Arsenic-induced neurotoxicity in patients with acute promyelocytic leukaemia.

Arsenic trioxide is an essential component of therapy for acute promyelocytic leukaemia (APL) and is currently dosed on actual body weight with no upper limit. Arsenic-induced neurotoxicity is a well-recognised complication; however, there is uncertainty about its relationship to arsenic dose and obesity. We conducted a large multicentre retrospective study of 487 patients with APL treated with arsenic-based therapy across 23 sites in Australia from 2008 to 2023. The primary outcome was incidence of neurotoxicity, and secondary outcomes included relationship of neurotoxicity to obesity and cumulative arsenic dose. Any-grade neurotoxicity occurred in 113 (23%) patients, predominantly peripheral neuropathy (91%). Most events were grade 1-2 severity (85%), with grade 3 events in 12% and grade 4-5 in 3%. The incidence of neurotoxicity increased with BMI (non-obese: 16%, obesity class I: 25%, obesity class II-III: 41%; p < 0.001). On univariable analysis, obesity class I (OR 1.81, p = 0.036), obesity class II-III (OR 3.93, p < 0.001), weight >100 kg (OR 2.72, p < 0.001), daily arsenic trioxide dose >15 mg (OR 5.05, p < 0.001) and cumulative induction dose >500 mg (OR 3.95, p < 0.001) were all significantly associated with neurotoxicity. Obesity class II-III and induction dose >500 mg remained significant on multivariable analysis. Our study highlights the strong association between BMI, arsenic trioxide dose and neurotoxicity. Pre-emptive dose reductions should be considered for obese patients receiving high doses of arsenic.

Nuclear PTEN Regulates Thymidylate Biosynthesis in Human Prostate Cancer Cell Lines.

The phosphatase and tensin homologue deleted on chromosome 10 (PTEN) tumor suppressor governs a variety of biological processes, including metabolism, by acting on distinct molecular targets in different subcellular compartments. In the cytosol, inactive PTEN can be recruited to the plasma membrane where it dimerizes and functions as a lipid phosphatase to regulate metabolic processes mediated by the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin complex 1 (mTORC1) pathway. However, the metabolic regulation of PTEN in the nucleus remains undefined. Here, using a gain-of-function approach to targeting PTEN to the plasma membrane and nucleus, we show that nuclear PTEN contributes to pyrimidine metabolism, in particular de novo thymidylate (dTMP) biosynthesis. PTEN appears to regulate dTMP biosynthesis through interaction with methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), a key enzyme that generates 5,10-methylenetetrahydrofolate, a cofactor required for thymidylate synthase (TYMS) to catalyze deoxyuridylate (dUMP) into dTMP. Our findings reveal a nuclear function for PTEN in controlling dTMP biosynthesis and may also have implications for targeting nuclear-excluded PTEN prostate cancer cells with antifolate drugs.

Working memory control predicts fixation duration in scene-viewing.

When viewing scenes, observers differ in how long they linger at each fixation location and how far they move their eyes between fixations. What factors drive these differences in eye-movement behaviors? Previous work suggests individual differences in working memory capacity may influence fixation durations and saccade amplitudes. In the present study, participants (N = 98) performed two scene-viewing tasks, aesthetic judgment and memorization, while viewing 100 photographs of real-world scenes. Working memory capacity, working memory processing ability, and fluid intelligence were assessed with an operation span task, a memory updating task, and Raven's Advanced Progressive Matrices, respectively. Across participants, we found significant effects of task on both fixation durations and saccade amplitudes. At the level of each individual participant, we also found a significant relationship between memory updating task performance and participants' fixation duration distributions. However, we found no effect of fluid intelligence and no effect of working memory capacity on fixation duration or saccade amplitude distributions, inconsistent with previous findings. These results suggest that the ability to flexibly maintain and update working memory is strongly related to fixation duration behavior.

Strong Southern Ocean carbon uptake evident in airborne observations.

The Southern Ocean plays an important role in determining atmospheric carbon dioxide (CO2), yet estimates of air-sea CO2 flux for the region diverge widely. In this study, we constrained Southern Ocean air-sea CO2 exchange by relating fluxes to horizontal and vertical CO2 gradients in atmospheric transport models and applying atmospheric observations of these gradients to estimate fluxes. Aircraft-based measurements of the vertical atmospheric CO2 gradient provide robust flux constraints. We found an annual mean flux of ­0.53 ± 0.23 petagrams of carbon per year (net uptake) south of 45°S during the period 2009­2018. This is consistent with the mean of atmospheric inversion estimates and surface-ocean partial pressure of CO2 (Pco2)­based products, but our data indicate stronger annual mean uptake than suggested by recent interpretations of profiling float observations.

