorly investigated. Single additional alterations to del(5q) by balanced chromosome rearrangements were rarely found in myelodysplasia. In particular, balanced alterations involving TP63 and FOXP1 genes were never reported in the literature.
Case presentation
Here we report on a 79-year woman with an aggressive form of myelodysplastic syndrome with del(5q), no TP53 mutation, and a novel complex rearrangement of chromosome 3 in bone marrow cells. Our results revealed that the FOXP1 and TP63 genes were both relocated along chromosome 3. Strikingly, immunohistochemistry analysis showed altered protein levels, disclosing that this rearrangement triggered the expression of FOXP1 and TP63 genes. FOXP1 was also found activated in other patients with myelodysplasia and acute myeloid leukemia, showing that it is an important, recurrent event.
Conclusions
We document an apparent role of FOXP1 and TP63, up to now poorly documented, in the progression of MDS in our patient who is lacking mutations in the TP53 tumor suppressor gene normally associated with poor outcome in myelodysplastic syndrome with 5q-. Finally, our results may suggest a possible broader role of FOXP1 in the pathogenesis and progression of myelodysplasia and acute myeloid leukemia.
doi:10.1186/1471-2407-14-396
PMCID: PMC4059025  PMID: 24893616
Double inversion; Myeloid leukemia; TP53; Gene activation; Chromosome 3
5.  Multiple scalp metastases from colonic neuroendocrine carcinoma: case report and literature review 
BMC Cancer  2014;14:305.
Background
Colonic neuroendocrine neoplasms (NENs) are relatively rare tumors with an incidence rate of 0.11–0.21/100,000. NENs account for approximately 0.4% of colorectal neoplasms. Cutaneous metastases of colonic neuroendocrine carcinomas (NECs) are very infrequent, while cases of scalp metastasis are even fewer. Cutaneous metastases are more rare than visceral metastases and usually develop later; therefore, cutaneous metastases as initial distant metastases can be easily overlooked. This is the second case report of a colonic NEC with scalp metastasis. Compared with the previous case, in this instance scalp metastasis developed before visceral metastasis, and the cutaneous lesions were confined to the scalp alone.
Case presentation
A 62-year-old Chinese man, who had undergone radical surgery for a “locoregional” colonic NEC one and half months before, came to our hospital for adjuvant chemotherapy. We found multiple scalp nodules during physical examination. Moreover, these nodules had occurred and had not been detected prior to the patient undergoing radical surgery. The scalp nodules proved to be metastases from colonic NEC as determined using pathological and immunohistochemical examinations following lumpectomy. After one and half months, visceral metastases were detected in this patient. Ultimately, the patient died two months later.
Conclusions
In this report an unusual case of a colonic NEC with initial distant metastasis confined to the scalp is presented. This case is unusual because of the development of cutaneous metastasis before visceral metastasis. The scalp metastasis were initially overlooked, leading to inaccurate staging and radical surgery that was not curative. This demonstrates that distant metastasis can occur during the early phase of tumor growth in these aggressive lesions. Thus, the possibility of distant metastases should be assessed in the initial work up to avoid mistaken clinical staging especially when distant metastases occur only in skin.
doi:10.1186/1471-2407-14-305
PMCID: PMC4012716  PMID: 24884973
Colon cancer; Neuroendocrine carcinoma; Scalp; Metastasis
6.  Large cell anaplastic medulloblastoma metastatic to the scalp: tumor and derived stem-like cells features 
BMC Cancer  2014;14:262.
Background
Extraneural metastases (ENM) rarely occur in medulloblastoma (MBL) patients and only few cases of subcutaneous localizations have been described. ENM indicate an aggressive disease associated with a worse prognosis. The characterization of metastatic tumours might be useful to understand their pathogenesis and to identify the most appropriate therapeutic strategies.
Case presentation
We present the case of a child with Large Cell Anaplastic (LC/A) MBL, who developed multiple subcutaneous metastases in the scalp area after a ventriculo-peritoneal shunting procedure. The disease rapidly progressed and the child died despite chemotherapy and primary tumour surgical debulking.
We molecularly classified the tumour as a group 3 MBL; in addition, we derived stem-like cells (SLC) from a metastatic lesion. Primary tumour, metastases and SLC were further analysed, particularly focusing on features linked to the cutaneous dissemination. Indeed, molecules involved in angiogenesis, cell invasion and epidermal growth factor signalling resulted highly expressed.
