Daoud Rahal

Prognostic and diagnostic potential of local and circulating levels of pentraxin 3 in lung cancer patients

There is a well‐established link between inflammation and cancer of various organs, but little data are available on inflammation‐associated markers of diagnostic and prognostic clinical utility in pulmonary malignancy. Blood samples were prospectively collected from 75 resectable lung cancer patients before surgery and in a cohort of 1,358 high‐risk subjects. Serum levels of long pentraxin 3 (PTX3) were determined by high‐sensitivity ELISA. PTX3 immunostaining was evaluated by immunohistochemistry in cancer tissue. Serum PTX3 levels in the high‐risk population were not predictive of developing subsequent lung cancer or any other malignancy; however, serum PTX3 values in patients with lung cancer were significantly higher compared with cancer‐free heavy smokers. With a cutoff of 4.5 ng/ml, specificity was 0.80, sensitivity 0.69, positive predictive value 0.15 and negative predictive value 0.98. The receiver operating curve (ROC) for serum PTX3 had an area under the curve (AUC) of 83.52%. Preoperative serum PTX3 levels in lung cancer patients did not correlate with patient outcome, but high interstitial expression of PTX3 in resected tumor specimens was a significant independent prognostic factor associated with shorter survival (p < 0.001). These results support the potential of serum PTX3 as a lung cancer biomarker in high‐risk subjects. Furthermore, PTX3 immunohistochemistry findings support the role of local inflammatory mechanisms in determining clinical outcome and suggest that local expression of PTX3 may be of prognostic utility in lung cancer patients.

A prospective randomized study comparing 25-G and 22-G needles of a new platform for endoscopic ultrasound-guided fine needle aspiration of solid masses

BACKGROUND A new needle platform for endoscopic ultrasound-guided fine-needle aspiration biopsy has been developed that allows interchangeability of all needle sizes. AIMS To prospectively compare the efficacy of the new 25-G needles and 22-G needles for obtaining an adequate aspirate of solid masses. METHODS Randomized controlled trial of 144 patients referred for endoscopic ultrasound-guided fine-needle aspiration of solid pancreatic masses, intraparietal tumours, or lymph-nodes, randomized to the 25-G or 22-G needle arms. RESULTS An adequate specimen was obtained from 74.3% of cases. The sample tended to be more adequate in the 25-G compared to the 22-G group (81% vs. 68%; p=0.09). Crossover was required in 14 (19%) and 12 (17%) cases in the 22-G and in the 25-G groups, respectively (p=0.7). The overall rate of adequacy improved from 74% before crossover to 90% after crossover (p<0.01). When comparing the two groups after crossover, the rate of obtaining adequate samples was significantly higher in the 25-G arm than in the 22-G arm (95.8% vs. 86.1%; p=0.03). CONCLUSIONS The 25-G needle was superior to the 22-G needle for endoscopic ultrasound-guided fine-needle aspiration biopsy. The adequacy and diagnostic accuracy improved after crossover, reaching 90%.

Surgical sentinel lymph node biopsy in early breast cancer. Could it be avoided by performing a preoperative staging procedure? A pilot study.

Summary Background The aim of this pilot trial was to study the feasibility of sentinel node percutaneous preoperative gamma probe-guided biopsy as a valid preoperative method of assessment of nodal status compared to surgical sentinel lymph node biopsy. Material/Methods This prospective study enrolled 10 consecutive patients without evidence of axillary lymph node metastases at preoperative imaging. All patients underwent sentinel node occult lesion localization (SNOLL) using radiotracer intradermic injection that detected a “hot spot” corresponding to the sentinel node in all cases. Gamma probe over the skin detection with subsequent ultrasonographically guided needle biopsy of the sentinel node were performed. The percutaneous needle core histopathological diagnosis was compared to the results of the surgical biopsy. Results Preoperative sentinel node identification was successful in all patients. Conclusions The combination of preoperative gamma probe sentinel node detection and ultrasound-guided biopsy could represent a valid alternative to intraoperative sentinel node biopsy in clinically and ultrasonographically negative axillary nodes, resulting in shorter duration of surgery and lower intraoperative risks.

Idiopathic Thrombocytopenic Purpura and Splenic Marginal-zone B-cell Lymphoma: A Casual Correlation?

