Immune-related intestinal pseudo-obstruction associated with nivolumab treatment in a lung cancer patient.

Immune checkpoint inhibition therapy using targeted monoclonal antibodies is a new therapeutic approach with significant survival benefit for patients with several cancer types. However, their use can be associated with unique immune-related adverse effects as a consequence of impaired self-tolerance due to loss of T-cell inhibition via a nonselective activation of the immune system. Nivolumab is an anti-PD-1 immune checkpoint inhibitor that was recently developed for cancer immunotherapy with remarkable responses in nonsmall cell lung cancer patients. We present a 62-year-old Caucasian male with recurrent lung adenocarcinoma and currently under third-line therapy with nivolumab, who was admitted in our hospital with abdominal distension. Radiologic findings were consistent with small bowel ileus. After four days of conservative treatment, the patient underwent exploratory laparotomy where no cause of ileus was discovered. Postoperative the ileus persisted and considering that an adverse effect of the immune checkpoint inhibition therapy occurred, the patient received high-dose prednisone resulting in gradual improvement of symptoms. Immune checkpoint inhibitors may induce adverse effects to unaffected organ systems and tissues including the skin, gastrointestinal, hepatic, pulmonary, and endocrine system. The mainstay treatment consists of immunosuppression with corticosteroids in the majority of cases. As the clinical use of immune checkpoint inhibitors is expanding rapidly, there is an emergence of unique immune-related adverse effects in a growing patient population. Gaining early awareness is essential in these patients in order to ensure prompt diagnosis and management.

A 12-year experience at a tertiary hospital on patients with multiple primary malignant neoplasms.

PURPOSE: The incidence of multiple primary malignant neoplasms (MPMN) has dramatically increased. The purpose of this retrospective study was to present the 12-year experience at a University Hospital in patients with MPMN and to investigate the role of genetic factors in their pathogenesis. METHODS: The medical records of 7516 cancer patients, treated in our Institution from 2000 to 2012, were reviewed. Diagnosis of MPMN was based on the Warren and Gates' criteria. RESULTS: Among 7516 patients, 39 (0.5%) (10 men, mean age 70.0±6.98 years, and 29 women, mean age 64.7±8.24 years) presented with MPMN. Eighty-two percent of them developed 2 primary malignant neoplasms (PMNs), whereas 3 PMNs were developed in 7 patients. Breast cancer was the most common cancer type diagnosed among female patients (59%); 14 and 3 had 2 and 3 PMNs, respectively. Eight had a family history of breast cancer while in 3 genetic testing revealed mutations in BRCA1 and BRCA2 genes. The second most common type of malignancy was colorectal cancer (24%); 5 developed 2 PMNs, whereas 2 developed 3 PMNs. Five patients had a family history of colorectal cancer. Colon cancer was the most frequent neoplasm among male patients (50%; 3 developed 2 and 2 3 PMNs. In 2 patients the family history was positive for colorectal cancer. CONCLUSIONS: Although many factors may contribute to MPMN development, positive family history and inherent mutations significantly predispose to MPMN appearance. Thus, management of MPMN patients should be based on a detailed family history and genetic testing.

Periodic Limb Movements during Sleep in Acute Stroke: Prevalence, Severity and Impact on Post-Stroke Recovery.

