Raja Pramanik

Complete response after autologous stem cell transplant in multiple myeloma.

We evaluated long‐term outcome of patients achieving complete response (CR) after autologous stem cell transplantation (ASCT) for multiple myeloma. Between April 1990 and June 2012 191 patients underwent ASCT. The median age was 53 years (range, 26–68 years), 135 were men. Pretransplant, patients received induction therapy with VAD (vincristine, doxorubicin, dexamethasone; n = 77), novel agents (n = 92), or alkylating agent‐based, n = 22); 43% received more than one line of induction regimen. Response to transplant was defined as per EBMT criteria. The median follow‐up for the entire group was 85 months (range, 6–232.5 months). Following transplant 109 (57.1%) patients achieved CR. Median progression‐free survival (PFS) for patients with CR was higher compared to those with VGPR and PR, (107 vs. 18 vs. 18 months, P < 0.001). Number of lines of therapy pretransplant (one or two vs. more than two lines of therapy (P < 0.001), and absolute lymphocyte count of ≤3000/cmm were predictors of superior PFS. Median overall survival (OS) for patients with CR was higher, (204 months), compared to those with VGPR (71.5 months, P < 0.001) and PR (51.5 months, P < 0.001), respectively. On Cox regression analysis, patients who received one line of induction therapy pretransplant (hazard ratio, HR 2.154, P < 0.001) and those with absolute lymphocyte count of ≤3000/mm3 (HR 0.132, P < 0.001) had superior PFS. For overall survival, induction treatment up to one line (HR 2.403, P < 0.004) and Hb > 7.1 G/dL at diagnosis (HR 4.756, P < 0.01) were associated with superior outcome. On landmark analysis at 12 months, PFS and OS continued to remain superior for patients attaining CR. Achievement of CR post transplant is associated with longer OS and PFS. Among complete responders, those who receive one line of induction therapy pretransplant have superior outcome.

Metronomic Chemotherapy vs Best Supportive Care in Progressive Pediatric Solid Malignant Tumors: A Randomized Clinical Trial

Importance Although oral metronomic chemotherapy is often used in progressive pediatric solid malignant tumors, a literature review reveals that only small single-arm retrospective or phase 1 and 2 studies have been performed. Skepticism abounds because of the lack of level 1 evidence. Objectives To compare the effect of metronomic chemotherapy on progression-free survival (PFS) with that of placebo in pediatric patients with primary extracranial, nonhematopoietic solid malignant tumors that progress after at least 2 lines of chemotherapy. Design, Setting, and Participants A double-blinded, placebo-controlled randomized clinical trial was conducted from October 1, 2013, through December 31, 2015, at the cancer center at All India Institute of Medical Sciences in children aged 5 to 18 years with primary extracranial, nonhematopoietic solid malignant tumors that progressed after at least 2 lines of chemotherapy and had no further curative options. Interventions One arm received a 4-drug oral metronomic regimen of daily celecoxib and thalidomide with alternating periods of etoposide and cyclophosphamide, whereas the other arm received placebo. Disease status was assessed at baseline, 9 weeks, 18 weeks, and 27 weeks or at clinical progression. Main Outcomes and Measures The primary end point was PFS as defined by the proportion of patients without disease progression at 6 months, and PFS duration and overall survival (OS) were secondary end points. Results A total of 108 of the 123 patients screened were enrolled, with 52 randomized to the placebo group (median age, 15 years; 40 male [76.9%]) and 56 to the metronomic chemotherapy group (median age, 13 years; 42 male [75.0%]). At a median follow-up of 2.9 months, 100% of the patients had disease progression by 6 months in the placebo group vs 96.4% in the metronomic chemotherapy group (P = .24). Median PFS and OS in the 2 groups was similar (hazard ratio [HR], 0.69; 95% CI, 0.47-1.03 [P = .07] for PFS; and HR, 0.74; 95% CI, 0.50-1.09 [P = .13] for OS). In post hoc subgroup analysis, cohorts receiving more than 3 cycles (HR for PFS, 0.46; 95% CI, 0.23-0.93; P = .03) and those without a bone sarcoma (ie, neither primitive neuroectodermal tumor nor osteosarcoma) (HR for PFS, 0.39; 95% CI, 0.18-0.81; P = .01) appeared to benefit from metronomic chemotherapy. Conclusions and Relevance Metronomic chemotherapy does not improve 6-month PFS, compared with placebo, among pediatric patients with extracranial progressive solid malignant tumors . However, patients without bone sarcoma and those able to tolerate therapy for more than 3 cycles (9 weeks) benefit. Trial Registration clinicaltrials.gov Identifier: NCT01858571.