Evolution of eligibility criteria for diffuse large B-cell lymphoma randomised controlled trials over 30 years.

Eligibility criteria for randomised control trials (RCT) in diffuse large B-cell lymphoma (DLBCL) may be becoming increasingly strict. In this analysis, 42 first-line phase III RCTs enrolling DLBCL patients since 1990 were identified from PubMed and clinicaltrials.gov. Changes in 31 individual eligibility criteria were assessed using three pre-defined eras [(1) 1993-2005; (2) 2006-2013; and (3) 2014-2020]. The presence of 15/31 criteria increased significantly over time, and the total number of criteria per study also increased over time [median Era 1: 14·5, interquartile range (IQR) 12·6-16·4; Era 2: 21, 18·8-23·3; Era 3: 23, 21-25; P < 0·001]. When each trial's eligibility criteria were applied to 215 consecutive patients from an institutional database treated between 2010 and 2020, a median of 57% (IQR 47-70) of patients were hypothetically eligible for trial enrolment. The median percentage of patients eligible was 68% (56-91), 54% (37-81) and 47% (38-82) for Era 1, 2 and 3 respectively (P = 0·004). Phase III front-line DLBCL trial criteria have become increasingly restrictive over the last three decades, resulting in a diminishing proportion of trial-eligible patients, with less than 50% of our patients eligible for modern-era studies. This potentially impacts generalisability of recent trial results and will likely limit recruitment to ongoing studies.

Use of Ultrasonography Facilitates Noninvasive Evaluation of Lymphadenopathy in a Lymph Node Diagnostic Clinic.

BACKGROUND: Prompt and accurate diagnosis of lymphadenopathy is important, yet there is wide variability in clinical approach and referral patterns, leading to unnecessary investigations and delays in diagnosis. To address this, a lymph node diagnostic clinic (LNDC) was established at our tertiary referral center. PATIENTS AND METHODS: We retrospectively analyzed data from 320 consecutive patients referred to the LNDC from March 2008 to March 2020, to describe their management and outcomes. RESULTS: The most common diagnoses were reactive (57%) and malignant lymphadenopathy (28%). In those with reactive lymphadenopathy, 33% did not undergo further investigations, 37% underwent imaging only, and 29% underwent biopsy. For malignant lymphadenopathy, diagnosis was made at a median (interquartile range) of 9 (6-16) days from first LNDC review, with the decision to biopsy made at the first LNDC review in 95% of cases. Clinical features significantly associated with malignancy included age > 45, B symptoms, history of malignancy, and lymphadenopathy that was ≥ 2 cm, in multiple regions, bilateral, multiple nodes, or supraclavicular. At least 3 of these features were present in 88% of patients with malignant lymphadenopathy. Ultrasound had a sensitivity of 98% and negative predictive value of 97% for detecting malignant lymphadenopathy. CONCLUSION: A dedicated LNDC in a tertiary referral center facilitates rapid assessment and diagnosis of lymphadenopathy through a risk-stratified model of management. Ultrasonography, as well as the presence of defined clinical risk factors, were most useful to differentiate benign from malignant lymphadenopathy.

Mesenteric metastases from mature teratoma of the testis: A case report.

Metastatic spread of testicular cancer has been well documented, with 95% of cases involving para-aortic retroperitoneal lymph nodes. Mesenteric lymphatic basins do not lie within the canonical drainage pathway of the testes and represent a rare site of metastasis. Various mechanisms of spread to the mesentery have been described, including direct extension and haematogenous dissemination. We present a case of a previously-well 43-year-old man who presented with right scrotal discomfort and intermittent lower back pain, who was found to have mesenteric metastases from a non-seminomatous germ cell tumour of the testis. Managing lymphadenopathy that lies outside of standard resection templates remains a complex surgical challenge. Here we present the first case in the English medical literature with co-existing supradiaphragmatic axillary and mediastinal nodal disease.

Routine Blood Tests in Asymptomatic Patients With Indolent Lymphoma Have Limited Ability to Detect Clinically Significant Disease Progression.