BACKGROUND: Periodic Limb Movements during Sleep (PLMS) have been described to be frequently present in stroke patients. We aimed to evaluate the prevalence and severity of PLMS in acute stroke patients and clarify the association between PLMS and coexisting Sleep Disordered Breathing (SDB). Additionally, we focused on identifying variables that could independently predict the presence of PLMS in patients with acute stroke. The potential impact of PLMS on stroke outcome at three months was investigated as well. METHODS: In this study, we performed overnight polysomnography on consecutive stroke patients within 72 h from symptom onset. Data regarding clinical and imaging characteristics were prospectively collected. National Institute of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS) and Epworth-Sleepiness Scale (ESS) were used to evaluate stroke severity on admission, stroke outcome at three months and history of daytime sleepiness, respectively. We documented PLMS and SDB using standard polysomnography criteria. RESULTS: We prospectively assessed 126 patients with acute stroke [109 with ischemic and 17 with hemorrhagic stroke, mean age 60 ± 11 years, 68% men, median NIHSS score on admission: 3 (IQR: 2-7)]. The overall rate of PLMS in our cohort was 76%, and the rate of SDB among patients with PLMS was 83%. PLMS detection rates differed significantly (p-value: <0.001) according to SDB, with PLMS prevalence increasing with greater SDB severity. SDB could independently (OR:4.869, 95% CI: 1.884-12.784, p-value: 0.001) predict the presence of PLMS in the acute stroke phase in multivariable analyses adjusting for potential confounders. Moreover, baseline stroke severity (NIHSS-score increase in per-1 point: OR: 0.819, 95% CI: 0.737-0.895, p-value < 0.001) and PLMS (OR:0.099, 95% CI: 0.009-0.482, p-value = 0.015) were significantly associated with the likelihood of excellent functional outcome (mRS-scores: 0-1) at 3 months. CONCLUSION: The common presence of mostly severe PLMS in patients with acute stroke and their negative effect on stroke outcomes point out the necessity for early PLMS detection and treatment.

Successful treatment with the mTOR inhibitor everolimus in a patient with perivascular epithelioid cell tumor.

Perivascular epithelioid cell tumor (PEComa) is an extremely rare neoplasm that appears to arise most commonly at visceral (especially gastrointestinal and uterine), retroperitoneal, and abdominopelvic sites. Malignant PEComas exist but are very rare. These tumors represent a family of mesenchymal neoplasms, mechanistically linked through activation of the mTOR signaling pathway. Metastatic PEComa is a rare form of sarcoma for which no effective therapy has been described previously and that has a uniformly fatal outcome. Although there is no known effective therapy, the molecular pathophysiology of aberrant mTOR signaling provides a scientific rationale to target this pathway therapeutically. The difficulty in determining optimal therapy, owing to the sparse literature available, led us to present this case. On this basis, we report a case of metastatic retroperitoneal PEComa treated with an oral mTOR inhibitor, with everolimus achieving significant clinical response.

Resistance to CDK4/6 inhibition: Mechanisms and strategies to overcome a therapeutic problem in the treatment of hormone receptor-positive metastatic breast cancer.

Selective CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, have been approved in combination with hormone therapy for the treatment of patients with HR+, HER2-negative advanced or metastatic breast cancer (mBC). Despite their promising activity, approximately 10 % of patients have de novo resistance, while the rest of them will develop acquired resistance after 24-28 months when used as first-line therapy and after a shorter period when used as second-line therapy. Various mechanisms of resistance to CDK4/6 inhibitors have been described, including cell cycle-related mechanisms, such as RB loss, p16 amplification, CDK6 or CDK4 amplification, and cyclin E-CDK2 amplification. Other bypass mechanisms involve the activation of FGFR or PI3K/AKT/mTOR pathways. Identifying the different mechanisms by which resistance to CDK4/6 inhibitors occurs may help to design new treatment strategies to improve patient outcomes. This review presents the currently available knowledge on the mechanisms of resistance to CDK4/6 inhibitors, explores possible treatment strategies that could overcome this therapeutic problem, and summarizes relevant recent clinical trials.

Safety and Efficacy of RAD001 (Everolimus) Administered Upon Relapse During or After Adjuvant Treatment in Post-menopausal Women With Hormone Receptor Positive, HER2/neu Negative Locally Advanced or Metastatic Breast Cancer (CRAD001JGR08 "MELPOMENI" study).

