Ranjit Kumar Sahoo

Lactobacillus brevis CD2 lozenges prevent oral mucositis in patients undergoing high dose chemotherapy followed by haematopoietic stem cell transplantation

Background Oral mucositis is a common inflammatory complication in patients undergoing high-dose chemotherapy and radiation followed by haematopoietic stem cell transplantation (HSCT). Lactobacillus brevis CD2 has been proven efficacious in preventing chemoradiotherapy-induced oral mucositis in squamous cell carcinoma of head and neck. Methods This phase II study aimed to evaluate the safety and efficacy of L. brevis CD2 lozenges in preventing oral mucositis in patients undergoing HSCT. Eligible patients received four to six lozenges of L. brevis CD2 per day, beginning from 4 to 7 days before initiation of chemotherapy and continuing until resolution of mucositis or till day +24. Results Of 31 patients enrolled, 7 (22.6%) patients did not develop any mucositis, 6 (19.4%) patients developed grade 1, 12 (38.7%) patients developed grade 2, 4 (12.9%) and 2 (6.5%) patients developed grade 3 and grade 4 mucositis, respectively. Median time to onset and for resolution of mucositis were 6 days and 8 days, respectively. No adverse events were reported with usage of study drug. However, one patient died of Klebsiella sepsis. Conclusion Promising results from the study encourage the use of L. brevis CD2 lozenges as a supportive care treatment option; however, a randomised, double-blind, multicentric trial in a larger population is warranted. Trials registration number NCT01480011 at https://www.clinicaltrials.gov/ (Registered on Nov 04, 2011).

Concomitant 177lu-dotatate and Capecitabine Therapy in Patients With Advanced Neuroendocrine Tumors: A Long-term-outcome, Toxicity, Survival, and Quality-of-life Study

Purpose The purpose of this study was to evaluate the outcome, toxicity, survival, and quality of life in patients with advanced neuroendocrine tumors. Methods One hundred sixty-seven patients were enrolled in the study. All patients underwent baseline 68Ga-DOTANOC PET/CT scans. 177Lu-DOTATATE therapy was administered quarterly along with oral capecitabine therapy in group 1 patients (n = 88), whereas group 2 patients (n = 79) were treated only with 177Lu-DOTATATE. Hematologic, kidney function, liver function tests and chromogranin A levels were recorded before and after therapy at 2-week, 4-week, and 3-month intervals. Biochemical and morphological responses were assessed with the trend in chromogranin A levels and Response Evaluation Criteria in Solid Tumors 1.1 criteria, respectively. Results There was no significant difference in the hemoglobin levels after 177Lu-DOTATATE therapy (P = 0.4892). In most patients, there was a decrease in the platelet levels; however, all the patients had platelet counts greater than 100,000/&mgr;L with no platelet toxicity. There was no toxicity related to leukocytes. Two patients showed renal insufficiencies. No hepatotoxicity was observed in any of the patients. According to Response Evaluation Criteria in Solid Tumors 1.1 criteria, in group 1 patients, the response was partial response in 34% of the patients, stable disease in 50.2%, and progressive disease in 6.8% versus partial response in 6.3%, stable disease in 60.9%, and progressive disease in 26.5% among group 2 patients. The median overall survival (OS) and progression-free survival (PFS) was not reached in group 1 patients. The median OS and PFS in group 2 patients were 48 months. Ki-67 tumor proliferation index was significantly associated with increased risk of disease progression. Conclusions Addition of capecitabine therapy with 177Lu-DOTATATE therapy lengthens the OS and PFS. Patients with aggressive disease may benefit from this synergetic therapeutic approach.

A clinicopathological study of primary central nervous system lymphomas & their association with Epstein-Barr virus