PURPOSE: Patients with indolent non-Hodgkin lymphoma (iNHL) undergo regular active surveillance in between treatment periods to detect disease relapse or progression. As part of surveillance, international guidelines recommend regular routine blood testing, which is based on consensus rather than evidence of utility. METHODS: We conducted a retrospective analysis of all patients older than age 16 years diagnosed with grade 1-3A follicular or marginal zone lymphoma between 2008 and 2017 from 2 Australian cancer centers to assess the utility of full blood examination, lactate dehydrogenase, and ß2-microglobulin in detecting progression events, defined as either disease relapse or progression of disease. RESULTS: One hundred eighty patients attended 1,757 outpatient appointments (median follow-up, 36 months). Routine blood tests (RBTs) were performed before 83% of appointments. Seventy-four progression events occurred in 62 patients. Only 2 events (3%) were detected by RBTs alone, both of which occurred in treatment-naïve patients who subsequently developed symptoms within 3 weeks. The remainder of progression events were suspected clinically (88%) or detected by imaging (9%). RBT results were frequently abnormal in asymptomatic patients (19%), with abnormal results leading to either additional investigations or an increased surveillance frequency in 8% of cases. The overall sensitivity and positive predictive value of abnormal RBT results in detecting progression events were 39% and 9%, respectively. CONCLUSION: RBTs have poor performance characteristics and rarely detect clinically significant disease progression or relapse in asymptomatic patients with iNHL.

RET-rearranged non-small-cell lung cancer and therapeutic implications.

First-line tyrosine kinase inhibitors are standard of care for non-small-cell lung cancers (NSCLC) harbouring an epidermal growth factor receptor mutation, anaplastic lymphoma kinase fusion or c-ros oncogene 1 rearrangement. Other targetable oncogenic drivers have been identified but testing for these is neither funded nor commonly performed in Australia. Using a case example, we discuss the importance of considering several other genomic aberrations in our population, such as rearrangements in the RET proto-oncogene, which occur in 1-2% of lung adenocarcinoma. New oncogenic drivers and corresponding targeted agents are constantly being discovered; these will continue to refine the treatment of non-small-cell lung cancer in the era of precision medicine.

Standard dose osimertinib for erlotinib refractory T790M-negative EGFR-mutant non-small cell lung cancer with leptomeningeal disease.

BACKGROUND: Leptomeningeal spread in non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations who experience disease progression on TKIs portends a poor prognosis. Mutation profiling of tumour DNA in cerebrospinal fluid (CSF) samples can be used to determine the presence of the EGFR T790M resistance mutation, indicating that osimertinib, a CNS-penetrating 3rd generation TKI may be efficacious. METHODS: Eight patients on EGFR TKIs who progressed with cytology-proven leptomeningeal disease at our institution were studied. EGFR mutations were profiled in CSF using droplet digital PCR (ddPCR) and compared to matched plasma samples. Clinical characteristics and survival outcomes on subsequent therapies tailored to ddPCR analysis were reported. RESULTS: None of the four patients who developed leptomeningeal disease while receiving 1st generation EGFR TKIs developed the EGFR T790M mutation in CSF. One patient who did not have extra-cranial disease and was EGFR T790M-negative in both plasma and CSF was nevertheless treated with standard-dose osimertinib, and achieved a rapid and durable response lasting 9 months to date. Three patients developed leptomeningeal disease on osimertinib, with one patient developing the EGFR C797S mutation in a cis-allelic conformation with the EGFR T790M mutation in plasma. CONCLUSIONS: Standard-dose osimertinib resulted in a clinically meaningful response in a patient with EGFR T790M-negative 1st generation EGFR TKI refractory leptomeningeal disease. Next generation sequencing and ddPCR has a role at identifying the C797S mutation and its allelic conformation with the T790M mutation with clinical implications.

Effect of Reasons for Screen Failure on Subsequent Treatment Outcomes in Cancer Patients Assessed for Clinical Trials.