BACKGROUND/AIM: This study aimed to provide real-world safety and effectiveness data of everolimus (EVE) plus exemestane (EXE) in estrogen receptor positive/human epidermal growth factor receptor 2 negative (ER+/HER2-) advanced breast cancer (aBC). PATIENTS AND METHODS: This prospective observational study was conducted by 19 hospital-based oncologists in Greece. Eligible patients were treated with EVE+EXE in the first-line setting; EVE was initiated according to the approved label. RESULTS: Overall, 75 eligible patients (mean age: 66.9 years; visceral metastases: 49.3%; bone-only metastases: 37.3%) were included in the effectiveness analyses. Over a median (interquartile range) of 12.1 months (range=4.2-20.5 months) of EVE treatment, the median progression-free survival was 18.0 months and the overall response rate was 22.7%. Among patients that received ≥1 EVE dose (n=80), the incidence of EVE-related adverse events was 72.5% (serious: 55.0%); stomatitis (22.5%), fatigue (22.5%), pneumonitis (18.8%); and cough (18.8%) were the most common. CONCLUSION: In the routine care in Greece, EVE demonstrates clinical benefit and a predictable safety profile.

Genetic Predisposition to Male Breast Cancer: A Case Series.

BACKGROUND/AIM: Male breast cancer (MBC) is a very rare disorder affecting approximately 1 in 833 men. Genetic predisposition is one of the most important risk factors of MBC with BRCA2 being the most commonly mutated gene in males diagnosed with breast cancer. However, a large part of MBC heritability is still unexplained. This study sought to add to the data already available on the genetics of MBC. MATERIALS AND METHODS: Our study initially involved comprehensive analysis of BRCA1 and BRCA2, followed by analysis of 43 genes implicated in cancer predisposition in a series of 100 Greek patients diagnosed with MBC between 1995-2015. RESULTS: Pathogenic variants were identified in 13 patients, with BRCA2 being the most commonly affected gene, followed by BRCA1, RAD50, RAD51B, and MSH3. CONCLUSION: In agreement with previous reports, BRCA2 is the most important genetic factor of MBC predisposition, while the remaining known cancer predisposition genes are each very rarely involved, rendering conclusions as to their cumulative effect difficult to draw.

Abscess formation mimicking disease progression, in a patient with metastatic renal cell carcinoma during sunitinib treatment.

BACKGROUND: Renal cell carcinoma (RCC) represents approximately 3% of all adult cancers and is more common in males. Systemic treatment for RCC has improved following the introduction of tyrosine kinase inhibitors, such as sunitinib. The molecular targets of sunitinib are receptor tyrosine kinases (RTKs). Moreover, sunitinib has an additional anti-angiogenic effect through its inhibition of the vascular endothelial growth factor receptor activation. CASE PRESENTATION: We present a case of intra-abdominal abscess formation mimicking disease progression, in a patient with metastatic renal cell carcinoma during sunitinib treatment. CONCLUSION: In the advancing era of molecular therapy of solid tumours, sunitinib has demonstrated significant efficacy in the post-cytokine setting treatment of metastatic renal cancer. Concurrently, however, increasing evidence has emerged to indicate that this class of drugs exert profound immunomodulatory effects on T cells and play major roles in immune tumor surveillance.

Recurrence-free Survival and Safety of Imatinib in Patients With Gastrointestinal Stromal Tumour (GIST) in Greece.

AIM: The purpose of the Imadje study was to confirm the efficacy and safety of imatinib, following resection of kit-positive gastrointestinal stromal tumour (GIST), in the adjuvant setting in the Greek population. PATIENTS AND METHODS: A total of 34 adult patients already receiving imatinib were enrolled. Recurrence-free (RFS) and overall survival, as well as time to treatment failure and safety were assessed. RESULTS: Overall survival could not be estimated in the present study, as no death occurred. Overall, 91.2% of patients were recurrence-free at 36 months, while the median time to treatment failure was 35 months. No new or unexpected safety findings were observed. Mutation analysis in 14 patients showed that the most frequent mutations were located in KIT exon 11 (64.3%) and exon 9 (28.6%). Univariate analysis showed that only surgical resection with a margin classification of R0 was associated with better RFS. CONCLUSION: Adjuvant treatment with imatinib for 3 years in patients with intermediate to high risk of recurrence was proven to prolong RFS, while being well-tolerated and not exhibiting a negative impact on patient compliance with therapy.

Low-dose capecitabine plus docetaxel as first-line therapy for metastatic breast cancer: phase II results.

