Constitutional Mismatch Repair Deficiency (CMMRD) Syndrome: A Case Report of a Patient With Multiple Metachronous Malignancies.

Defective repair of DNA when heterozygous leads to Lynch syndrome (LS) which is inherited in an autosomal dominant fashion. When homozygous, defective repair of DNA leads to constitutional mismatch repair deficiency syndrome (CMMRD), inherited in an autosomal recessive fashion with a predisposition to develop a pattern of childhood malignancies including hematological and solid cancers. We report such a case of a 21-year-old male who developed anaplastic astrocytoma, Burkitt lymphoma, osteochondroma, and colon cancer successively. Each cancer was treated successfully except for colon cancer which developed liver metastasis after the initial treatment with curative intent. However, the patient has been treated for liver metastasis with curative intent and is currently on follow-up. This case report highlights the importance of maintaining a low threshold for investigating CMMRD and other potential cancer predisposition syndromes when a patient presents with multiple cancers in the early years of their life.

Clinicopathological Features and Outcomes of Granulosa Cell Tumor of the Ovaries - A Retrospective Study.

Background Granulosa cell tumor (GCT) is rare among all ovarian cancers. Its overall prognosis is favorable; however, the presence of extra-ovarian disease is associated with worse clinical outcomes. We report a retrospective analysis of granulosa cell tumors to evaluate the clinicopathological features and their outcomes.  Methods This retrospective study included 54 adult patients aged 13 years and older. After data extraction and scrutiny, only those patients who were treated and followed up later at our institute were included in this study. Results Fifty-four patients were evaluated in this study, with a median age of 38.5 years. Most of the patients had dysfunctional uterine bleeding and abdominal pain (40.7%, n=22). The majority (n=26, 48%) underwent completion surgery as per ovarian protocol; however, 16.7% (n=09) patients underwent simple total abdominal hysterectomy with a bilateral salpingo-oophorectomy (TAH+BSO), debulking surgery in 3.7% (n=2), unilateral salpingo-oophorectomy in 20.4% (n=11) and fertility-sparing surgery in 11.1% (n=06) of the patients. Pathological stage I-A was found in 59.3%(n=32), I-C in 25.9% (n=14), II-A in 1.9% (n=1), III-A in 1.9% (n=1), III-C in 9.3% (n=5) and IV-B in 1.9% (n=1) of the population. Eleven (20.3%) patients relapsed during their course of treatment. Out of these 11 patients, three went into remission, two still have active disease, and six patients died. Conclusion Post-menopausal patients, more advanced disease at presentation, capsular rupture, presence of ascites, omental involvement, peritoneal spread, and residual disease after surgical resection were the main contributing factors towards poorer outcomes affecting disease-free survival. Overall median disease-free survival was 60 months for all the stage groups, while the overall survival was 62 months.

One-pot hydrothermal synthesis of a carbon quantum dot/CaFe2O4 hybrid nanocomposite for carcinogenic Congo red dye degradation.

Semiconductor materials show a restricted degradation response to organic pollutants due to limited photocatalytic activity under visible light. Therefore, researchers have devoted much attention to novel and effective nanocomposite materials. For the first time, herein, a novel nano-sized semiconductor calcium ferrite modified by carbon quantum dots (CaFe2O4/CQDs) photocatalyst is fabricated via simple hydrothermal treatment for the degradation of aromatic dye using a visible light source. The crystalline nature, structure, morphology, and optical parameters of each of the synthesized materials were investigated using X-ray diffraction spectroscopy (XRD), Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), and UV-visible spectroscopy. The nanocomposite exhibits excellent photocatalytic performance (90% degradation) against Congo red (CR) dye. In addition, a mechanism for CaFe2O4/CQDs improving photocatalytic performance has been proposed. The CQDs in the CaFe2O4/CQD nanocomposite are considered to act as an electron pool and transporter, as well as a strong energy transfer material, during photocatalysis. CaFe2O4/CQDs appear to be a promising and cost-effective nanocomposite for dye-contaminated water purification, according to the findings of this study.