INTRODUCTION: The cancer research community increasingly question the rigidity of eligibility criteria in clinical trials. Common reasons for "screen failure" (RFSF) are well documented; however, their effect on subsequent standard therapy (SST) and outcomes is unclear. METHODS: This retrospective study evaluated patients aged ≥18 years with solid malignancy who were listed as ineligible on a screening log between February 2011 and March 2018. Patients screen-failed for biomarker results or incorrect cancer stage/prior treatment profile were excluded. Data were collected from electronic hospital records, including demographics, cancer history, RFSF, subsequent therapy, and outcomes. RESULTS: Overall, 217 patients were eligible. The most common histologies were lung (28%), melanoma, colon, and pancreatic (all 11%); 90% were metastatic. The most common RFSF were rapid disease progression (PD; 16%), performance status (PS) ≥2 (12%), and abnormal liver function tests (aLFT; 12%). After screen failure, 129/217 (59%) had SST; 9 were dose-reduced. Treatment-naïve or phase III trial-ineligible patients were more likely to receive SST than those pre-treated or phase I trial-ineligible (72/104 vs. 52/113, p = 0.0006; 71/109 vs. 15/42, p = 0.00013), respectively. RFSF stabilised/improved in 104/217 (48%); the main RFSF was co-morbidity (19/104). The most common RFSF to deteriorate were rapid PD (27/72), PS ≥2 (20/72), and aLFT with liver metastases (LM; 13/72). CONCLUSIONS: RFSF related to organ function rarely deteriorate unless directly involved with underlying malignancy. Most RFSF do not prevent patients from having SST, nor increase dose reductions, especially in treatment-naïve/phase III trial-ineligible patients. Those with RFSF of poor PS, rapid PD, and aLFT from LM are less suitable for SST. Careful broadening of trial eligibility is warranted.

Comprehensive geriatric assessment is useful in an elderly Australian population with diffuse large B-cell lymphoma receiving rituximab-chemotherapy combinations.

Elderly patients may be heterogeneous in their abilities to tolerate immunochemotherapy-associated toxicities. We describe the morbidity of rituximab-chemotherapy combinations among 205 newly-diagnosed diffuse large B-cell lymphoma (DLBCL) patients aged ≥60 years from 3 tertiary hospitals between 2009 and 2016, and explore the utility of retrospectively-assigned baseline Comprehensive Geriatric Assessment (CGA) in predicting these toxicities. Seventy-three percent (146/201) experienced grade ≥3 toxicities, 81% (163/201) needed admission, 52% (107/205) had ≥2 unplanned admissions, 82/201 (41%) required dose reductions (DR) subsequent to Cycle 1, 39/166 (23%) had chemotherapy delays and 26/198 (13%) ceased therapy early. CGA was associated with pre-emptive baseline DR and perhaps because of this, did not predict grade ≥3 toxicities, ≥2 unplanned admissions or subsequent DR. Three-year overall survival (OS) of CGA-fit, CGA-unfit and CGA-frail patients was 82%, 60% and 53%, respectively. Three-year progression-free survival (PFS) of CGA-fit, CGA-unfit and CGA-frail patients was 66%, 58% and 46%, respectively. OS of CGA-fit patients was not statistically different from CGA-unfit patients, but was superior to CGA-frail patients (hazard ratio 2·892, 95% confidence interval 1·275-6·559, P = 0·011). PFS differences were not statistically significant. Baseline DR and early therapy cessation were associated with inferior OS and PFS independent of CGA. Prospective studies are needed to confirm if CGA-adapted treatment strategies minimize morbidity and improves survival.

The pharmacological and functional characterization of the serotonergic system in Anopheles gambiae and Aedes aegypti: influences on flight and blood-feeding behavior.

Aedes aegypti and Anopheles gambiae harbor the causative agents of diseases such as dengue fever and malaria, afflicting human morbidity and mortality worldwide. Given the worldwide emergence of resistance to insecticides, the current mainstay for vector control, identification of alternative modes of action for future insecticides is paramount. The serotonergic (5-HT) system has been documented to impact physiological mechanisms involved in disease transmission, suggesting its potential as a new mode of action target for future insecticide development. Target 5-HT receptors were cloned and expressed in the HEK293 cell line for functional and pharmacological characterization. Manipulation of the 5-HT system through microinjection of compounds suggests its involvement in the modulation of flight performance and blood-feeding behavior. By attenuating these two determinants of vectorial capacity, transmission and burden of disease could effectively be reduced. Considering these positive global health implications, the 5-HT system is a compelling target for the novel insecticide pipeline.

Impact of universal immunohistochemistry on Lynch syndrome diagnosis in an Australian colorectal cancer cohort.