The addition of capecitabine to docetaxel significantly improves overall survival in anthracycline-pretreated metastatic breast cancer. We evaluated a low-dose capecitabine-docetaxel regimen as first-line therapy. Patients who had received adjuvant anthracyclines received docetaxel 75 mg/m2 on day 1 and capecitabine 950 mg/m2 twice daily, days 1-14, every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was time to progression. Forty-five patients were evaluable (median age 56 years, range 35-75). The response rate was 42%, including two complete responses. Nine patients (20%) attained stable disease. Median time to progression was 8 months and median overall survival was 23 months. Five patients (11%) experienced grade 3 neutropenia but febrile neutropenia was absent. Three patients (7%) experienced grade 3 hand-foot syndrome; there was no significant gastrointestinal toxicity. This capecitabine-docetaxel regimen is an active first-line therapy and appears better tolerated than regimens using a higher capecitabine dose. Data from the randomized trial comparing the registered versus a lower capecitabine dose, both in combination with docetaxel, should definitively answer whether a lower dose provides a better safety profile while maintaining the considerable efficacy of this combination.

Devastating epidemics in recent ages Greek populations

In the recent Greek ages the most devastating epidemics were plague, smallpox, leprosy and cholera. In 1816 plague struck the Ionian and Aegean Islands, mainland Greece, Constantinople and Smyrna. The Venetians ruling the Ionian Islands effectively combated plague in contrast to the Ottomans ruling all other regions. In 1922, plague appeared in Patras refugees who were expelled by the Turks from Smyrna and Asia Minor. Inoculation against smallpox was first performed in Thessaly by the Greek women, and the Greek doctors Emmanouel Timonis (1713, Oxford) and Jakovos Pylarinos (1715, Venice) made relevant scientific publications. The first leper colony opened in Chios Island. In Crete, Spinalonga was transformed into a leper island, which following the Independence War against Turkish occupation and the unification of Crete with Greece in 1913, was classified as an International Leper Hospital. Cholera struck Greece in 1853-1854 brought by the French troops during the Crimean War, and again during the Balkan Wars (1912-13) when the Bulgarian troops brought cholera to northern Greece. Due to successive wars, medical assistance was not always available, so desperate people turned many times to religion through processions in honor of local saints, for their salvation in epidemics.

Gemcitabine in combination with vinorelbine for heavily pretreated advanced breast cancer.

PURPOSE: To evaluate the activity and toxicity of gemcitabine and vinorelbine in patients with metastatic breast cancer (MBC), previously treated with anthracyclines alone or with taxanes. PATIENTS AND METHODS: A total of 86 pretreated patients with MBC (median age 62 years), entered the study. Thirty-six patients had been pretreated with anthracyclines and 8 were resistant. The combination of gemcitabine (1000 mg/m2) and vinorelbine (25 mg/m2) was administered on days 1 and 8 every 3 weeks, for a total of 6 cycles. RESULTS: A total of 344 cycles of chemotherapy were administered (median 4 cycles per patient). Partial responses were observed in 31 patients (36.0%; 95% CI: 23-56). The median duration of response was 7 months (range 3-11 months) and the median overall survival was 14 months (range 6-21). The scheme was well tolerated. CONCLUSION: The combination of vinorelbine and gemcitabine is an active scheme in pretreated MBC, demonstrating an acceptable toxicity profile, and may well represent a valuable therapeutic choice after anthracycline/taxane regimens.

Gemcitabine combined with 5-fluorouracil for the treatment of advanced carcinoma of the pancreas.