Conclusions
The present report describes a very rare case of subcutaneous metastatic MBL. The tumour, metastases and SLC have been clinically, pathologically and molecularly characterized. Our case is an example of multidisciplinary approach aiming to characterize MBL aggressive behaviour.
doi:10.1186/1471-2407-14-262
PMCID: PMC4013534  PMID: 24739212
Medulloblastoma; Stem-like cells; Molecular features; Subcutaneous metastasis
7.  Complete clinical regression of a BRAF V600E-mutant pediatric glioblastoma multiforme after BRAF inhibitor therapy 
BMC Cancer  2014;14:258.
Background
Standard therapies for high grade glioma have failed to substantially improve survival and are associated with significant morbidity. At relapse, high grade gliomas, such as glioblastoma multiforme, are refractory to therapy and universally fatal. BRAF V600E-mutations have been described in a modest 6% to 7% of primary central nervous system (CNS) tumors, but with increased prevalence in the pediatric population and in certain brain tumor subtypes. The use of BRAF inhibitors have transformed melanoma therapy however their use in brain tumors remains unproven.
Case presentation
We describe the pediatric case of a now 12 year old Caucasian male who originally presented at age 9 with a right fronto-parietal glioblastoma multiforme that recurred 2 ½ years from diagnosis. Molecular analysis of the primary tumor revealed a BRAF V600E mutation and the patient was placed on the BRAF inhibitor vemurafenib. A complete response was observed after 4 months of therapy and remains sustained at 6 months.
Conclusion
This is the first report of a complete response of relapsed glioblastoma multiforme to targeted BRAF inhibitor therapy. While not a predominant mutation in glioblastoma multiforme, the increased prevalence of BRAF V600 mutations in pediatric CNS tumors and certain subtypes marks a population to whom this therapy could be applied. Response to this therapy suggests that BRAF inhibitors can affect primary CNS lesions when a documented and targetable mutation is present.
doi:10.1186/1471-2407-14-258
PMCID: PMC3996187  PMID: 24725538
High-grade glioma; Glioblastoma multiforme; BRAF mutations; V600E; Pediatric brain tumor; BRAF inhibitors
8.  Complete pathologic response of HER2-positive breast cancer liver metastasis with dual Anti-HER2 antagonism 
BMC Cancer  2014;14:242.
Background
Although breast cancer frequently metastasizes to the bones and brain, rarely breast cancer patients may develop isolated liver metastasis. There is increasing data that anti-HER2 targeted therapy in conjunction with systemic chemotherapy may lead to increased rates of pathologic complete response in the primary breast cancer. However, little is known about its effects on metastatic liver disease.
Case presentation
We report the treatment of a 54-year-old female who was diagnosed with HER2-positive invasive ductal carcinoma and synchronous breast cancer liver metastasis (BCLM). The patient underwent eight cycles of standard docetaxel with two anti-HER2 targeted agents, trastuzumab and pertuzumab. Subsequent radiographic imaging demonstrated complete radiographic response in the primary lesion with an approximate 75% decrease in the liver metastasis. After informed consent the patient underwent modified radical mastectomy that revealed pathologic complete response. Re-staging demonstrated no new disease outside the liver and a left hepatectomy was performed for resection of BCLM. Final pathologic examination revealed no residual malignant cells in the liver specimen, indicating pathologic complete response. Herein, we discuss the anti-HER2 targeted agents trastuzumab and pertuzumab and review the data on dual HER2 antagonism for HER2-positive breast cancer and the role of surgical resection of BCLM.
Conclusions
The role of targeted agents for metastatic HER2-positive breast cancer is under active clinical trial investigation and we await the maturation of trial results and long-term survival data. Our results suggest that these agents may also be effective for producing considerable pathologic response in patients with BCLM.
doi:10.1186/1471-2407-14-242
PMCID: PMC3978138  PMID: 24708527
HER2-positive breast cancer; Targeted therapy; Breast cancer liver metastases; Trastuzumab; Pertuzumab; Complete pathologic response
9.  A novel deleterious PTEN mutation in a patient with early-onset bilateral breast cancer 
BMC Cancer  2014;14:70.