Comparison of the effects of perioperative and adjuvant chemotherapy on outcomes of operable gastric cancer: A retrospective cohort experience from a tertiary cancer center.

OBJECTIVE: To compare the overall survival and disease-free survival rates with perioperative or adjuvant chemotherapy regimens in operable gastric cancer cases. METHODS: The retrospective, observational study was conducted at the Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan, and comprised date from January 2015 to December 2020 of operable gastric cancer patients who had perioperative or adjuvant chemotherapy. Overall survival and disease-free survival were evaluated. Data was analysed using SPSS 23. RESULTS: Of the 108 patients in the aga range 27-80 years, 71(65.74%) were males. The overall median age was 49.50 years (interquartile range: 28 years). There were 69(63.88%) patients on perioperative and 39(36.12%) on adjuvant chemotherapy. The probability of 2- and 3-year overall survival was 68.20% and 57.32% in the perioperative group, and 51.09% and 45.43%, respectively, in the adjuvant group. The probability of 2- and 3-year disease-free survival was 55.45% and 49.30% in the perioperative group, while 2-year disease-free survival was 38.39% in the adjuvant group which had no patient reaching the 3-year mark. The median overall survival for the perioperative group was 49.29 months (interquartile range: 44.50 months) and for the adjuvant group it was 28.23 months (interquartile range: 25.00months) (p=0.07). The median disease-free survival was 35.46 months (interquartile range: 38.50 months) for the perioperative group and 10.19 months (interquartile range: 14.00months) for adjuvant group (p=0.16). The difference between the groups was not significant (p>0.05), but there was a trend suggestive of the superiority of perioperative chemotherapy over adjuvant chemotherapy. CONCLUSIONS: In operable gastric cancer cases, the difference between the groups was not significant, but there was a trend suggestive of the superiority of perioperative chemotherapy over adjuvant chemotherapy with respect to overall survival and disease-free survival.

Bleomycin-Induced Fulminant Hyperpyrexia: A Report of Two Cases and Review of Literature.

Bleomycin is a commonly used cytotoxic agent that has proven its efficacy over the years. Though a common part of many protocols targeting lymphomas and germ cell tumors, it does have some serious adverse effects. Bleomycin is notorious for pulmonary toxicity and very rarely may cause fulminant hyperpyrexia. We describe two cases of classical Hodgkin's lymphoma (cHL) developing acute fulminant hyperpyrexia after administration of the first dose of bleomycin as part of chemotherapy protocol. This is a rare adverse reaction that closely mimics anaphylaxis and has an unpredictable and possibly fatal course. Health care professionals involved in the administration of chemotherapy need to be very vigilant in monitoring for symptoms of this reaction.

Cisplatin-Induced Bradycardia: A Silent Risk Observed in Two Different Clinical Cases.

Cisplatin is a platinum-containing drug that inhibits DNA synthesis by inhibiting cross-linking, denaturing DNA strands. It is used in combination with other chemotherapeutic agents to treat several types of cancers. Numerous adverse effects have been reported with this compound. However, it is considered a safe medication in terms of cardiotoxicity. In this report, we discuss the case of two patients who experienced bradycardia while receiving cisplatin as part of combination therapy. A workup was undertaken to rule out other possible causes of bradycardia, and the diagnosis of cisplatin-induced bradycardia was made.

Impact of processing methods on the dissolution of artemether from two non-ordered mesoporous silicas.