Autoimmunity, defined as an abnormal immunological reactivity to self antigens, is commonly seen in lymphoproliferative disorders. Idiopathic thrombocytopenic purpura (ITP) is encountered in these particular settings. The two conditions are usually diagnosed simultaneously or ITP may follow the diagnosis of lymphoma [ 1,2]. There are only a few reports of ITP as the presenting feature of non-Hodgkins lymphoma or Hodgkins disease [3,4]. We describe two cases of splenic marginal-zone-cell lymphoma (SMZCL) discovered after splenectomy in patients treated for refractory ITP. Case 1: In March 2000, a 46-year-old woman was referred from another hospital because of steroid-resistant ITP. Hemoglobin and leucocyte levels were within the normal range and Hepatitis B and C markers were negative. No platelet clumping was detectable in peripheral blood, and serum antibodies targeted to specific antigens for platelet membrane were not found. Bone marrow aspiration revealed normal cellularity, increased megakaryocytes and neither major myelodysplastic features nor atypical lymphocyte infiltration. Finally, when steroid therapy failed to achieve an adequate platelet response, splenectomy was performed. A prominent marginal zone was present, containing small to intermediate-sized lymphoid cells with round to oval to slightly irregular nuclei and small nucleoli (Fig. 1). Residual germinal centers were present within some of these lymphoma nodules. Extensive tumor infiltration of the red pulp was also found. Immunohistochemistry showed neoplastic cells expressing CD20 and lacking reactivity for CD3, CD5, CD23 and CDlO, consistent with SMZCL. Complete staging assessment was performed without evidence of lymphoma. Following splenectomy, the platelet count rapidly increased. As of September 2002, the patient is alive and well with a normal number of platelets and no evidence of lymphoma. Case 2: A 73-year-old lady was found to be severely thrombocytopenic in September 2000 with a platelet count of 3 X 109/l. After biochemical, imaging and bone marrow work-up a diagnosis of ITP was performed. Treatment with prednisone was started and resulted in a slow but full platelet recovery. However, severe thrombocytopenia, with a platelet count of 20 x 109/1, recurred 11 months later, and splenectomy was then performed. The spleen showed infiltration by lymphocytes with morphologic and immunohistochemical features consistent with SMZCL, as detailed above (Fig. 2). All staging assessments were negative for lymphoma. Post operatively, she had an excellent platelet response, but this was short lived (1 month). Before restarting steroid therapy, a bone marrow aspirate was performed. This was again consistent with ITP and excluded lymphoma. At present, the patient requires chronic steroid therapy to maintain a satisfactory platelet count and rituximab is being considered. Several models have been proposed to explain the increased rate of autoimmunity in lymphoproliferative disorders. Rather than a specific autoantibody being produced by the monoclonal malignant cell population itself, it is more likely that the disease allows the emergence of clones which have autoantibody activity. According to this hypothesis, our two ITP cases can be interpreted as a para neoplastic phenomenon, potentially curable by specific therapy. The occurrence of ITP in our two cases could have been a consequence of the activity of the underlying lymphoma and thus represent the first manifestation of the active disease. As far as we are aware, these are the first described cases of ITP occurring as

Inhibition of chronic graft-vs-host disease with retention of anti-myeloma effects by the proteasome inhibitor bortezomib.