Background
An early age at Breast Cancer (BC) onset may be a hallmark of inherited predisposition, but BRCA1/2 mutations are only found in a minority of younger BC patients. Among the others, a fraction may carry mutations in rarer BC genes, such as TP53, STK11, CDH1 and PTEN. As the identification of women harboring such mutations allows for targeted risk-management, the knowledge of associated manifestations and an accurate clinical and family history evaluation are warranted.
Case presentation
We describe the case of a woman who developed an infiltrating ductal carcinoma of the right breast at the age of 32, a contralateral BC at age 36 and another BC of the right breast at 40. When she was 39 years-old, during a dermatological examination, mucocutaneous features suggestive of Cowden Syndrome, a disorder associated to germ-line PTEN mutations, were noticed. PTEN genetic testing revealed the novel c.71A > T (p.Asp24Val) mutation, whose deleterious effect, suggested by conservation data and in silico tools, was definitely demonstrated by the incapacity of mutant PTEN to inhibit Akt phosphorylation when used to complement PTEN-null cells. In BC tissue, despite the absence of LOH or somatic mutations of PTEN, Akt phosphorylation was markedly increased in comparison to normal tissue, thus implying additional somatic events into the deregulation of the PI3K/Akt/mTOR pathway and, presumably, into carcinogenesis. Hence, known oncogenic mutations in PIK3CA (exons 10 and 21) and AKT1 (exon 2) were screened in tumor DNA with negative results, which suggests that the responsible somatic event(s) is a different, uncommon one.
Conclusion
This case stresses the importance of clinical/genetic assessment of early-onset BC patients in order to identify mutation carriers, who are at high risk of new events, so requiring tailored management. Moreover, it revealed a novel PTEN mutation with pathogenic effect, pointing out, however, the need for further efforts to elucidate the molecular steps of PTEN-associated carcinogenesis.
doi:10.1186/1471-2407-14-70
PMCID: PMC3922036  PMID: 24498881
Hereditary breast cancer; PTEN; Cowden syndrome; PI3K/Akt/mTOR pathway
10.  Systemic effect of catumaxomab in a patient with metastasized colorectal cancer: a case report 
BMC Cancer  2013;13:618.
Background
Catumaxomab, the first anti-EpCAM antibody, was approved in 2009 for the treatment of malignant ascites in cancer patients with EpCAM positive tumors. We consider this case of interest as treatment with catumaxomab not only prolonged the puncture-free interval but also showed a systemic effect in a patient with metastasized colorectal cancer by regression of a pulmonary metastasis.
Case presentation
We describe the case of a 78 year old patient initially diagnosed with locally advanced colon cancer and one synchronous liver metastasis in September 2010 who was treated by hemicolectomy and simultaneous atypical liver resection. During adjuvant chemotherapy the patient developed a peritoneal carcinomatosis with ascites in March 2011. Palliative chemotherapy was not well tolerated and therefore refused by the patient. Because of disease progression in June 2011 with one pulmonary metastasis and clinically predominant ascites an immunotherapy with intraperitoneal catumaxomab was started in December 2011. After treatment with catumaxomab a puncture free survival of 12 months as well as a regression of the pulmonary lesion was achieved until January 2013.
Conclusion
This case suggests that treatment with catumaxomab does not only improve quality of life by local suppression of malignant ascites but also might have a systemic antitumor effect.
doi:10.1186/1471-2407-13-618
PMCID: PMC3880167  PMID: 24380380
Immunotherapy; Catumaxomab; Systemic effect; Colorectal cancer; Ascites
11.  Safety and efficacy of vemurafenib in end stage renal failure 
BMC Cancer  2013;13:581.
Background
Serine-threonine inhibitors, such as vemurafenib, are being used increasingly in cancer treatment, and the toxicity and therapeutic benefit need to be balanced carefully both before and during treatment.
Case presentation
A patient with metastatic melanoma and end stage renal failure who was on peritoneal dialysis was treated with the serine-threonine kinase inhibitor, vemurafenib. After 5 months of treatment, a substantial response to vemurafenib was observed using imaging, but when he developed a prolonged QTc interval (common toxicity criteria (CTC) grade 3), treatment was interrupted. Vemurafenib was restarted at a reduced dose when the QTc interval returned to normal. The patient has had a significant response to vemurafenib and continued on treatment for 12 months after beginning the therapy.