BACKGROUND: Gemcitabine is an active agent in pancreatic cancer, showing clinical synergy with 5-fluorouracil (5-FU). The aim of the study was to evaluate the safety and efficacy of the combination of gemcitabine and 5-FU in patients with advanced adenocarcinoma of the pancreas. PATIENTS AND METHODS: Forty-two patients (median age, 62 years), with advanced or metastatic pancreatic adenocarcinoma, were enrolled in the study. The combination of gemcitabine (1000 mg/m2) and 5-FU (600 mg/m2) was administered on days 1, 8 and 15 and repeated every 28 days. RESULTS: A total of 168 cycles (median 4 cycles per patient) were administered. Partial responses were observed in 6 patients (14.2%) and stable disease in 11 (26.2%). The overall clinical benefit was 40.4%. Symptom relief and improvement of performance status were observed in 18 (42.8%) patients. The median time to progression, median duration of response and the median overall survival, were 6, 7 and 13 months, respectively. The most common grade 3 to 4 toxicities were neutropenia, anaemia and diarrhoea. CONCLUSION: The combination of gemcitabine and 5-FU is an active regimen for the treatment of advanced pancreatic cancer with an acceptable toxicity profile.

Third-line hormonal treatment with exemestane in postmenopausal patients with advanced breast cancer progressing on letrozole or anastrozole. A phase II trial conducted by the Hellenic Group of Oncology (HELGO).

AIMS AND BACKGROUND: The understanding of hormonal therapies in postmenopausal women with metastatic breast cancer has advanced greatly in the past several decades. With the introduction of orally active, potent and selective third-generation aromatase inhibitors (anastrozole, letrozole and exemestane), approaches to the treatment of hormone-sensitive advanced breast cancer are undergoing reevaluation. For treatment of advanced or metastatic disease that has progressed on tamoxifen, all three agents are active. The purpose of the study was to assess the antitumor efficacy and tolerance of exemestane administered as third-line hormonal therapy to postmenopausal women with metastatic breast cancer refractory to letrozole and anastrozole. STUDY DESIGN: Sixty postmenopausal women with stage IV hormone receptor-positive carcinoma of the breast were enrolled in the study. All patients had received two prior hormonal manipulations and had measurable or assessable disease. All adverse events were monitored. RESULTS: Objective tumor response was achieved in 12 (20%) patients (95% CI, 9.6-30.4). The overall clinical benefit was 38.3% (95% CI, 21.2-49.3), and the median duration of objective tumor response was 20 months (range, 9-26). The median time to death was 17.4 months (95% CI, 16.14-18.66). CONCLUSIONS: Exemestane represents an active and well-tolerated treatment option in pretreated patients with advanced breast cancer who have received standard first- and second line hormonal therapies. By extending the sequence of hormonal therapy, disease progression and the need for chemotherapy may be significantly delayed.

Granuloma Mimicking Local Recurrence on PET/CT after Liver Resection of Colorectal Liver Metastasis: A Case Report.

Positron emission tomography-computed tomography (PET/CT) improves the diagnostic interpretation of fluorine-18 fluorodeoxyglucose (18F-FDG ) PET and CT in oncologic patients and has an impact on both diagnostic and therapeutic aspects of patient management. However, false positive findings from the PET/CT imaging should be taken into consideration as they mislead physicians into improper therapeutic actions. We present a 48-year-old female patient with a history of left colectomy for colorectal cancer and subsequent liver metastasectomy. After one year of follow-up, she presented with a highly suspicious lesion in the liver, which was confirmed on PET/CT as a metastatic liver tumor. Consequently, the patient underwent surgical excision of the tumor, and the definitive histological diagnosis showed a granulomatous tissue with giant cells and foreign body tissue reaction. Based on this report, we briefly review the dangerous pitfalls from radiological and PET/CT imaging concerning the preoperative diagnostic workup examination, as they may significantly alter the treatment plan in oncologic patients.

Effects of hormone replacement therapy on the main fatty acids of serum and phospholipids of postmenopausal women.

BACKGROUND: The anti-atherosclerotic effects of hormone replacement therapy (HRT) in postmenopausal women are partly mediated by improvement of the lipid and lipoprotein profiles. The present study aimed to investigate the effects of HRT on the main fatty acids of serum and phospholipids in postmenopausal women. PATIENTS AND METHODS: Serum samples of two groups of postmenopausal women, receiving either single oestrogen or in combination with progestogens, were analysed before and after a 6- month treatment period. RESULTS: Of the main serum fatty acids, there was a significant reduction in palmitic (p < 0.05) and arachidonic acids (p < 0.001), followed by an increase in oleic (p < 0.05) and linoleic acids (p < 0.05) in postmenopausal women receiving HRT compared to single oestrogen. The main fatty acids in phospholipids showed a similar pattern in those women. CONCLUSION: The above results demonstrate the beneficial effects of HRT in reducing the risk of cardiovascular disease through modification of the fatty acid profiles of postmenopausal women.