Background & objectives: Primary central nervous system lymphomas (PCNSLs) are relatively uncommon, accounting for 2-3 per cent of primary brain tumours. Majority of these are diffuse large B cell lymphomas (DLBCL) occurring both in immunocompromised and immunocompetent patients. We undertook this study to classify PCNSL into germinal centre (GC) and non-germinal centre (NGC) type based on Hans classification and to find the role of Epstein-Barr virus (EBV) in pathogenesis both by conventional immunohistochemistry (IHC) and chromogenic in situ hybridization (CISH). Methods: The consecutive cases of PCNSL during a 10 years period were analysed by IHC for CD45, CD20, CD3, B-cell lymphoma 2 and 6 (Bcl-2 and Bcl-6), B-cell specific octamer binding protein-1 (BOB-1), multiple myeloma oncogene-1 (MUM-1), EBV latent-membrane protein 1 (LMP-1), cyclin-D1, CD10, CD5 and CD23, as well as by CISH for EBV. Results: During a period of 10 years, 65 PCNSL were diagnosed which comprised 0.69 per cent (65/9476) of all intracranial tumours. The mean age of presentation was 49 yr with sex ratio (M:F) of 1.4:1. Most common location was supratentorial region with predominant involvement of frontal lobe. Single lesions were seen in 38 (58.4%) and multifocal lesions in 27 (41.5%) patients. None of the patients were immunocompromised. All cases were B cell immunophenotype and were DLBCL except one case of follicular lymphoma. According to Hans classification, majority of them were NGC (n=51, 79.6%) and 13 (20.3%) were GC type. Bcl-2 expression was noted in 34 (52.3%) tumours. EBV was positive in three (4.6%) cases; two were detected both by IHC and CISH and one case by CISH only. Interpretation & conclusions: In Indian population, PCNSL occurs mainly in immunocompetent patients, and a decade earlier than in western population. Immunophenotyping revealed that all cases were DLBCL with predominance of NGC type. No prognostic difference was seen between GC and NGC DLBCL. Association of EBV was rare and this virus was possibly not involved in the pathogenesis of PCNSL in immunocompetent individuals. CISH was an easy, economical and less cumbersome method for detection of EBV in PCNSL.

Sinusoidal obstruction syndrome during induction therapy for acute lymphoblastic leukemia managed with N‐acetyl Cysteine

To the Editor: Sinusoidal obstruction syndrome (SOS) or veno-occlusive disease of liver (VOD) is characterized by jaundice, hepatomegaly, weight gain and fluid retention (ascites, pleural effusion, and pedal edema). An 18-year-old female pre-B ALL relapsed during maintenance phase of her chemotherapy. She was started on re-induction using dexamethasone, vincristine, L-asparaginase, and epirubicin according to UKALL XI protocol. Between days 7 and 9 she was noted to have weight gain of 9 kg with jaundice, tender hepatomegaly, moderate ascites, bilateral pleural effusion, and pedal edema. On day 13, her clinical status worsened with high-grade fever, tachypnea, and progression to encephalopathy. Laboratory tests revealed hyperbilirubinemia (total/direct 1⁄4 12.1/11.2 mg/dl, range: 0.8–1 mg/dl), normal liver enzymes and abnormal coagulation parameters: prothrombin time (PT) 13/19 sec, activated partial thromboplastin time (aPTT) 30/48.4 sec, d-dimer more than 5 ng/ml. Serologic tests for infectious hepatitis (HBV, HCV) and HIV were negative. Ultrasound scan of the abdomen revealed gall bladder wall thickening, hepatomegaly, ascites, patent inferior vena cava, hepatic, splenic, and portal veins. Blood culture on day 18 was suggestive of vancomycin resistant enterococci sensitive only to linezolid; fever responded to the same antibiotic. A diagnosis of fulminant hepatic failure (FHF) due to SOS was made. As defibrotide is not available in our country, we administered NAC at a dose of 150 mg/kg IV for 1 hr followed by 50 mg/kg over 4 hr and thereafter 6.25 mg/kg/hr for the next 67 hr. There was progressive improvement in encephalopathy, serum bilirubin decreased from 12.1 to 6 mg/dl, PT from 19 to 13 sec and aPTT from 48.4 to 34 sec. Sepsis is known to produce cholangitis lenta [1] and FHF [2]. Onset of fever and enterococcal bacteremia occurred after hepatic dysfunction. Thus, sepsis was likely a complication in this case, not the etiology of FHF. The possibility of leukemic infiltration of liver [3] was also unlikely as bone marrow aspirate done on day 28 confirmed morphological complete remission. Other potential factors included use of norethisterone [4] and total parenteral nutrition (TPN). However, patient was taking norethisterone for previous 9 months without any hepatic dysfunction. TPN was started 3 days before the onset of hepatic dysfunction, hence unlikely to cause it. SOS has rarely been described in ALL induction. One case was successfully treated with defibrotide and another was treated with alteplase which resulted in fatality [5,6]. Both reports attributed SOS to the use of vincristine. Vincristine was, however, unlikely as a cause because we were able to retreat her without any further recurrence of SOS. SOS is also reported in myeloid malignancies [7,8]. NAC appears to have a role in treating SOS in allogeneic HSCT when administered for 2–5 weeks after loading dose [9]. We used NAC for 72 hr in a manner similar to the treatment of paracetamol poisoning. We are reporting a case of SOS during reinduction therapy of ALL, successfully treated by NAC. Since defibrotide is not universally available and use of thrombolytics and anticoagulants is risky, NAC perhaps needs to be considered in such settings.