Conclusion
This is the first reported case of end stage renal failure in a patient who is taking vemurafenib. Although the patient developed QTc prolongation, it appears to be asymptomatic, and was managed with dose reduction. This case highlights the need for closer QTc monitoring at the start and during treatment.
doi:10.1186/1471-2407-13-581
PMCID: PMC4029063  PMID: 24314265
Renal excretion; Metastatic melanoma; Vemurafenib
12.  Papillary thyroid carcinoma with massive metastasis in the uterine corpus: a case report 
BMC Cancer  2013;13:551.
Background
Distant metastases stemming from a papillary thyroid carcinoma (PTC) are quite rare. Here we report an exceptional case of PTC presenting with cervical lymphatic and uterine metastases. This is the first case report of a PTC with uterine involvement.
Case presentation
A 60-year-old Chinese woman came to our hospital complaining of discomfort in the throat that she had been experiencing for about half a month. PTC and cervical lymphatic metastasis were diagnosed after ultrasound examinations. A massive heterogeneous mass was found beside the uterus during the pre-operative checkup and a diagnosis of ovarian carcinoma was suspected after a thorough case discussion. However, it proved to be a metastasis from the PTC as determined by pathological and immunohistochemical examinations after the operation. The patient declined further treatments. She was followed for 22 months with no sign of recurrence detected.
Conclusions
In this report, an unusual case of PTC was presented. The patient had not only regional lymphatic metastasis, but also had a massive metastasis in the uterine corpus, which was initially misdiagnosed as ovarian carcinoma. This case is of interest because of its rarity and exceptionally good prognosis. The reason for the misdiagnosis was attributed to overlooking the possibility of a distant metastasis coming from a PTC. This case raises the issue that completing an iodine-131 scan before operating on patients with PTC may be warranted.
doi:10.1186/1471-2407-13-551
PMCID: PMC3870965  PMID: 24252387
Papillary thyroid carcinoma; Metastasis; Ultrasound; Uterine
13.  Separate episodes of capillary leak syndrome and pulmonary hypertension after adjuvant gemcitabine and three years later after nab-paclitaxel for metastatic disease 
BMC Cancer  2013;13:542.
Background
Systemic capillary leak syndrome is a rare disease with a high mortality rate. This syndrome is characterised by generalised edema, hypotension, hemoconcentration, and hypoproteinemia. The cause is the sudden onset of capillary hyperpermeability with extravasations of plasma from the intravascular to the extravascular compartment. We present the case of a patient who experienced two episodes of systemic capillary leak syndrome and pulmonary hypertension; the first after gemcitabine in an adjuvant setting and the second three years later after treatment with nab-paclitaxel for metastatic disease.
Case presentation
A 65-year-old patient underwent a pancreatectomy in January 2010 for ductal carcinoma (pT3 N0 M0, stage IIa), followed by adjuvant chemotherapy. Seven days after the last cycle, she developed dyspnea associated with orthopnea and cough. A transthoracic cardiac ecocolordoppler was performed, with evidence of pulmonary hypertension (58 mmHg). Blood tests showed an increase in creatinine, pro-BNP and D-Dimer. She began high-dose diuretic therapy combined with cortisone. After a month, the patient was eupneic and the anasarca had resolved. We decided gradually to reduce the steroid and diuretic therapy. After ten days of the reduction, the patient began to re-present the same symptoms after treatment with gemcitabine. Corticosteroid therapy was restored with rapid clinical benefit and decreased pro-BNP after a week of treatment. After two years, the disease returned. As a first line treatment, it was decided to use nab-paclitaxel 100 mg/m2 weekly. After two doses, followed by approximately 14 days of treatment, the patient developed acute respiratory distress syndrome. The clinical suspicion was a relapse of capillary leak syndrome and treatment with a high-dose diuretic (furosemide 250 mg daily) was started combined with cortisone (40 mg methylprednisolone). The patient showed a progressive clinical benefit.
Conclusions
In patients treated with gemcitabine and nab-paclitaxel who experience a sudden onset of diffuse edema with respiratory distress, capillary leak syndrome should be suspected. Immediate treatment with corticosteroids may be life-saving.
doi:10.1186/1471-2407-13-542
PMCID: PMC3840643  PMID: 24215543
Capillary leak syndrome; Chemotherapy; Gemcitabine; Nab-paclitaxel; Abraxane; Pulmonary hypertension
14.  FELD better not thinking of metastases only when liver lesions appear after bleomycin-based treatment for non-seminoma testis from metastases 
BMC Cancer  2013;13:491.