Poor aqueous solubility is often linked with a poor dissolution rate and ultimately, limited bioavailability of pharmaceutical compounds. This study describes the application of mesoporous materials (Syloid 244 and Syloid AL1) in improving the dissolution rate of a drug with poor aqueous solubility, namely artemether, utilising different processing methods including physical mixing, co-grinding and solid dispersions prepared by solvent evaporation and the lyophilisation technique. The prepared formulations were extensively characterised for their solid-state properties and the drug release attributes were studied. Differential scanning calorimetry and X-ray diffraction confirmed conversion of crystalline artemether into a disordered and amorphous form, whilst no intermolecular interactions were detected between artemether and silica. Both silica grades enhanced the dissolution rate of artemether in comparison with drug alone, for example from 17.43% (±0.87%) to 71.55% (±3.57%) after 120mins with lyophilisation and Syloid 244 at a 1:3 ratio. This enhancement was also dependant on the choice of processing method, for example, co-ground and lyophilised formulations prepared with Syloid 244 at 1:3 ratio produced the most extensive dissolution, thus endorsing the importance of materials as well as choice of formulation method.

Influence of polymer ratio and surfactants on controlled drug release from cellulosic microsponges.

Microsponge refers to a highly cross-linked particle system with a capacity to adsorb (like a dry sponge) pharmaceutical materials. There are various methods available to prepare microsponge formulations, in this study we used quasi emulsion-solvent diffusion method with a combination of hydrophobic (ethyl cellulose) and hydrophilic (hydroxypropyl methylcellulose) polymers mediated via Tween 80 and polyvinyl alcohol. Various ratios and amounts of the polymers and surfactants were used to prepare microsponge formulations using ketoprofen as a model drug and extensively characterised. Our results, for the first time, indicate successful and optimised formulation with desired pharmaceutical characteristics using a combination of hydrophobic and hydrophilic polymers.

Docetaxel-resistance in prostate cancer: evaluating associated phenotypic changes and potential for resistance transfer via exosomes.

BACKGROUND: Hormone-refractory prostate cancer remains hindered by inevitable progression of resistance to first-line treatment with docetaxel. Recent studies suggest that phenotypic changes associated with cancer may be transferred from cell-to-cell via microvesicles/exosomes. Here we aimed to investigate phenotypic changes associated with docetaxel-resistance in order to help determine the complexity of this problem and to assess the relevance of secreted exosomes in prostate cancer. METHODOLOGY/PRINCIPAL FINDINGS: Docetaxel-resistant variants of DU145 and 22Rv1 were established and characterised in terms of cross-resistance, morphology, proliferation, motility, invasion, anoikis, colony formation, exosomes secretion their and functional relevance. Preliminary analysis of exosomes from relevant serum specimens was also performed. Acquired docetaxel-resistance conferred cross-resistance to doxorubicin and induced alterations in motility, invasion, proliferation and anchorage-independent growth. Exosomes expelled from DU145 and 22Rv1 docetaxel-resistant variants (DU145RD and 22Rv1RD) conferred docetaxel-resistance to DU145, 22Rv1 and LNCap cells, which may be partly due to exosomal MDR-1/P-gp transfer. Exosomes from prostate cancer patients' sera induced increased cell proliferation and invasion, compared to exosomes from age-matched controls. Furthermore, exosomes from sera of patients undergoing a course of docetaxel treatment compared to matched exosomes from the same patients prior to commencing docetaxel treatment, when applied to both DU145 and 22Rv1 cells, showed a correlation between cellular response to docetaxel and patients' response to treatment with docetaxel. CONCLUSIONS/SIGNIFICANCE: Our studies indicate the complex and multifaceted nature of docetaxel-resistance in prostate cancer. Furthermore, our in vitro observations and preliminary clinical studies indicate that exosomes may play an important role in prostate cancer, in cell-cell communication, and thus may offer potential as vehicles containing predictive biomarkers and new therapeutic targets.

Challenges of drug resistance in the management of pancreatic cancer.