Neoadjuvant chemotherapy in gynaecological cancers – Implications for staging

The management of advanced gynaecological cancers remains a therapeutic challenge. Neoadjuvant chemotherapy has been used to reduce tumour size, thus facilitating subsequent local treatment in the form of surgery or radiation. For advanced epithelial ovarian cancer, data from several non-randomized and one randomized studies indicate that neoadjuvant chemotherapy followed by interval debulking surgery is a reasonable approach in patients deemed inoperable. Such an approach results in optimum debulking (no visible tumour) in approximately 40% of the patients with reduced operative morbidity. Overall and progression free-survival is comparable to the group treated with primary debulking surgery followed by chemotherapy. Neoadjuvant chemotherapy followed by surgery is associated with improved survival for women with stage IB2-IIA cervix cancer. There is a resurgence of interest for using short-course neoadjuvant chemotherapy prior to concurrent chemo-radiation. Currently, this is being tested in randomized trials.

Solid pseudopapillary neoplasm of the ovary with metastases to the omentum and regional lymph nodes

Extrapancreatic solid pseudopapillary neoplasms (SPNs) are rare tumors, which bear morphological, immunohistochemical, and molecular features similar to those of pancreatic counterparts. SPN occurs primarily in adolescent girls and young women. It is considered to be a malignant neoplasm with low-grade biology. Ovarian SPNs are uncommon, have benign morphology, usually limited to the ovary and local surgical excision is curative. We report an unusual case of SPN of right ovary with extraovarian spread and metastases to lymph nodes. To the best of our knowledge, this is the second documented case of extragonadal spread of ovarian SPN.

Neutropenia due to palbociclib: A word of caution?

REFERENCES 1. Fry DW, Harvey PJ, Keller PR, Elliott WL, Meade M, Trachet E, et al. Specific inhibition of cyclin‐dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther 2004;3:1427‐38. 2. Turner NC, Huang Bartlett C, Cristofanilli M. Palbociclib in hormone‐receptor‐positive advanced breast cancer. N Engl J Med 2015;373:1672‐3. 3. Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, et al. The cyclin‐dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first‐line treatment of oestrogen receptor‐positive, HER2‐negative, advanced breast cancer (PALOMA‐1/TRIO‐18): A randomised phase 2 study. Lancet Oncol 2015;16:25‐35. 4. Flaherty KT, Lorusso PM, Demichele A, Abramson VG, Courtney R, Randolph SS, et al. Phase I, dose‐escalation trial of the oral cyclin‐dependent kinase 4/6 inhibitor PD 0332991, administered using a 21‐day schedule in patients with advanced cancer. Clin Cancer Res 2012;18:568‐76. Sir,

Pattern of mitochondrial D-loop variations and their relation with mitochondrial encoded genes in pediatric acute myeloid leukemia