Background
Bleomycin has become an integral part of chemotherapy in patients with germ-cell tumors. One of the most feared side effects is bleomycin-induced pneumonitis. In patients with mild or moderate BIP, radiological signs disappear almost completely within nine months after discontinuation of bleomycin treatment.
Case presentation
We present a patient with a history of non seminoma of the testis and bleomycin-induced pneumonitis. During follow-up, regression of the hypothesis of eosinophilic migration to the liver after regression of bleomycin-induced pneumonitis is highly suspicious based on transient eosinophilia and focal eosinophilic liver disease.
Conclusion
As follow up may consist of CT scanning in germ-line tumor patients, transient eosinophilic liver lesions reported during regressive bleomycin-induced pneumonitis should not be presumed automatically as metastatic tumor relapse and require further sequential imaging and pathological examination.
doi:10.1186/1471-2407-13-491
PMCID: PMC4015643  PMID: 24148527
Transient; Eosinophilia; Liver lesions; Non-seminoma testis
15.  Malignant extra-adrenal pancreatic paraganglioma: case report and literature review 
BMC Cancer  2013;13:486.
Background
Pancreatic paragangliomas are rare tumors, with only 16 reported cases to date. One of these cases demonstrates metastasis to lymph node, while another case was functional, however, none of these cases showed malignant and large, pancreatic paraganglioma with marked invasion. Also another unique feature was the age of our patient compared to the average reported ages in published literature (42–85 years).
Case presentation
A 19-year-old woman presented with a one-year history of intermittent abdominal pain. Physical examination showed a palpable mass in the right upper abdomen, but initial laboratory results were within normal ranges; tumor markers (CEA, AFP, and CA19-9) were negative. An abdominal and pelvic computed tomography (CT) scan showed a well-defined retroperitoneal para-aortic mass. The CT scan revealed that the surrounding lymph nodes were not enlarged, but the liver showed evidence of parenchymal infiltration. Intraoperatively, a large, firm tumor originating from the head of pancreas was found pushing on the caudate hepatic lobe and the inferior vena cava (IVC). The tumor was resected through a pancreaticoduodenectomy, involving segment VI of the liver and a small segment of the IVC. The blood pressure spiked (>220 mm Hg) when the tumor was manipulated during the operation. The final pathology report showed a 9-cm tumor with lymphovascular invasions; immunohistochemistry was positive for synaptophysin and chromogranin. All resection margins were negative and 1/15 lymph nodes was positive for metastasis. Post-operative recovery was unremarkable. One month after discharge, the patient was re-admitted with abdominal pain and found to have an abdominal collection at the resection site, which was drained under CT guidance. She received a therapeutic dose of I131-metaiodobenzylguanidine (MIBG). Follow-ups showed the absence of recurrence, and she has remained disease free.
Conclusion
This patient was an extraordinary example of a rare tumor. Even more remarkable was that the tumor was malignant with lymph node invasion. To our knowledge, a case similar to that presented here has not been previously reported in the literature.
doi:10.1186/1471-2407-13-486
PMCID: PMC4015757  PMID: 24138700
Pancreatic tumors; Extra adrenal paraganglioma; Malignant paraganglioma; Functional paragangiloma; Pancreatic paragangilioma
16.  Activity of EGFR-tyrosine kinase and ALK inhibitors for EML4–ALK-rearranged non–small–cell lung cancer harbored coexisting EGFR mutation 
BMC Cancer  2013;13:262.
Background
The EML4–ALK (echinoderm microtubule-associated protein-like 4 gene and the anaplastic lymphoma kinase gene) fusion oncogene represents a novel molecular target in a small subset of non–small–cell lung cancers (NSCLCs). The EML4–ALK fusion gene occurs generally in NSCLC without mutations in epidermal growth factor receptor (EGFR) and KRAS.
Case presentation
We report that a case of EML4–ALK-positive NSCLC with EGFR mutation had a response of stable disease to both an EGFR tyrosine kinase inhibitor (EGFR-TKI) and ALK inhibitor.