Graft-vs-host-disease (GVHD) is a major complication of allogeneic stem cell transplantation (ASCT) [1]. Bortezomib is a proteasome inhibitor that has recently been approved for myeloma treatment. It has been shown to have numerous biological effects, including inhibition of NF-kB activation [2]. NF-kB is a transcription factor that has been detected in most cell types and that controls the expression of a number of genes involved in mediating immune and inflammatory responses [3]. A recent study on murine acute graft-vs-host disease (aGVHD) models has shown that bortezomib induces a selective depletion of alloreactive T lymphocytes by decreasing the production of Th1 cytokines [4]; it inhibits aGVHD and preserves graft-versus-tumor (GVT) effects [5]; and also that NF-kB is the target of bortezomib activity for aGVHD prevention [6]. However, there are only sparse data available on the effect of bortezomib on human GVHD [7]. We report a case of extensive chronic GVHD (cGVHD) and post-ASCT extramedullary myeloma progression, which were both responsive to bortezomib. A 49-year-old Caucasian patient with IgGk Stage III A multiple myeloma (Durie and Salmon) upon diagnosis, in partial remission because of a persistent positive immunofixation [8] after conventional chemotherapy and high-dose melphalan, received lenograstim-stimulated CD34þ cells from an HLAidentical sibling (on Day 0) after reduced-intensity conditioning with fludarabine 30 mg/m/die 73, 72, 71 i.v. and cyclophosphamide 300 mg/m/die 73, 72, 71 i.v. GVHD prophylaxis consisted of cyclosporine A and short-course methotrexate. Neutropenia and thrombocytopenia were not observed. Disease evaluation after ASCT showed stable disease. Full donor chimerism (revealed by PCR analysis) on total marrow and peripheral cells was reached six months after transplant and coincided with cyclosporine withdrawal. Eight months after ASCT the patient developed extensive cGvHD with involvement of the liver, skin, and bilateral conjunctiva and mouth mucosa, which was treated with cyclosporine and steroids until complete remission was reached. Sixteen months after ASCT the patient experienced extramedullary disease progression as revealed by a huge mass (12.56 9 cm) extending to the upper left chest wall, reappearance of monoclonal immunoglobulin (M component) by electrophoresis, and absence of bone marrow infiltration by plasma cells. The chest mass biopsy confirmed the presence of myelomatous cells. Cyclosporine was tapered and stopped, and loco-regional radiotherapy (total 20 Gy) was administered without any disease response. Then the patient received three monthly escalating doses of donor lymphocytes (DLIs, 16 10 kg; 56 10 kg; 16 10 kg) from his HLA-identical donor without any perceivable reduction of the extramedullary mass. Therefore, in June 2005, a few days after the third DLI, he was started on standard-dose bortezomib (1.3 mg/m i.v. for four times on Days þ1, þ4, þ8, þ11) to be

Cutaneous Melanoma Metastatic to Uterine Adenomyoma: Report of a Case

Rare cases of metastasis to uterine polyps have been reported in English literature but not, to the best of our knowledge, to uterine adenomyomas. All these cases are represented by breast cancer, most of them involving tamoxifen-associated polyps. We first report a case of cutaneous malignant melanoma metastatic to uterine adenomyoma. A computed tomography scan did not reveal any further evidence of disease, suggesting that this metastatic localization may represent something more than a fortuitous case. Based on these observations it is suggested that a subset of malignant melanoma and breast cancer cells share a sort of “homing” phenomenon to polypoid lesions of uterus, due probably to the presence of some chemokines and their specific receptors. Pathologists should be aware of this possibility in order to look carefully for metastatic implants in similar lesions. It is proposed that chemokine profile of neoplastic cells can be a useful tool in predicting metastatic targets.

Hepatic Rosai-Dorfman Disease With Coincidental Lymphoma: Report of a Case

Rosai—Dorfman disease (RDD; sinus histiocytosis with massive lymphoadenopathy) is a rare, usually nodal self-limited disease. Sometimes nodal disease is coupled with extranodal localizations, in which case the disease can follow a protracted clinical course characterized by remissions and relapses and, exceptionally, a fatal outcome. Exclusive extranodal localizations are rare and their prognosis variable. This study reports a case of RDD apparently limited to the liver coexisting with a diffuse (stage IV) relapsing follicular lymphoma. The patient is alive and well 24 months after the diagnosis of the lymphoma. It is conceivable that the lymphoma has induced RDD via an immunological disorder, possibly involving interleukin expression. The favorable outcome supports the belief that the prognosis of RDD is largely dependent on the number of extranodal sites involved, rather than on the specific sites themselves.

Comorbidity, postoperative morbidity and survival in patients undergoing radical surgery for malignant pleural mesothelioma.

OBJECTIVES We examined a series of malignant pleural mesothelioma (MPM) patients who underwent radical surgery to explore relationships among comorbidity, postoperative morbidity and survival. METHODS A retrospective analysis was carried out of all MPM patients operated on in a single centre from 2000 to 2015. The Charlson Comorbidity Index (CCI) was used to classify patients according to their underlying condition. Postoperative complications were scored according to WHO-derived criteria. Survival comparisons were performed by Cox analysis. RESULTS Ninety-one patients underwent extrapleural pneumonectomy (EPP), 47 underwent pleurectomy decortication (PD) and 25 underwent palliative pleurectomy. The mean CCI of PD patients was significantly higher compared with that of EPP patients (P= 0.044). The frequency of grade 3+ complications was similar between EPP and PD (27 vs 26%). However, EPP patients had a 6-fold higher frequency of pleural sepsis (24 vs 4%, P= 0.002) occurring up to 695 days postoperatively. Median overall survival was 19 months (95% CI 13-25) after EPP, 30 months (95% CI 20-35) after PD and 13 months (95% CI 5-32) after palliative pleurectomy. At multivariate analysis, CCI (P< 0.001), histology (P= 0.014) and pleural sepsis (P= 0.001), but not complete resection, were significantly associated with survival. There was a trend in favour of PD over palliative resection after adjusting for histology and CCI. CONCLUSIONS The CCI is an independent predictor of survival in MPM patients undergoing radical surgery. Owing to its significant frequency and adverse impact, pleural sepsis may contribute to a reduced life expectancy after EPP. Surgical treatment of MPM remains debatable.