Role of mitochondrial DNA variations, particularly in D loop region, remains investigational in acute myeloid leukaemia (AML). Consecutive 151 pediatric AML patients were prospectively enrolled from June 2013 to August 2016, for evaluating pattern of variations in mitochondrial D-loop region and to determine their association, if any, with expression of mitochondrial-encoded genes. For each patient, D-loop region was sequenced on baseline bone marrow, buccal swab and mothers blood sample. Real time PCR was used for relative gene expression of four mitochondrial DNA encoded genes viz. Nicotinamide-adenine-dineucleotide-dehydrogenase subunit 3 (ND3), Cytochrome-B (Cyt-B), Cytochrome c oxidase-I (COX1) and ATP-synthetase F0 subunit-6 (ATP6). Total 1490 variations were found at 237 positions in D-Loop; 1206 (80.9%) were germline and 284 (19.1%) were somatic. Positions 73-263 were identified as a probable hotspot region. G bases appeared to be most stable nucleotide (least number of single base substitutions) whereas T appeared to be most susceptible to variations with germline T-C being the commonest. Gene expression of Cyt-B was found to be significantly higher for any variation (somatic or germline) at positions 16,192 and 16,327 while it was significantly lower for variations at positions 16,051 and 207. Any variation at positions 152, 207 and 513 significantly decreased COX1 expression while those at positions 16,051 and 152 attenuated ATP6 expression. This first study evaluated type and overall pattern of D-loop variations in AML, and also showed that some of these variations in D loop region might have an effect on the mitochondrial-encoded genes which is new and valuable information in AML genomics.

Cytogenetic Profiles of 472 Indian Children with Acute Myeloid Leukemia

ObjectiveTo analyze the cytogenetic abnormalities of a large cohort of consecutive pediatric Acute Myeloid Leukemia (AML) patients, treated on a uniform protocol.DesignReview of case records.SettingPediatric Cancer Center of tertiary care hospital between June 2003 and June 2016.Participants617 consecutive de novo pediatric AML patients were screened and 472 patients were found eligible. Eligibility criteria included non M3 patients, successful cytogenetic profile and availability of complete recordsMain outcome measureCytogenetic profile.ResultsGum-hypertropy, chloromas and rate of complete remission were significantly different between European Leukemia Network classification (ELN) cytogenetic risk groups (P<0.01). t (8;21) (141, 29.8%), loss of Y chromosome (61,12.9%) and trisomy 8 (39, 8.3%) were the most common abnormalities. Among the chromosomal gains, trisomy 8 and trisomy 21 (both P<0.01) were significantly different among the three ELN risk groups. Among the chromosome losses, monosomy 5, 7 (both P<0.01) and 9 (P=0.03), loss of X and loss of Y (both P<0.01) were statistically different amongst three cytogenetic risk groups. Event-free survival (P<0.01) and overall survival (P<0.01) were found to be significantly different among the three risk groups.ConclusionsThe higher frequency of t (8; 21) and its association with chloroma in Indian pediatric patients is different from other studies around the world.

SMARCB1 (INI1) -deficient sinonasal carcinoma: a series of thirteen cases with assessment of histological patterns

A significant proportion of sinonasal malignancies comprise poorly differentiated/undifferentiated carcinomas that defy accurate histologic classification and behave aggressively. Recent years have seen a refinement of this spectrum by inclusion of novel entities harboring specific genetic alterations, including SMARCB1 (INI1)-deficient sinonasal carcinoma (SDSC), characterized by inactivating alterations in SMARCB1 gene, as demonstrated by loss of INI1 immunoexpression. Cyclin D1 is a cell-cycle regulatory protein downstream of INI1. Loss of INI1 leads to derepression of cyclin D1 transcription, suggesting its role as a putative therapeutic target. However, cyclin D1 expression has not been assessed in SDSCs. We retrieved all sinonasal carcinomas, including sinonasal undifferentiated carcinoma, undifferentiated carcinoma, poorly differentiated squamous cell carcinoma, and adenocarcinoma. Histopathologic features were reviewed. INI1 immunohistochemistry was performed. Cyclin D1 was performed in cases showing INI1 loss. Loss of INI1 staining was seen in 13 cases (5.8%), including 11 males and 2 females (age range, 11-65 years). Original diagnoses included SDSC (3/13), sinonasal undifferentiated carcinoma (3/13), adenocarcinoma (3/13), poorly differentiated squamous cell carcinoma (2/13), and poorly differentiated carcinoma (2/13). Tumors were predominantly basaloid in 6 cases and plasmacytoid/rhabdoid in 5 cases. We identified 2 cases having oncocytoid cells arranged in a gland-like pattern. Significant cyclin D1 immunoexpression was absent. SDSC is a rare, emerging entity that resembles a poorly differentiated carcinoma. Histomorphologic spectrum of these tumors is evolving. In addition to basaloid and plasmacytoid/rhabdoid cells, oncocytoid/adenocarcinoma-like pattern can also be seen in SDSC and predicts INI1 loss. These histologic patterns can further be subjected to INI1 immunohistochemistry for correct diagnosis.