Conclusions
We described the first clinical report of a patient with EML4–ALK-positive NSCLC with EGFR mutation that had a response of stable disease to both single-agent EGFR-TKI and ALK inhibitor. EML4–ALK translocation may be associated with resistance to EGFR-TKI, and EGFR signaling may contribute to resistance to ALK inhibitor in EML4–ALK-positive NSCLC.
doi:10.1186/1471-2407-13-262
PMCID: PMC3671182  PMID: 23714228
EML4–ALK; EGFR mutation; Lung cancer
17.  [No title available] 
PMCID: PMC3640977  PMID: 23617826
18.  [No title available] 
PMCID: PMC3637265  PMID: 23570263
19.  A word of caution: do not wake sleeping dogs; micrometastases of melanoma suddenly grew after progesterone treatment 
BMC Cancer  2013;13:132.
Background
Hormonal treatment might affect the immune response to tumor antigens induced in cancer patients who are being vaccinated.
Case presentation
A 33 years-old woman was diagnosed with cutaneous melanoma in May 2009. Her melanoma was located in the intermammary sulcus, had a Breslow thickness of 4 mm, a Clark’s level IV, it was ulcerated and highly melanotic. The bilateral sentinel node biopsy was negative. She entered into a randomized Phase II/III clinical study comparing a vaccine composed of irradiated melanoma cells plus BCG plus GM-CSF versus IFN-alpha 2b and she was assigned to the vaccine arm. During the two years treatment she remained disease-free; the final CAT scan being performed in August 2011. Between November and December 2011, her gynecologist treated her with three cycles of 200 mg progesterone/day for ten days, every two weeks, for ovary dysfunction. In November 2011 the patient returned to the Hospital for clinical and imaging evaluation and no evidence of disease was found. At the next visit in March 2012 an ultrasound revealed multiple, large metastases in the liver. A CAT scan confirmed the presence of liver, adrenal glands and spleen metastases. A needle biopsy of a liver lesion revealed metastatic melanoma of similar characteristics to the original tumor. We suggest that progesterone treatment triggered proliferation of so far dormant micrometastases that were controlled during CSF470 vaccine treatment.
Conclusion
The use of progesterone in patients with melanoma that are under immunological treatments should be carefully considered, since progesterone could modify the balance of pro-inflammatory and Th1 functions to a regulatory and anti-inflammatory profile of the immune system that could have an impact in tumor progression.
doi:10.1186/1471-2407-13-132
PMCID: PMC3607845  PMID: 23510193
Melanoma; Vaccine treatment; Progesterone treatment; Metastasis
20.  Case report: long-term survival of an infant syndromic patient affected by atypical teratoid-rhabdoid tumor 
BMC Cancer  2013;13:100.
Background
Atypical teratoid rhabdoid tumor (ATRT) patients display a dismal median overall survival of less than 1 year. A consistent fraction of cases carries de-novo SMARCB1/INI1 constitutional mutations in the setting of the “rhabdoid tumor predisposition syndrome” and the outcome is worst in infant syndromic ATRT patients.
Case presentation
We here describe a patient affected by mosaic Klinefelter syndrome and by rhabdoid tumor predisposition syndrome caused by constitutional SMARCB1/INI1 heterozygous mutation c.118C>T (Arg40X). Patient’s ATRT primary tumor occurred at 2 years of age concurrent with metastatic lesions. The patient was rendered without evidence of disease by combined surgery, high-dose poli-chemotherapy and craniospinal irradiation, followed by autologous hematopoietic stem cell transplantation. At the onset of a spinal lesion 5.5 years later, both tumors were pathologically and molecularly evaluated at the national central pathology review board and defined as ATRT in a syndromic patient, with strong evidence of a clonal origin of the two lesions. The patient was then treated according to SIOP guidelines and is now alive without evidence of disease 24 months after the detection of metastatic disease and 90 months after the original diagnosis.
Conclusion
The report underscores the current utility of multiple comprehensive approaches for the correct diagnosis and clinical management of patients affected by rare and atypical brain neoplasms. Successful local control of disease and achievement of long-term survival is possible in ATRT patients even in the setting of rhabdoid tumor predisposition syndrome, infant age at diagnosis and metastatic spread of disease, thus justifying the efforts for the management of this severe condition.
doi:10.1186/1471-2407-13-100
PMCID: PMC3600022  PMID: 23510391
Atypical teratoid rhabdoid tumor; ATRT; SMARCB1/INI1; Medulloblastoma; MLPA
21.  First description of an acinic cell carcinoma of the breast in a BRCA1 mutation carrier: a case report 
BMC Cancer  2013;13:46.