Altered long chain fatty acids composition in Duchenne muscular dystrophy erythrocytes.

BACKGROUND: Biochemical abnormalities, increased efflux of soluble enzymes and muscle proteins, and altered permeability of muscle membranes imply the presence of a disorganized erythrocyte membrane in Duchenne muscular dystrophy (DMD). The purpose of the present study was to investigate this hypothesis of a generalized membrane defect. MATERIALS AND METHODS: Twenty-five patients with the disease were analyzed for their erythrocyte lipid composition and for alterations in their fatty acid content compared to twenty-five healthy subjects. RESULTS: DMD patients showed a decreased concentration of total phospholipids compared to healthy volunteers, with striking fluctuations in concentrations of erythrocyte long chain fatty acids. Specifically, the unsaturated fatty acids such as oleic, linoleic and arachidonic acids were significantly decreased in the disease, whereas the saturated fatty acid, palmitic acid was increased in DMD patients compared to healthy controls. CONCLUSION: Our findings suggest an abnormal fatty acid composition and disorganization of erythrocyte membrane in patients with DMD associated with possible functional alterations.

Chromophobe renal cell carcinoma with prolonged response to targeted therapy: a case report.

INTRODUCTION: Chromophobe renal cell carcinoma is universally accepted as a distinct subtype of renal cell carcinoma. There are conflicting reports on prognosis, and few data on response to treatment exist. Currently, we do not have any effective treatment for the metastatic disease apart from surgical procedures. Current strategies are based on results obtained in the context of clear cell-type renal cell carcinoma. Separate trials for rare histologies seem unfeasible and are unlikely to be performed. For these cases, clinical observations are an important part for advancing therapeutic insight. In recent years, novel tyrosine kinase inhibitors have been shown to have significant clinical benefit in advanced renal cell carcinoma. CASE PRESENTATION: We present the case of a 43-year-old Caucasian man with advanced chromophobe renal cell carcinoma treated with the tyrosine kinase inhibitor sunitinib and subsequently with sorafenib and the mammalian target of the rapamycin inhibitor everolimus, achieving a prolonged response and significant clinical benefit. We report an unexpectedly high efficacy of everolimus as a third-line treatment in a patient with metastatic chromophobe renal cell carcinoma. CONCLUSIONS: Up to now, no published data from randomized clinical studies have addressed the question of efficacy of everolimus as a third-line treatment after failure of tyrosine kinase inhibitors. To the best of our knowledge, this case is the first report of chromophobe renal cell carcinoma treated successfully with sequential tyrosine kinase and mammalian target of rapamycin inhibitor therapy. Notably, the time on treatment with sunitinib exceeded four years. The case presented here implies that everolimus could be a viable option for patients with metastatic chromophobe renal cell carcinoma.

Muscle metastasis from hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma is the most common primary tumor of the liver. Disease dissemination occurs through hematogenous routes and frequently involves the lungs, bone, adrenal glands, and pancreas. The patterns of the extrahepatic manifestations are diverse. Soft tissue metastasis is extremely rare and mandates systematic pathological analysis, which may include the use of specific immunohistochemical staining. We report metastasis from a hepatocellular carcinoma, as a discrete subcutaneous mass to the right humerus muscle. MATERIALS AND METHODS: We detail the approach to diagnosis and management of an unusual case of a patient with hepatocellular carcinoma, in whom we found a metastatic lesion as a subcutaneous mass to the right humerus muscle nine years after right hepatectomy. CONCLUSION: This condition poses differential diagnostic problems in the settings of clinical and pathological investigations. Metastasis of hepatocellular carcinoma should be included in the differential diagnosis of rapidly growing lesions.