Myeloid Sarcoma Predicts Superior Outcome in Pediatric AML; Can Cytogenetics Solve the Puzzle?

&NA; We retrospectively evaluated the clinical, cytogenetic, and molecular profiles, and survival outcomes of pediatric acute myeloid leukemias (AMLs) with and without myeloid sarcoma (MS). MS was present in 121 of 570 patients (21.2%). The most frequent site was the orbit. Event‐free survival (P = .003) and overall survival (P = .001) were better among AML with MS. The t (8; 21) was significantly associated with MS (odds ratio = 3.92). Background: The purpose of our study was to evaluate the clinical, cytogenetic, and molecular features, and survival outcomes in patients with acute myeloid leukemia (AML) with myeloid sarcoma (MS) and compare them with patients with AML without MS. Patients and Methods: This was a retrospective analysis of de novo pediatric AML patients with or without MS diagnosed at our cancer center between June 2003 and June 2016. Results: MS was present in 121 of 570 (21.2%), the most frequent site being the orbit. Patients with MS had a younger median age (6 years vs. 10 years) and presented with higher hemoglobin and platelet but lower white blood cell count compared with patients without MS. Further, t (8; 21) (P < .01), loss of Y chromosome (P < .01), and deletion 9q (P = .03) were significantly higher in patients with AML with MS. Event‐free survival (EFS; P = .003) and overall survival (OS; P = .001) were better among patients with AML with MS (median EFS 21.0 months and median OS 37.1 months) compared with those with AML without MS (median EFS 11.2 months and median OS 16.2 months). The t (8; 21) was significantly associated with MS (odds ratio, 3.92). In a comparison of the 4 groups divided according to the presence or absence of MS and t (8; 21), the subgroup of patients having MS without concomitant t (8; 21) was the only group to have a significantly better OS (hazard ratio, 0.53; 95% confidence interval, 0.34‐0.82; P = .005). Conclusion: Although t (8; 21) was more frequently associated with MS, it did not appear to be the reason for better outcome.

Isolated breast relapse mimicking breast cancer in elderly patient with acute lymphoblastic leukemia.

Received/Gelis tarihi : August 7, 2013 Accepted/Kabul tarihi : November 5, 2013 To the Editor, Acute lymphoblastic leukemia (ALL) in adults is associated with high relapse rates. Isolated extramedullary relapse other than in the central nervous system is rare in adult females with ALL. We present a case of isolated breast relapse in a 65-year-old female with ALL, mimicking breast cancer. A 65-year old female presented with a 2-month history of fever and generalized lymphadenopathy in December 2006. Physical examination revealed generalized lymphadenopathy and hepatosplenomegaly. Her hemoglobin was 11.9 g/dL, total leukocyte count 9.2x109/L, and platelet count 106x109/L. Peripheral blood smear showed 5% myeloperoxidase-negative blast cells and the bone marrow revealed near total replacement with lymphoblasts (Figures 1A and 1B), which on flow cytometry were positive for CD19 and CD22 and negative for CD10, CD5, and CD7. The cerebrospinal fluid was uninvolved. She was diagnosed with pre-B ALL and received induction as per the MCP-841 protocol [1]. Remission was achieved at the end of induction chemotherapy. Thereafter, she completed intensification, followed by oral maintenance for 1.5 years. Twenty-four months later, she presented with a lump in the left breast. On clinical examination, she had a large, non-tender mass in her left breast with a 1-cm mobile axillary lymph node on the same side. Systemic examination was normal. We considered a diagnosis of breast cancer in view of the classical presentation, supported by a mammogram finding suggestive of Breast Imaging Reporting and Data System Score V (Figures 1C and 1D). Blood counts, peripheral blood smear, and bone