BACKGROUND: Current guidelines recommend a step-wise screening algorithm for all colorectal carcinomas (CRC) to identify patients with Lynch syndrome (LS). AIM: To describe the frequencies of mismatch repair deficiency (dMMR), BRAFV600E mutations and MLH1 methylation in resected CRC, and evaluate the impact of universal screening on LS detection. METHODS: Retrospectively, 1171 consecutive cases of resected CRC were identified between 2010 and 2017 from a large multi-centre pathology service. Testing for dMMR by immunohistochemistry (IHC) was initiated by the reporting pathologist from 2010, until universal testing was introduced in 2015. Patients with dMMR were referred to the Family Cancer Clinic (FCC) for consideration of germline mutation analysis. RESULTS: IHC was performed on 680 tumours, with abnormal expression in 124 (18%). Referral to FCC was made for 44 of the 88 patients with abnormal IHC (excluding those with BRAFV600E mutations). Of the 29 who attended, 16 underwent germline genetic testing, and LS was diagnosed in 7 with a germline mutation. After implementation of universal testing, there was a greater incidence of dMMR (17% vs 10%, P = 0.02), rate of BRAFV600E testing (79% vs 25%, P < 0.0001), and referral to FCC (61% vs 33%, P < 0.0001), but no difference in FCC attendance rate (65% vs 67%, P = 0.59) or new LS diagnoses (1.6% vs 0%, P = 0.06). CONCLUSION: Universal IHC testing may increase the detection of LS, and should be implemented where possible. However, the full benefit was limited by low referral to and uptake of genetic testing, and further strategies are needed to overcome these barriers.

Urine cultures at the onset of febrile neutropenia rarely impact antibiotic management in asymptomatic adult cancer patients.

PURPOSE: There is a paucity of data regarding the utility of routine urine cultures in adults with febrile neutropenia (FN) without urinary symptoms receiving protocolised antibiotics. This is reflected by inconsistent recommendations in international and regional FN guidelines. We addressed this issue by retrospectively reviewing the impact of routine urine cultures on antibiotic management in haematology cancer inpatients at a tertiary hospital. METHODS: All haematology inpatients over a 5-year period (2011-2015) were retrospectively reviewed for episodes of FN (neutrophil count < 0.5 × 109/L and fever > 37.5 °C). For each episode, demographic data, urinary tract symptoms and signs (absence of which was termed 'asymptomatic'), urinalysis and urine culture results, antibiotic therapy and duration, and patient outcomes were collected. A urine culture was considered positive if > 105 colony forming units (CFU)/L were detected. Empiric antibiotic therapy for FN consisted of intravenous piperacillin/tazobactam in stable patients, with the addition of vancomycin and a single dose of gentamicin if systemically compromised. RESULTS: Four hundred and thirty-three episodes of FN were identified in 317 patients. Urine cultures were performed in 362 (84%) episodes. Cultures were positive in 9 of 48 (19%) symptomatic episodes versus 8 of 314 (2.5%) asymptomatic episodes (RR = 7.4, p < 0.0001). A change in antibiotic management due a positive urine culture occurred in only 5 episodes (1.4%): 3 of 48 (6.3%) symptomatic and 2 of 314 (0.6%) asymptomatic episodes respectively (RR = 9.8, p = 0.01). CONCLUSION: Routine urine cultures in FN patients without urinary symptoms who are already receiving protocolised broad spectrum antibiotics rarely impact subsequent antibiotic management.

Routine blood investigations have limited utility in surveillance of aggressive lymphoma in asymptomatic patients in complete remission.

BACKGROUND: Patients with aggressive lymphoma achieving complete remission (CR) after first-line combination chemotherapy undergo regular surveillance to detect relapse. Current international guidelines recommend routine follow-up blood tests in this context, but evidence supporting this practice is limited. METHODS: We conducted a multi-centre retrospective analysis of all patients diagnosed with aggressive lymphoma treated with curative-intent chemotherapy who achieved CR for at least 3 months between 2000 and 2015. An abnormal blood test was defined as any new and unexplained abnormality for full blood examination, lactate dehydrogenase or erythrocyte sedimentation rate. RESULTS: Three hundred and forty-six patients attended a total of 3084 outpatient visits; blood tests were performed at 90% of these appointments. Fifty-six (16%) patients relapsed. Routine laboratory testing detected relapse in only three patients (5% of relapses); in the remaining patients, relapse was suspected clinically (80%) or detected by imaging (15%). The sensitivity of all blood tests was 42% and the positive predictive value was 9%. No significant difference in survival was shown in patients who underwent a routine blood test within 3 months prior to relapse versus those who did not (p = 0.88). CONCLUSIONS: Routine blood tests demonstrate unacceptably poor performance characteristics, have no impact on survival and thus have limited value in the detection of relapse in routine surveillance.