Intramedullary spinal cord hemorrhage in childhood acute lymphoblastic leukemia following lumbar puncture

To the Editor: Lumber puncture (LP) is a common procedure performed in childhood hematologic malignancies for therapeutic and diagnostic purposes. Common complications following LP include headache, backache, cerebellar herniation, trauma to conus medullaris, and iatrogenic meningitis. Bleeding in subdural, epidural, and subarachnoid spaces following LP are well-recognized sites of bleeding [1,2] and occasionally intracranial hemorrhage [3] may also be seen. Hematomyelia (intramedullary spinal cord hemorrhage) is an uncommon cause of myelopathy and can be acute, subacute, or chronic. An 11-year-old male with B-precursor acute lymphoblastic leukemia (ALL) underwent diagnostic LP with a 22-gauge spinal needle at L4/L5 intervertebral space following which clear cerebrospinal fluid (CSF) was obtained. During the procedure, patient complained of weakness in lower limbs and within few seconds he became completely paraplegic with urinary retention and a sensory level corresponding to D12-L1 dermatome. Magnetic resonance imaging (MRI) showed signal alteration in spinal cord extending from D11 to L1 level suggestive of hematomyelia and subarachnoid hemorrhage at L1–L2 level (Fig. 1A,B). Base line coagulation profile was normal and platelet count was 20 10/L a day before the procedure. Surgical drainage was not considered as the bleed was intramedullary. The patient received intensive platelet transfusions and antileukemic therapy consisting of vincristine, daunorubicin, prednisolone, and Lasparginase. The bone marrow was in complete remission one month later, but there was no improvement in paraplegia. MRI showed complete resolution of subarachnoid hemorrhage, but persistence of hematomyelia. After 6 months, repeat MRI showed myelomyletic changes in D11–L1 region (Fig. 1C,D) and patient continues to be paraplegicwith no improvement inmotor, sensory or bladder function at 10 months of follow-up. Spinal vascular malformations such as intramedullary cavernomas and intradural arteriovenous malformations, and anticoagulation therapy with warfarin or heparin are common causes of atraumatic hematomyelia [4]. Hematomyelia has been rarely reported following LP in a premature neonate [5] and in a patient of childhood leukemia who developed intramedullary hematoma and resultant quadriplegia after a C1–C2 puncture [6]. One out of 234 patients with hemophilia developed hematomyelia after LP [7] and spontaneous hematomyelia with paraparesis has been reported in a hemophilic patient [8]. The threshold for prophylactic platelet transfusions before LP is controversial [9]. Retrospective studies, however, showed that LP is generally a safe procedure in patients with platelet counts as low as 10 10/L without blood product support [10,11]. In our case, symptoms of paraplegia started while the procedure was being performed. Clear CSF was obtained during the procedure which suggests that the needle had gone in the subarachnoid space. A procedurewherein the LP needlewent in too deep seems unlikely as the site of puncture (L4) is not same as the site of hematomyelia (T11–L1). It is possible that withdrawal of CSF caused altered pressure changes in the blood vessels resulting in their rupture and bleeding which was further precipitated by thrombocytopenia. This illustrates that a higher threshold of platelet might be considered for prophylactic platelet transfusions prior to LP, although cannot be definitively concluded from this one case.

Post-therapeutic dosimetry of 177Lu-DKFZ-PSMA-617 in the treatment of patients with metastatic castration-resistant prostate cancer.