Synchronous Bilateral Primary Breast Lymphoma

B reast lymphoma is a rare condition, both as a primary and a metastatic manifestation. The primary form has an incidence ranging from 0.04% to 0.5% of all breast neoplasms, whereas the metastatic form has an incidence of 0.07%. Reports of synchronous development of bilateral lymphoma in the breasts without any evidence of systemic disease are rare. We hereby present a case of synchronous bilateral primary breast lymphoma. A 53-year-old woman was referred to the Breast Unit for painless bilateral lumps localized into right and left lower inner quadrant. The patient had no family history for malignant disease. At clinical examination the breast surgeon appreciated palpable, poorly mobile, firm suspicious masses corresponding to the lumps localized in the lower quadrants. No skin involvement was observed. The patient had an outside recent bilateral mammography which was unremarkable except for the high density of the glandular tissue (ACR 4). An ultrasound examination was performed (on location) showing two solid nodules (2.5 cm on the left and 3 cm on the right side), with lobulated shape, well-defined margins, and slightly heterogeneous echostructure. Within both nodules, cystic collections were appreciated in between hypoechoic solid parts (Fig. 1). The lesions were mildly vascularized at the colorDoppler evaluation. There was no acoustic shadowing, bilaterally and no sonographic sign of adjacent tissue invasion. There was no axillary lymphadenopathy. The ecographic findings were not considered suspicious for malignancy; the diagnosis was rather oriented to a benign etiology as pseudo angiomatous stromal hyperplasia (PASH), fibroadenoma or hamartoma. The lesions were biopsied under US guidance using a 14 G automatic needle. Both masses resulted to be a follicular B cell non-Hodgkin lymphoma at histology (CD20+, CD10+, Bcl6+, Bcl2+, CD30), CD3) and MUM1)), grade1-2 at right and grade 3 at left, according to the WHO classification (Fig. 2). The lack of B symptoms, the normal hematological and blood chemistry values, the absence of lymphomatous colonies at the bone marrow biopsy, and total body multislice computed tomography and ultrasound examination targeted to axilla, groin, and neck (most common lymphatic involvement sites) confirmed the breast only manifestation of the lymphoproliferative disorder, than a primitive breast lymphoma. The aim of this manuscript is to highlight an uncommon oncologic disorder, such as synchronous primary bilateral breast follicular B cell lymphoma, describing its clinical, radiological, and pathological manifestations. Considering the radiological features only, (lobulated shape, well-defined margins, heterogeneous echostructure, absence of the acoustic shadow, and expansive pattern of growth) the diagnosis of a benign

18F-FDG PET/CT for response assessment in Hodgkin lymphoma undergoing immunotherapy with checkpoint inhibitors

Abstract Our aim was to evaluate Hodgkin Lymphoma (HL) response to checkpoint inhibitors with 18F-FDG PET/CT. Forty three refractory or relapsed HL patients were investigated before immunotherapy, 8 weeks and 17 weeks after administration of either nivolumab or pembrolizumab. The median follow-up was 19 months. Best clinical response was complete response (CR) in 26 patients, partial response (PR) in 5 patients, stable disease (SD) in 8 patients, and progression disease (PD) in 4 patients. At the early assessment, Deauville Score (DS) resulted significantly different in responder group compared to nonresponders. SUVmax was significantly lower in responders, while there was no relevant modification in the tumor burden. At interim evaluation, DS well differentiated responder group. A significant decrease in glucose metabolism and tumor burden parameters was observed in responder patients, who presented with a longer progression-free survival then nonresponders. 18F-FDG PET/CT provides a reliable indication of treatment response under checkpoints inhibitors, even at an early assessment.