Echocardiography has low utility in cancer patients with Staphylococcus aureus bacteraemia: findings from a retrospective study.

AIM: To describe the incidence of infective endocarditis (IE) detected on echocardiography in cancer patients with confirmed Staphylococcus aureus bacteraemia (SAB). METHODS: We retrospectively identified 95 cases of SAB in cancer patients from January 2007-March 2016. Echocardiography was ordered at the discretion of the treating team, and positive findings defined according to the Modified Duke Criteria. Complicated bacteraemia was defined by prolonged bacteraemia, presence of intracardiac device/prosthetic valve, or signs of metastatic infection. RESULTS: Major predisposing risk factors for IE (intracardiac device, prosthetic valve, valvular disease, diabetes mellitus, renal dialysis) were present in 27% of cases. Fifty-one of 95 (54%) had a central venous catheter and 17 (18%) patients had complicated bacteraemia. Echocardiography was performed in 75/95 (79%) episodes, with transthoracic echocardiography (TTE) alone in 56, transoesophageal echocardiography (TOE) alone in 4 and both in 15. Echocardiography was diagnostic for IE in 2 patients (1 TTE, 1 TOE), including one result that led to the diagnosis of IE in a clinically unsuspected case. Four further cases of IE were diagnosed on clinical findings, resulting in an overall rate of IE of 6% (6/95). Five of these cases occurred in patients with complicated bacteraemia or ≥ 1 risk factor for IE. No patient was readmitted due to IE. CONCLUSION: IE is infrequent in cancer patients with uncomplicated SAB and no risk factors for IE. Performing echocardiography routinely in all cancer patients with SAB rarely alters diagnosis or affects antibiotic management and therefore should be reserved for patients with specific risk factors.

Limited utility of routine chest X-ray in initial evaluation of neutropenic fever in patients with haematological diseases undergoing chemotherapy.

BACKGROUND: Routine chest X-ray (CXR) is recommended for neutropenic fever (NF) management however its role is relatively understudied in haematology patients. AIM: To investigate the utility of CXR in the diagnosis and management of patients with haematological conditions complicated by NF. METHODS: Retrospective, single-centre analysis of haematology patients admitted with NF between January 2011 and December 2015. Baseline demographics, treatment details and outcomes were collected from electronic patient records. CXR underwent independent radiology review. Primary endpoints were a proportion of NF episodes in which CXR detected a probable chest infection in the absence of respiratory symptoms/signs and/or resulted in a change in antibiotic management. RESULTS: Four hundred and thirty-five episodes were identified; CXR was performed in 75% of patients (65% within 2 days of NF). In 4 of 164 (2.4%) asymptomatic patients, CXR was consistent with infection, in contrast to 19 of 119 (16%) patients with clinical signs of respiratory infection. Only 3 of 283 (1.1%) CXR resulted in a change to antibiotics. CXR consistent with infection was not associated with increased mortality or increased admission length, although there was an association with intensive care unit admission (odds ratios: 7.61, 95% confidence interval: 2.04-28.31). CONCLUSION: In haematology patients with NF, CXR rarely detected chest infection or changed management in patients with no respiratory symptoms or signs. CXR in our institution is no longer part of routine assessment of NF in the absence of these features.

Infrared spectra and ab initio calculations for the Cl--(CH4)n (n = 1-10) anion clusters.

In an effort to elucidate their structures, mass-selected Cl--(CH4)n (n = 1-10) clusters are probed using infrared spectroscopy in the CH stretch region (2800-3100 cm(-1)). Accompanying ab initio calculations at the MP2/6-311++G(2df,2p) level for the n = 1-3 clusters suggest that methane molecules prefer to attach to the chloride anion by single linear H-bonds and sit adjacent to one another. These conclusions are supported by the agreement between experimental and calculated vibrational band frequencies and intensities. Infrared spectra in the CH stretch region for Cl--(CH4)n clusters containing up to ten CH4 ligands are remarkably simple, each being dominated by a single narrow peak associated with stretching motion of hydrogen-bonded CH groups. The observations are consistent with cluster structures in which at least ten equivalent methane molecules can be accommodated in the first solvation shell about a chloride anion.