Background
Acinic cell carcinoma (ACC) is a rare malignant epithelial neoplasm characterized by the presence of malignant tubular acinar exocrine gland structures. Diagnosis is generally made in salivary glands and in the pancreas. ACC of the breast has been reported in few cases only. Carriers of inherited mutations in the BRCA1 gene are prone to the development of breast cancer, mainly invasive ductal or medullary type carcinomas. We describe for the first time a BRCA1 mutation carrier with a diagnosis of ACC of the breast.
Case presentation
The patient developed an invasive ductal carcinoma (IDC) at the age of 40 years and an ACC in the contralateral breast at 44 years. Immunohistochemical examination of the ACC revealed a triple negative status (i.e., negativity for estrogen receptor, progesterone receptor and HER2 protein) and positivity for p53. Using a combination of loss of heterozygosity (LOH) and sequencing analyses, the loss of the wild-type BRCA1 allele was detected in both the ACC and the IDC. In addition, two different somatic TP53 mutations, one in the ACC only and another one in the IDC only, were observed.
Conclusion
Both the immunohistochemical and molecular features observed in the ACC are typical of BRCA1-associated breast cancers and suggest an involvement of the patient’s germline mutation in the disease. The occurrence of rare histological types of breast cancers, including malignant phyllodes tumor, atypical medullary carcinoma and metaplastic carcinoma, in BRCA1 mutation carriers has been already reported. Our findings further broaden the spectrum of BRCA1-associated breast malignancies.
doi:10.1186/1471-2407-13-46
PMCID: PMC3636039  PMID: 23374397
Acinic cell carcinoma; Breast cancer; BRCA1; Triple negative; TP53 mutation
22.  Early onset recall pneumonitis during targeted therapy with sunitinib 
BMC Cancer  2013;13:3.
Background
Sunitinib interacts with radiation therapy, leading to synergism of the toxicities of these treatments. Radiation recall pneumonitis is a rare but serious complication of targeted therapy with tyrosine kinase inhibitors.
Case presentation
The case of a patient with metastatic renal cell cancer (RCC) who developed recall pneumonitis on the first cycle of systemic sunitinib treatment is reported here. A 65-year-old man with RCC and bone metastasis underwent radiation therapy on his thoracic vertebrae (Th5-8) with a total dose of 24 Gy. Sunitinib (37.5 mg) was started 14 days after completing the radiation therapy. On the 14th day of sunitinib treatment, the patient developed progressive fever with worsening of dyspnea and general weakness. Treatment with pulse administration of prednisolone 1,000 mg for 3 days was initiated. Thereafter, the symptoms and the radiological findings regarding the interstitial filtration gradually improved over 7 days.
Conclusion
To our knowledge, this is the first report of early onset recall pneumonitis during sunitinib therapy. At present, how sunitinib interacts with radiation therapy remains unclear. The possibility that tyrosine kinase inhibitor therapy, including with sunitinib, after radiation therapy may lead to adverse effects should be kept in mind.
doi:10.1186/1471-2407-13-3
PMCID: PMC3582599  PMID: 23282195
Sunitinib; Renal cell cancer; Recall pneumonitis; Radiation; Radiation pneumonitis
23.  Functioning glucagonoma associated with primary hyperparathyroidism: multiple endocrine neoplasia type 1 or incidental association? 
BMC Cancer  2012;12:614.
Background
Diagnosis of multiple endocrine neoplasia type 1 (MEN1) is commonly based on clinical criteria, and confirmed by genetic testing. In patients without known MEN1-related germline mutations, the possibility of a casual association between two or more endocrine tumors cannot be excluded and subsequent management may be difficult to plan. We describe a very uncommon case of functioning glucagonoma associated with primary hyperparathyroidism (pHPT) in which genetic testing failed to detect germline mutations of MEN-1 and other known genes responsible for MEN1.