The current treatment of choice for metastatic pancreatic cancer involves single-agent gemcitabine or a combination of gemcitabine with capecitabine or erlotinib (a tyrosine kinase inhibitor). Only 25–30% of patients respond to this treatment and patients who do respond initially ultimately exhibit disease progression. Median survival for pancreatic cancer patients has reached a plateau due to inherent and acquired resistance to these agents. Key molecular factors implicated in this resistance include: deficiencies in drug uptake, alteration of drug targets, activation of DNA repair pathways, resistance to apoptosis and the contribution of the tumor microenvironment. Moreover, for newer agents including tyrosine kinase inhibitors, overexpression of signaling proteins, mutations in kinase domains, activation of alternative pathways, mutations of genes downstream of the target and/or amplification of the target represent key challenges for treatment efficacy. Here we will review the contribution of known mechanisms and markers of resistance to key pancreatic cancer drug treatments.

A role for mu opioid receptors in cocaine-induced activity, sensitization, and reward in the rat.

RATIONALE: Considerable evidence suggests that the endogenous opioid system plays a role in mediating the behavioral effects of psychostimulants. Opioidergic drugs have been shown to have profound effects on cocaine-induced behavioral sensitization and conditioned reward. However, the role specifically of the mu opioid receptor in this regard is unclear as most previous pharmacological studies have used nonselective opioid receptor ligands. OBJECTIVES: The objective of this series of experiments was to elucidate the role of mu opioid receptors in the behavioral effects of cocaine in the rat. MATERIALS AND METHODS: Adult male rats were used to assess the effects of the selective mu opioid receptor antagonist D: -Phe-Cys-Tyr-D: -Trp-Arg-Thr-Pen-Thr (CTAP) on acute hyperactivity, locomotor sensitization, and conditioned place preference induced by cocaine. Intracerebroventricular administration of CTAP, 4 microg, was paired with peripheral injections of cocaine, 10-15 mg/kg. RESULTS: Mu receptor blockade significantly attenuated cocaine-induced hyperactivity, as well as the development of behavioral sensitization. Pretreatment with CTAP also prevented the development of conditioned place preference to cocaine. Administration of CTAP alone had neither effect on locomotor activity nor did it demonstrate aversive or rewarding properties. CONCLUSIONS: These results suggest that activation of mu opioid receptors by endogenous opioids is an important contributor to cocaine-induced hyperactivity and the development of behavioral sensitization and conditioned reward.

Regulation of retinal vascular endothelial growth factor and receptors in rabbits exposed to hyperoxia.

PURPOSE: To evaluate the molecular responses of vascular endothelial growth factor (VEGF) and its receptors to dexamethasone (Dex) and celecoxib (Cel) during hyperoxia and during hyperoxia followed by recovery in room air, in newborn rabbit retinas. METHODS: Newborn rabbits at 3 days postnatal age (n = 96) received room air or oxygen (80%-100%) for 4 days, during which they were administered saline (Sal), Dex, vehicle (Veh), or Cel (n = 12/treatment group). Six animals from each group were killed immediately after hyperoxia (or room air) and the remainder exposed to room air for 5 days. Retinal mRNA expression of VEGF(121), VEGF(165), VEGF receptor-1 (VEGFR-1, or Flt-1), and VEGFR-2 (or KDR/Flk-1) was determined. RESULTS: Hyperoxia resulted in increased retinal expression of mRNA of the VEGF splice variants in the groups treated with Sal, Dex, and Veh, whereas a decrease in VEGF(121) was noted in the Cel-treated group. In contrast, retinal Flt-1 receptor mRNA was markedly increased in the Cel-treated group only, whereas retinal VEGFR-2 (KDR/Flk-1) receptor mRNA was suppressed in all the treatment groups. Hyperoxia followed by recovery in room air resulted in a minimal decrease in expression of retinal Flt-1 mRNA in the Sal and Dex groups. Cel treatment abolished its expression. CONCLUSIONS: The findings of increased retinal expression of VEGF mRNA in the newborn rabbit in response to hyperoxia are most likely due to species differences. Selective targeting of VEGF(121) and Flt-1 mRNA by Cel may represent one regulatory pathway for their anti-inflammatory effects. Further studies are needed to evaluate the therapeutic benefits of cyclooxygenase (COX)-2 inhibitors for the treatment and/or prevention of diseases associated with neovascularization.