Objective 177Lu-DKFZ-PSMA-617, a urea-based compound, binds to the extracellular domain of prostate-specific membrane antigen, thus providing an effective target for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Before its therapeutic use, it is necessary that the radiation dosimetry of this radiopharmaceutical be studied to determine the safe activity that can be administered in patients to prevent haematological, renal and liver toxicity. The present study thus aimed to assess the pharmacokinetics and dosimetry of 177Lu-DKFZ-PSMA-617 in CRPC patients. Materials and methods After obtaining ethical clearance from the institute ethics review board, we enrolled mCRPC patients who were positive on a Glu-NH-CO-NH-Lys-(Ahx)-[68Ga(HBED-CC)] PET/CT scan. For kidney protection, a cocktail of lysine and arginine diluted in 2 litres of normal saline was infused, starting from 30 to 60 min before 177Lu-DKFZ-PSMA-617 infusion. The mean administered activity in the overall population was 2.52±1.3 GBq. For the purpose of dosimetry, each patient underwent nine planar whole-body scans along with blood and urine sample collection at 0.5, 3.5, 24, 48, 72, 96, 120, 144 and 168 h, respectively. SPECT/CT was performed to derive the volume of salivary glands (parotid and submandibular glands) and tumour. Dosimetric evaluation was carried out using the OLINDA/EXM 1.0 software. Results A total of 26 mCRPC patients with a mean age of 66.30±9.95 years (range: 38–81 years) were recruited. Normal physiological uptake was observed in all the patients in the lacrimal glands, salivary glands (parotid glands and submandibular glands), liver, spleen, kidneys, intestines and urinary bladder. Organs with the highest absorbed doses were the salivary glands, followed by the kidneys, receiving 1.24±0.26 and 0.99±0.31 mGy/MBq, respectively. The mean absorbed doses to the liver, urinary bladder and red marrow were 0.36±0.10, 0.243±0.09 and 0.048±0.05 mGy/MBq, respectively. The mean whole-body dose was 0.016±0.003 mGy/MBq. Conclusion 177Lu-DKFZ-PSMA-617 therapy is a safe option in the treatment of mCRPC patients.

Management of multiple myeloma in resource-constrained settings

The prognosis of patients with multiple myeloma (MM) has improved significantly in the past two decades. This is attributed to use of novel agents for induction, high-dose chemotherapy and autologous stem cell transplantation (ASCT), maintenance therapy, and improved supportive care. Currently, evidence-based management guidelines/recommendations developed by International societies/groups are being followed partially in low-resource settings. Lack of quality diagnostics (eg, cytogenetics/fluorescence in situ hybridization (FISH), serum free light chains), novel therapeutics, and trained manpower, and limited financial resources are key challanges. An optimal utilization of available resources with continued educational activities of treating physicians focused on improving knowledge in the management of such patients may be a way forward to improve the outcome of myeloma patients in these countries. Our current approach to the management of this disease is presented here through a discussion of clinical vignettes.

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,

HIV-associated hematologic malignancies: Experience from a Tertiary Cancer Center in India.

Context and Aim: Data on HIV associated hematologic malignancies is sparse from India. This study attempts to analyze the spectrum and features of this disease at a tertiary cancer center in India. Setting and Methods: Retrospective study from case records of patients registered with a diagnosis of hematologic malignancy and HIV infection between January 2010 and June 2015. Results: Thirteen cases of HIV associated hematologic malignancies were identified, six of them pediatric. HIV diagnosis was concurrent to diagnosis of cancer in 12 and preceded it in one of them. ECOG PS at presentation was >1 in all of them. All patients, except one, had B symptoms. Six of the patients had bulky disease and six are stage 4. Predominant extranodal disease was seen in 67% of them. NHL accounted for 10 of 13 patients and DLBCL-Germinal center was the most common subtype. Mean CD4+ cell count was 235/μL (range, 32-494). HAART could be given along with chemotherapy to 11 patients. Two-thirds of patients received standard doses of therapy. Chemo-toxicity required hospitalization in 58%. CR was achieved in 45% and 36% had progressive disease with first-line therapy. At the time of last follow up, 3 patients were alive with responsive disease, 2 in CR and 1 in PR. None of the pediatric patients were long time responders. Conclusions: These malignancies were of advanced stage and higher grade. Goal of therapy, in the HAART era, is curative. Pediatric patients had dismal outcome despite good chemotherapy and HAART. There is an urgent need to improve data collection for HIV related cancers in India.

Acute promyelocytic leukemia relapsing into acute myeloid leukemia-M2 with normal cytogenetics

The use of all trans-retinoic acid (ATRA) and combination chemotherapy has made acute promyelocytic leukemia (APL) a potentially curable leukemia. Late sequelae of the treatment of APL have therefore become an important consideration in the overall treatment strategy. We report a patient with APL who achieved complete clinical and molecular remission after treatment with daunorubicin and ATRA. Three years later, she developed acute myeloid leukemia (AML), M2 subtype without any evidence of relapse of the APL clone. Karyotypic analysis showed a normal female karyotype.