Case presentation
The patient, a 65-year old woman, had been suffering for more than 1 year from weakness, progressive weight loss, angular cheilitis, glossitis and, more recently, skin rashes on the perineum, perioral skin and groin folds. After multidisciplinary investigations, functioning glucagonoma and asymptomatic pHPT were diagnosed and, since family history was negative, sporadic MEN1 was suspected. However, genetic testing revealed neither MEN-1 nor other gene mutations responsible for rarer cases of MEN1 (CDKN1B/p27 and other cyclin-dependent kinase inhibitor genes CDKN1A/p15, CDKN2C/p18, CDKN2B/p21). The patient underwent distal splenopancreatectomy and at the 4-month follow-up she showed complete remission of symptoms. Six months later, a thyroid nodule, suspected to be a malignant neoplasia, and two hyperfunctioning parathyroid glands were detected respectively by ultrasound with fine needle aspiration cytology and 99mTc-sestamibi scan with SPECT acquisition. Total thyroidectomy was performed, whereas selective parathyroidectomy was preferred to a more extensive procedure because the diagnosis of MEN1 was not supported by genetic analysis and intraoperative intact parathyroid hormone had revealed “adenoma-like” kinetics after the second parathyroid resection. Thirty-nine and 25 months after respectively the first and the second operation, the patient is well and shows no signs or symptoms of recurrence.
Conclusions
Despite well-defined diagnostic criteria and guidelines, diagnosis of MEN1 can still be challenging. When diagnosis is doubtful, appropriate management may be difficult to establish.
doi:10.1186/1471-2407-12-614
PMCID: PMC3543729  PMID: 23259638
Multiple endocrine neoplasia type 1; Glucagonoma; Primary hyperparathyroidism
24.  Fatal case of sorafenib-associated idiosyncratic hepatotoxicity in the adjuvant treatment of a patient with renal cell carcinoma 
BMC Cancer  2012;12:590.
Background
Sorafenib is an orally available kinase inhibitor with activity at Raf, PDGFβ and VEGF receptors that is licensed for the treatment of advanced renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC). Current evidence-based post-nephrectomy management of individuals with localized RCC consists of surveillance-based follow up. The SORCE trial is designed to investigate whether treatment with adjuvant sorafenib can reduce recurrence rates in this cohort.
Case presentation
Here we report an idiosyncratic reaction to sorafenib resulting in fatal hepatotoxicity and associated renal failure in a 62 year-old man treated with sorafenib within the SORCE trial.
Conclusion
This is the first reported case of sorafenib exposure associated fatal toxicity in the adjuvant setting and highlights the unpredictable adverse effects of novel adjuvant therapies.
doi:10.1186/1471-2407-12-590
PMCID: PMC3575366  PMID: 23231599
Sorafenib; Hepatotoxicity; Adjuvant; SORCE; RCC; DILI
25.  Pyloric gland adenoma of the cystic duct with malignant transformation: report of a case with a review of the literature 
BMC Cancer  2012;12:570.
Background
Pyloric gland adenoma consists of closely packed pyloric-type glands lined by mucus-secreting cells. To date, approximately 230 cases have been reported, mostly of gastric localization with a tumour size up to 3.5 cm and a mean age of occurrence around 70 years. Adenocarcinoma develops in about 40% of cases and may be difficult to detect due to relatively mild nuclear atypia.
Case presentation
We present the first case of a pyloric gland adenoma of the cystic duct in a 62-year-old male patient and demonstrate the clinicopathologic characteristics, including radiographic, molecular, and cytogenetic findings. The 2 cm-tumour developed in the cystic duct and protruded into the hepatic and common bile duct. On microscopic examination, it displayed closely packed pyloric-type glands, and focal architectural distortion with mild nuclear atypia. Immunohistochemically, it expressed MUC1, MUC5AC, MUC6 and p53, but not MUC2 and CD10. The Ki67-proliferation index was 25%. Furthermore, high-grade intraepithelial neoplasia was observed in the surrounding bile duct. We detected chromosomal gains at 7p, 7q11q21, 15q, 16p, 20, losses at 6p23pter, 6q, 18, and amplifications at 1q and 6p21p22 in the pyloric gland adenoma by comparative genomic hybridization. A KRAS codon 12 mutation (c.35G>T; p.G12V) was detected in the pyloric gland adenoma and in the adjacent dysplasia by sequencing analysis. The diagnosis of pyloric gland adenoma was established with transition into well-differentiated adenocarcinoma and high-grade biliary intraepithelial neoplasia.
Conclusion
Pyloric gland adenoma evolving in the cystic duct is a rare differential diagnosis of obstructive bile duct tumours. Other premalignant bile duct lesions may be associated. Due to the risk of developing adenocarcinoma, surgical resection should be performed.
doi:10.1186/1471-2407-12-570
PMCID: PMC3532145  PMID: 23206236
Pyloric gland adenoma; Adenocarcinoma; Cystic duct; Comparative genomic hybridization (CGH); KRAS mutation

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